Pembrolizumab, a humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody, is an antineoplastic agent.1, 7, 8
Pembrolizumab is used for the treatment of unresectable or metastatic melanoma.1, 9, 10, 11, 12 Pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.4
Pembrolizumab is used as adjuvant therapy for stage IIB, IIC, or III melanoma following complete resection in adult and pediatric patients ≥12 years of age.1, 39 Pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.4
Unresectable or Metastatic Melanoma
The current indication for pembrolizumab in the treatment of unresectable or metastatic melanoma is based principally on the results of an open-label, randomized phase 3 study (KEYNOTE-006) and a randomized phase 2 study (KEYNOTE-002).1, 9, 11
In the KEYNOTE-006 study, 834 patients with ipilimumab-naive unresectable or metastatic melanoma who had received no more than one prior systemic therapy for metastatic disease were randomized (stratified by number of prior therapies, Eastern Cooperative Oncology Group [ECOG] performance status, and programmed-death ligand-1 [PD-L1] expression) in a 1:1:1 ratio to receive pembrolizumab 10 mg/kg administered as a 30-minute IV infusion every 2 weeks or every 3 weeks for up to 24 months or ipilimumab 3 mg/kg every 3 weeks administered as a 90-minute IV infusion for a maximum of 4 cycles.1, 9 Treatment was continued for the specified duration or until the occurrence of unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, associated with a decline in performance status, requiring urgent intervention, or confirmed in 4-6 weeks by repeat radiographic studies.1, 9 The primary measures of efficacy were overall survival and progression-free survival (as evaluated by a blinded independent central review committee according to Response Evaluation Criteria in Solid Tumors [RECIST] modified to follow no more than 10 target lesions and no more than 5 target lesions per organ); additional outcome measures were objective response rate and duration of response.1, 9
The median age of patients enrolled in the KEYNOTE-006 study was 62 years; 98% were white and 60% were male.1, 9 All patients enrolled in the study had an ECOG performance status of 0 or 1.1, 9 Most patients (80%) had positive PD-L1 expression (defined as PD-L1 expression of any intensity on at least 1% of tumor cells as detected by an investigational assay), 65% had stage M1c disease, 66% had not received prior systemic therapies for metastatic disease, 68% had LDH concentrations within normal limits, 36% had tumors bearing the b-Raf serine-threonine kinase (BRAF) mutation, and 9% had a history of brain metastases.1, 9 Approximately one-half of patients (46%) with BRAF mutation-positive disease had received prior therapy with a BRAF inhibitor.1, 9 This study excluded patients with ocular melanoma, active brain metastases, autoimmune disease, conditions requiring therapy with immunosuppressive agents, human immunodeficiency virus (HIV) infection, or hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.1, 9
In the KEYNOTE-006 study, a planned interim analysis indicated significantly prolonged median progression-free survival in patients who received pembrolizumab every 3 or 2 weeks compared with those receiving ipilimumab (4.1 or 5.5 months, respectively, versus 2.8 months; hazard ratio for both pembrolizumab regimens compared to ipilimumab: 0.58).1, 9 The median follow-up period at the time of interim analysis was 7.9 months.9 At a follow-up of 12 months, the estimated survival rates were 74.1% and 68.4% in patients who received pembrolizumab every 2 weeks or 3 weeks, respectively, and 58.2% in patients who received ipilimumab.1, 9 Patients receiving pembrolizumab every 3 or 2 weeks also had a higher objective response rate compared with those receiving ipilimumab (33 or 34%, respectively, versus 12%); complete responses were achieved in 5-6% of patients treated with pembrolizumab compared with 1% of those treated with ipilimumab.1, 9 At the time of interim analysis, the median duration of response had not been reached in any group; however, responses were ongoing in 97, 89, or 88% of patients who received pembrolizumab every 3 weeks, pembrolizumab every 2 weeks, or ipilimumab, respectively.9 Overall survival, progression-free survival, and objective response rates for pembrolizumab- and ipilimumab-treated patients at the time of final analysis (at a median follow-up of 22.9 months) remained similar to the interim results; in the final analysis, no substantial differences in efficacy were observed between the 2 pembrolizumab dosage regimens.10 Results of a subgroup analysis (based on age, sex, ECOG performance status, serum LDH concentration, BRAF mutation status, number of prior therapies, PD-L1 status, and baseline tumor size) suggested that the effect of pembrolizumab on overall survival was consistent across all subgroups.10
At the end of the KEYNOTE-006 study, patients enrolled who were receiving study treatment or in the survival follow-up phase were eligible to transition to the KEYNOTE-587 study, an open-label phase 3 extension study designed to continue to collect long-term efficacy data in patients with solid tumors who previously received pembrolizumab in a clinical trial.43 A follow-up study assessed the efficacy of pembrolizumab and ipilimumab after 10 years in ipilimumab-naïve advanced melanoma from the KEYNOTE-006 and KEYNOTE-587 studies; this follow-up included patients who received a second course of pembrolizumab.43 Of the 211 patients who transitioned to KEYNOTE-587 from the 834 patients randomized in KEYNOTE-006, the median time to final data cut-off was 123.7 months.43 For the primary endpoint of overall survival, the median overall survival was 32.7 months for pembrolizumab-treated patients versus 15.9 months for ipilimumab-treated patients.43 The 10-year overall survival was 34% for pembrolizumab and 23.6% for ipilimumab.43
In the KEYNOTE-002 study, 540 patients with unresectable or metastatic melanoma were randomized (stratified by ECOG performance status, serum LDH concentrations, and BRAF mutation status) in a 1:1:1 ratio to receive pembrolizumab 2 or 10 mg/kg by IV infusion every 3 weeks or investigator's choice of chemotherapy (dacarbazine 1 g/m2 IV every 3 weeks; temozolomide 200 mg/m2 orally once daily for 5 days every 28 days; carboplatin at the dose required to obtain an AUC of 6 mg/mL per minute in combination with paclitaxel 225 mg/m2 IV every 3 weeks for 4 cycles followed by carboplatin at the dose required to obtain an AUC of 5 mg/mL per minute and paclitaxel 175 mg/m2 IV every 3 weeks; paclitaxel 175 mg/m2 IV every 3 weeks; or carboplatin at the dose required to obtain an AUC of 5 or 6 mg/mL per minute IV every 3 weeks).1, 11 Treatment with pembrolizumab was continued until the occurrence of unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, associated with a decline in performance status, requiring urgent intervention, or confirmed in 4-6 weeks by repeat radiographic studies.1, 11 Patients randomized to receive chemotherapy were permitted to cross over to pembrolizumab therapy following disease progression.1
Patients were enrolled in the KEYNOTE-002 study if their disease had progressed within 24 weeks of ipilimumab therapy and was refractory following at least 2 doses of ipilimumab (at a dose of at least 3 mg/kg) and, in those with tumors bearing the BRAF V600 mutation, refractory to therapy with a BRAF or mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor.1, 11 The primary measures of efficacy were progression-free survival (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ) and overall survival; additional outcome measures were objective response rate (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ) and duration of response.1, 11 The median age of patients enrolled in the study was 62 years; 98% were white, 61% were male, 40% had elevated LDH concentrations at baseline, and 23% had tumors bearing the BRAF mutation.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients (82%) had stage M1c disease and 73% had received at least 2 prior therapies for advanced or metastatic disease.1, 11 This study excluded patients with uveal melanoma, active brain metastases or carcinomatous meningitis, autoimmune disease, active infection requiring systemic therapy, a history of HIV infection, or active HBV or HCV infection.1, 11
In the KEYNOTE-002 study, a planned interim analysis at 6 months indicated a 34 and 38% progression-free survival rate for patients who received pembrolizumab 2 mg/kg and 10 mg/kg respectively, compared to 16% in patients who received investigator chosen chemotherapy.11 The median progression-free survival was 2.9 months for both dosing regimens of pembrolizumab versus 2.7 months for the chemotherapy control group.1, 11 Patients receiving pembrolizumab at either dosage also had a higher objective response rate compared with those receiving chemotherapy (21-25% versus 4%); complete responses were achieved in 2-3% of patients treated with pembrolizumab compared with none of those treated with chemotherapy.1, 11 At the final analysis (at a median follow-up of 28 months), median overall survival was non-substantially prolonged in patients who received pembrolizumab 2 or 10 mg/kg compared with those receiving chemotherapy (13.4 or 14.7 months, respectively, versus 11 months).1, 12 At the final analysis (at a median follow-up of 28 months), median overall survival was prolonged in patients receiving pembrolizumab 2 or 10 mg/kg compared with those receiving chemotherapy (13.4 or 14.7 months, respectively, versus 11 months).1, 12 At the time of final analysis, the median duration of response was 22.8 months in patients receiving pembrolizumab 2 mg/kg, had not been reached in those receiving pembrolizumab 10 mg/kg, and was 6.8 months in those receiving chemotherapy.12 Progression-free survival and objective response rates for pembrolizumab- and chemotherapy-treated patients at the time of final analysis remained similar to the interim results;1, 12 no substantial differences in efficacy were observed between the 2 pembrolizumab dosage regimens.12 Results of a subgroup analysis (based on ECOG performance status, baseline serum LDH concentration, BRAF mutation status, number of prior therapies, PD-L1 status, baseline tumor size, prior chemotherapy regimen, best response to ipilimumab, and disease stage) suggested that the effect of pembrolizumab on overall survival was consistent across all subgroups.12
Adjuvant Therapy for Locally Advanced Melanoma
The current indication for pembrolizumab as adjuvant therapy of stage III melanoma is based principally on the results of a phase 3 randomized, double-blind, placebo-controlled study (KEYNOTE-054).1, 39 In this study, 1019 adults with completely resected stage IIIA—IIIC melanoma were randomized (stratified by disease stage and geographic region) in a 1:1 ratio to receive either pembrolizumab (200 mg by IV infusion every 3 weeks) or placebo for up to 18 doses (approximately one year) or until disease progression or unacceptable toxicity occurred.1, 39 Upon disease recurrence, patients could cross over to pembrolizumab therapy or receive repeat treatment with the drug.39 Patients were eligible for enrollment in the study following complete regional lymphadenectomy and, if indicated, radiation therapy within 13 weeks prior to initiation of study treatment.1, 39 The primary measure of efficacy was recurrence-free survival in the entire study population and in the subset of patients with PD-L1-positive tumors (defined as a PD-L1 expression combined positive score of at least 1%, as measured by a clinical trial immunohistochemistry assay).1, 39
The median age of patients enrolled in the KEYNOTE-054 study was 54 years; 62% were male, 84% had positive PD-L1 expression, and 50% had tumors bearing the BRAF V600 mutation.1 Approximately one-half of patients (46%) had stage IIIB melanoma, 20% had stage IIIC disease with 4 or more positive lymph nodes, 18% had stage IIIC disease with 1-3 positive lymph nodes, and 16% had stage IIIA disease.1 All patients had an ECOG performance status of 0 or 1.1 The study excluded patients who had received prior systemic therapy for melanoma and those with autoimmune disease, uncontrolled infection, or any condition requiring use of systemic glucocorticoids.39
At a median follow-up of 15 months in the KEYNOTE-054 study, median recurrence-free survival was not reached in patients who received pembrolizumab and was 20.4 months in patients who received placebo.1, 39 A recurrence-free survival benefit was observed for pembrolizumab regardless of tumor PD-L1 expression.1, 39 At a follow-up of 18 months, the recurrence-free survival rate was 71.4% for pembrolizumab and 53.2% for placebo.39 For patients with PD-L1 positive tumors, pembrolizumab had a 12-month recurrence-free survival rate of 77.1% compared to 62.6% for placebo.39 Results of an exploratory analysis (based on age, sex, disease stage, number of positive lymph nodes, microscopic versus macroscopic lymph node involvement, presence of tumor ulceration, and BRAF mutation status) suggested that the effect of pembrolizumab on recurrence-free survival was consistent across subgroups.39 In a 5-year follow-up, the pembrolizumab group, regardless of PD-L1 status, had a recurrence-free survival rate of 55.4% compared to 38.3% for the placebo group.44 For PD-L1 positive tumors, the 5-year recurrence-free survival rate was 56.2% for pembrolizumab-treated patients versus 40% for patients treated with placebo.44
The current indication for pembrolizumab as adjuvant therapy of stage IIB or IIC melanoma in adults and pediatric patients ≥12 years of age is based principally on the results of a phase 3 randomized, double-blind, placebo-controlled study (KEYNOTE-716).1, 45, 46 In this study, 976 patients with newly diagnosed, completely resected stage IIA-IIC melanoma were randomized (stratified by disease stage and age group [12-17 years of age versus ≥18 years]) in a 1:1 ratio to receive either pembrolizumab (200 mg [or 2 mg/kg for pediatric patients] by IV infusion every 3 weeks) or placebo for up to 17 doses (approximately one year) or until disease recurrence or unacceptable toxicity occurred.1, 45, 46 Upon disease recurrence, patients could cross over to pembrolizumab therapy or receive repeat treatment with the drug.45, 46 Patients were eligible if they had not been previously treated for melanoma beyond complete surgical resection, including adjuvant radiation, prior to study entry.1, 45 The primary measure of efficacy was recurrence-free survival; distant metastasis-free survival was a secondary endpoint.1, 45, 46
The median age of patients enrolled in the KEYNOTE-716 study was 61 years; 60% were male, and 98% were white.1 There were 64% of patients who had stage IIB melanoma and 35% had stage IIC.1 All patients had an ECOG performance status of 0 or 1.1 The study excluded patients with autoimmune disease, uncontrolled infection, any condition requiring the use of systemic glucocorticoids, or any known additional malignancy that was progressing or required therapy within the past 5 years.45
In KEYNOTE-716, there was a substantial improvement in recurrence-free survival and distant metastasis-free survival.1 At an initial interim analysis, the median follow-up was 14.4 months for patients in the pembrolizumab group and 14.3 months for patients in the placebo group; the estimated 12-month recurrence-free survival rates were 90% and 83% for the pembrolizumab and placebo groups, respectively.45 At a second interim analysis, the estimated 18-month recurrence-free survival rate was 86% for patients treated with pembrolizumab compared to 77% of patients treated with placebo; neither group had reached median recurrence-free survival.45 For the secondary endpoint, median distant metastasis-free survival was not reached for either group at a median follow-up of 27.4 months.46 At 24 months, for the pembrolizumab group, the distant metastasis-free survival rate was 88% compared to 82% for the placebo group.46 A final analysis of KEYNOTE-716 was conducted at a median follow-up of 39.4 months; the median recurrence-free survival and distant metastasis-free survival had not been reached for either the pembrolizumab group or placebo group.47 The estimated 36-month recurrence-free survival rate was 76.2% for patients treated with pembrolizumab versus 63.4% for patients treated with placebo; the estimated 36-month distant metastasis-free survival rate was 84.4% and 74.7% for the pembrolizumab group and placebo group respectively.47
Pembrolizumab is used in combination with pemetrexed and platinum chemotherapy for the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC), without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.1
Pembrolizumab is also used in combination with carboplatin and paclitaxel (conventional or protein-bound) for the first-line treatment of metastatic squamous NSCLC.1
Pembrolizumab is also used as a single agent for the first-line treatment of stage III NSCLC, where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC expressing PD-L1 (i.e., tumor proportion score ≥1%), with no EGFR or ALK genomic aberrations.1 An FDA-approved diagnostic test is required to confirm the presence of PD-L1 expression prior to initiation of therapy.1
Pembrolizumab is also used as a single agent for the treatment of metastatic NSCLC expressing PD-L1 (i.e., tumor proportion score ≥1%) with disease progression on or after platinum-containing chemotherapy.1 An FDA-approved diagnostic test is required to confirm the presence of PD-L1 expression prior to initiation of therapy.1 Patients with EGFR or ALK genomic aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.1
Pembrolizumab is also used in combination with platinum-containing chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment after surgery, for the treatment of patients with resectable (i.e., tumors ≥4 cm or node positive) NSCLC.1
Pembrolizumab is also used as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for adults with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.1
First-line Therapy for Metastatic Nonsquamous Non-small Cell Lung Cancer
The current indication for pembrolizumab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of metastatic nonsquamous NSCLC, without EGFR or ALK genomic aberrations, is based principally on the results of a randomized, double-blind, phase 3 study (KEYNOTE-189).1, 38 In this study, 616 adults with previously untreated metastatic NSCLC with nonsquamous histology were randomized (stratified by PD-L1 expression, platinum-containing antineoplastic agent, and smoking status) in a 2:1 ratio to receive either pembrolizumab in combination with pemetrexed and investigator's choice of a platinum-containing antineoplastic agent (carboplatin or cisplatin) or placebo in combination with pemetrexed and investigator's choice of a platinum-containing antineoplastic agent; 72% of patients enrolled in the study received carboplatin.1, 38 Those randomized to the pembrolizumab combination regimen received pembrolizumab (200 mg by IV infusion) in combination with pemetrexed (500 mg/m2 by IV infusion) and either carboplatin (at the dose required to obtain an AUC of 5 mg/mL per minute by IV infusion) or cisplatin (75 mg/m2 by IV infusion) on day 1 of each 21-day cycle for 4 cycles followed by pembrolizumab (200 mg by IV infusion) in combination with pemetrexed (500 mg/m2 by IV infusion) every 3 weeks.1, 38 Those randomized to the placebo combination regimen received placebo in combination with pemetrexed and either carboplatin or cisplatin at the same dosages for 4 cycles followed by placebo in combination with pemetrexed (500 mg/m2 by IV infusion) every 3 weeks.1, 38 Treatment was continued for up to 24 months or until disease progression or unacceptable toxicity occurred; however, clinically stable patients with disease progression could continue treatment if they were considered to be deriving clinical benefit.1 In addition, patients randomized to receive placebo in combination with pemetrexed and a platinum-containing antineoplastic agent were permitted to cross over to single-agent pembrolizumab upon disease progression.1, 38 Approximately 41% of patients randomized to receive the placebo combination regimen crossed over to therapy with an anti-programmed-death receptor-1 (PD-1) or anti-PD-L1 antibody following disease progression.38
The primary measures of efficacy in the KEYNOTE-189 study were overall survival and progression-free survival (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ); additional outcome measures were objective response rate (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ) and duration of response.1, 38
The median age of patients enrolled in the KEYNOTE-189 study was 64 years; 94% were white and 3% were Asian, 59% were male, 56% had a baseline ECOG performance status of 1, 31% had a PD-L1 expression tumor proportion score of less than 1%, 18% had a history of brain metastases, and 12% had never smoked.1, 38 This study excluded patients with EGFR or ALK genomic aberrations, conditions requiring therapy with systemic corticosteroids or immunosuppressive agents, active autoimmune disease requiring systemic therapy within the previous 2 years, symptomatic CNS metastases, history of pneumonitis requiring therapy with glucocorticoids, or irradiation of the thoracic region at a dose exceeding 30 Gy within 26 weeks of enrollment.1, 38
In the KEYNOTE-189 study, pembrolizumab, in combination with chemotherapy, substantially improved overall survival and progression-free survival compared to placebo plus chemotherapy.1, 38 At a median follow-up of 10.5 months, patients receiving the pembrolizumab combination regimen had a longer median progression-free survival of 8.8 months compared to 4.9 months for patients who received the placebo combination regimen.1, 38 Although median overall survival for patients receiving the pembrolizumab combination regimen had not been reached at the time of analysis, median overall survival appeared to be prolonged in patients receiving pembrolizumab in combination with pemetrexed and a platinum-containing antineoplastic agent compared with those receiving placebo in combination with pemetrexed and a platinum-containing antineoplastic agent.1, 38 Patients receiving the pembrolizumab combination regimen also had higher objective response rates compared with those receiving the placebo combination regimen (48 versus 19%, respectively);1, 38 complete responses were achieved in 0.5% of patients in both treatment groups.1 At the time of analysis, the median duration of response was 11.2 and 7.8 months in patients receiving the pembrolizumab combination regimen and those receiving the placebo combination regimen, respectively.1, 38
Results of a subgroup analysis (based on age, sex, ECOG performance status, smoking status, presence of brain metastases, level of PD-L1 expression, and platinum-containing antineoplastic agent) suggested that the effect of pembrolizumab on overall survival and progression-free survival was evident across all subgroups.38 Subgroup analysis also indicated that the effect of pembrolizumab on objective response rate was evident regardless of level of PD-L1 expression, but objective response rates were substantially greater in patients with PD-L1 expression of any intensity on at least 50% of tumor cells (i.e., tumor proportion score of at least 50%) who received the pembrolizumab combination regimen compared with those who received the placebo combination regimen (61.4 versus 22.9%, respectively).38
In a protocol-specific final analysis of the KEYNOTE-189 study, outcomes were reported after a median follow-up of 31 months.48 Median overall survival was 22.0 months in the pembrolizumab plus chemotherapy group versus 10.6 months in the placebo plus chemotherapy group.1, 48 Median progression-free survival was 9.0 and 4.9 months for pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.48 Another study reported 5-year outcomes of KEYNOTE-189; the 5-year overall survival rates were 19.4% for patients treated with pembrolizumab plus chemotherapy versus 11.3% for patients treated with placebo plus chemotherapy.49 The 5-year progression-free survival rates were 7.5% and 0.6% for pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.49
First-line Therapy for Metastatic Squamous Non-small Cell Lung Cancer
The current indication for pembrolizumab in combination with carboplatin and paclitaxel (conventional or protein-bound) for the first-line treatment of metastatic squamous NSCLC is based principally on the results of a randomized, double-blind phase 3 study (KEYNOTE-407).1, 37 In this study, 559 adults with previously untreated metastatic NSCLC with squamous histology were randomized (stratified by PD-L1 expression, geographic region, and paclitaxel formulation) in a 1:1 ratio to receive either pembrolizumab in combination with carboplatin and investigator's choice of paclitaxel formulation (conventional or protein-bound paclitaxel) or placebo in combination with carboplatin and investigator's choice of paclitaxel formulation; 60% of patients enrolled in the study received conventional paclitaxel.1, 37 Those randomized to the pembrolizumab-carboplatin-paclitaxel regimen received pembrolizumab (200 mg by IV infusion) in combination with carboplatin (at the dose required to obtain an AUC of 6 mg/mL per minute by IV infusion) on day 1 of each 21-day cycle for 4 cycles and either conventional paclitaxel (200 mg/m2) on day 1 of each 21-day cycle or protein-bound paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 21-day cycle for 4 cycles followed by pembrolizumab (200 mg by IV infusion) every 3 weeks.1, 37 Those randomized to the placebo-carboplatin-paclitaxel regimen received placebo in combination with carboplatin and either conventional or protein-bound paclitaxel at the same dosages for 4 cycles followed by placebo every 3 weeks.1, 37 Therapy was continued for up to 24 months or until disease progression or unacceptable toxicity occurred; however, clinically stable patients with disease progression could continue receiving pembrolizumab if they were considered to be deriving clinical benefit.1 In addition, patients randomized to receive placebo-carboplatin-paclitaxel were permitted to cross over to single-agent pembrolizumab upon disease progression.1, 37 Approximately 32% of patients randomized to receive placebo-carboplatin-paclitaxel crossed over to therapy with an anti-PD-1 or anti-PD-L1 antibody following disease progression.37
The primary measures of efficacy in the KEYNOTE-407 study were progression-free survival and overall survival; additional outcome measures were objective response rate and duration of response, both as evaluated by a blinded independent central review committee according to RECIST, modified to follow no more than 10 target lesions and no more than 5 target lesions per organ.1, 37
The median age of patients enrolled in the KEYNOTE-407 study was 65 years; 81% were male, 77% were white and 19% were from East Asia, 71% had a baseline ECOG performance status of 1, 35% had a PD-L1 expression tumor proportion score of less than 1%, and 8% had a history of brain metastases.1, 37 This study excluded patients with conditions requiring therapy with immunosuppressive agents, active autoimmune disease requiring systemic therapy within the previous 2 years, symptomatic CNS metastases, history of pneumonitis requiring therapy with glucocorticoids, or irradiation of the thoracic region at a dose exceeding 30 Gy within 26 weeks of enrollment.1, 37
In the KEYNOTE-407 study, pembrolizumab, in combination with chemotherapy, substantially improved overall survival, progression-free survival, and overall response rate compared to placebo plus chemotherapy.1, 37 At a median follow-up of 7.8 months in the KEYNOTE-407 study, patients receiving pembrolizumab-carboplatin-paclitaxel had a longer median overall survival (15.9 versus 11.3 months, respectively) and progression-free survival (6.4 versus 4.8 months, respectively) compared with patients receiving placebo-carboplatin-paclitaxel.1, 37 In the primary efficacy population (consisting of the initial 204 patients enrolled in the study), patients receiving pembrolizumab-carboplatin-paclitaxel had higher objective response rates compared with those receiving placebo-carboplatin-paclitaxel (58 versus 35%); the median duration of response was 7.2 and 4.9 months in patients receiving these respective treatments.1
Results of a subgroup analysis (based on age, sex, ECOG performance status, level of PD-L1 expression, and paclitaxel formulation) suggested that the effect of pembrolizumab on overall survival and progression-free survival was evident across all subgroups.37 Subgroup analysis also indicated that the effect of pembrolizumab on objective response rate was evident regardless of level of PD-L1 expression, but objective response rates were substantially greater in patients with PD-L1 expression of any intensity on at least 50% of tumor cells (i.e., tumor proportion score of at least 50%) who received pembrolizumab-carboplatin-paclitaxel compared with those who received placebo-carboplatin-paclitaxel (60.3 versus 32.9%, respectively).37
In a protocol-specific final analysis of the KEYNOTE-407 study, outcomes were reported after a median follow-up of 14.3 months.50 Median overall survival was 17.1 months in the pembrolizumab plus chemotherapy group versus 11.6 months in the placebo plus chemotherapy group.1, 50 Median progression-free survival was 8.0 and 5.1 months for pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.50 Another study reported 5-year outcomes of KEYNOTE-407; the estimated 5-year overall survival rates were 18.4% for patients treated with pembrolizumab plus chemotherapy versus 9.7% for patients treated with placebo plus chemotherapy.51 The estimated 5-year progression-free survival rates were 10.8% and 3.5% for pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.51
First-line Therapy for Metastatic Non-small Cell Lung Cancer as Monotherapy
The current indication for use of pembrolizumab as a single agent for the first-line treatment of stage III NSCLC, where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC expressing PD-L1 is based principally on the results of 2 open-label, randomized phase 3 studies (KEYNOTE-024, KEYNOTE-042).1, 13, 52 In KEYNOTE-024, 305 patients with previously untreated metastatic NSCLC with high PD-L1 expression (tumor proportion score of at least 50%) were randomized (stratified by ECOG performance status, histology, and geographic region) in a 1:1 ratio to receive either pembrolizumab (200 mg by IV infusion every 3 weeks for up to 24 months) or investigator's choice of platinum-based chemotherapy (pemetrexed 500 mg/m2 IV and carboplatin at the dose required to obtain an AUC of 5-6 mg/mL per minute on day 1 of each 3-week cycle for 4-6 cycles, followed by an option to continue pemetrexed maintenance therapy; pemetrexed 500 mg/m2 IV and cisplatin 75 mg/m2 on day 1 of each 3-week cycle for 4-6 cycles, followed by an option to continue pemetrexed maintenance therapy; gemcitabine 1.25 g/m2 on days 1 and 8 and cisplatin 75 mg/m2 on day 1 of each 3-week cycle for 4-6 cycles; gemcitabine 1.25 g/m2 on days 1 and 8 and carboplatin at the dose required to obtain an AUC of 5-6 mg/mL per minute on day 1 of each 3-week cycle for 4-6 cycles; paclitaxel 200 mg/m2 and carboplatin at the dose required to obtain an AUC of 5-6 mg/mL per minute on day 1 of each 3-week cycle for 4-6 cycles, followed by an option to continue pemetrexed maintenance therapy).1 Use of pemetrexed chemotherapy regimens was only permitted for patients who had nonsquamous histologies.13 Treatment was continued for the specified duration or until disease progression or unacceptable toxicity occurred; however, clinically stable patients with disease progression could continue treatment if they were considered to be deriving clinical benefit.13 In addition, patients randomized to receive platinum-based chemotherapy were permitted to cross over to pembrolizumab therapy upon disease progression.13 Approximately 44% of the patients randomized to platinum-based chemotherapy crossed over to pembrolizumab therapy following disease progression.13 The primary measure of efficacy was progression-free survival (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ); additional outcome measures were overall survival and objective response rate (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1, 13
The median age of patients enrolled in the KEYNOTE-024 study was 65 years; 82% were white and 15% were Asian, 82% had nonsquamous histology, 61% were male, and 9% had a history of brain metastases.1 With one exception, all patients had a baseline ECOG performance status of 0 or 1.13 This study excluded patients with EGFR or ALK genomic aberrations, untreated brain metastases, active autoimmune disease that required systemic therapy within 2 years of randomization, conditions requiring therapy with systemic corticosteroids or immunosuppressive agents, active interstitial lung disease or a history of pneumonitis requiring glucocorticoid therapy, or irradiation of the thoracic region at a dose exceeding 30 Gy within 26 weeks of enrollment.1, 13
In the KEYNOTE-024 study, patients who received pembrolizumab had a substantially longer median progression-free survival compared with patients receiving platinum-based chemotherapy (10.3 versus 6 months, respectively).1, 13 Overall survival was also substantially longer for patients who received pembrolizumab compared with patients who received platinum-based chemotherapy (30 versus 14.2 months, respectively).1 Patients receiving pembrolizumab also had higher objective response rates compared with those receiving platinum-based chemotherapy (45 versus 28%);1, 13 complete responses were achieved in 4 or 1% of patients receiving pembrolizumab or platinum-based chemotherapy, respectively.1 The median time to response was similar in both treatment groups (2.2 months).13 Results of a subgroup analysis (based on age, sex, geographic region, ECOG performance status, histology, smoking status, presence of brain metastases, and prior use of pemetrexed in combination with platinum-based chemotherapy) suggested that the effect of pembrolizumab on progression-free survival was evident across all subgroups.13 A 5-year analysis of the KEYNOTE-024 estimated the overall survival rates at 5 years to be 31.9% for patients treated with pembrolizumab and 16.3% for patients treated with chemotherapy.53
In KEYNOTE-042, 1274 patients with metastatic NSCLC or previously untreated stage III NSCLC, who were not candidates for surgical resection or definitive chemoradiation, with PD-L1 expression (tumor proportion score of at least 1%) were randomized (stratified by ECOG performance status, histology, and geographic region) in a 1:1 ratio to receive either pembrolizumab or investigator's choice of chemotherapy.1, 52 Pembrolizumab was administered at 200 mg by IV infusion every 3 weeks for up to 24 months.1, 52 One of two chemotherapy regimens could be used in patients randomized to receive chemotherapy: 1) pemetrexed 500 mg/m2 IV and carboplatin at the dose required to obtain an AUC of 5-6 mg/mL per minute on day 1 of each 3-week cycle for 4-6 cycles, followed by an option to continue pemetrexed maintenance therapy for nonsquamous histologies; or 2) paclitaxel 200 mg/m2and carboplatin at the dose required to obtain an AUC of 5-6 mg/mL per minute on day 1 of each 3-week cycle for 4-6 cycles, followed by an option to continue pemetrexed maintenance therapy for nonsquamous histologies.1, 52 Treatment was continued for a maximum of 24 months or until disease progression or unacceptable toxicity occurred; however, clinically stable patients with disease progression could continue treatment if they were considered to be deriving clinical benefit.1, 52 No crossover from chemotherapy to pembrolizumab was allowed for KEYNOTE-042.52 The primary efficacy measures were overall survival in patients with a PD-L1 tumor proportion scale ≥50% and overall survival in patients with a PD-L1 tumor proportion scale ≥1%.1, 52 Additional efficacy measures included progression-free survival (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ) in the PD-L1 ≥50% subgroup population and PD-L1 ≥1% population.1, 52
The median age of patients enrolled in the KEYNOTE-042 study was 63 years; 64% were white, 2% were Black, and 30% were Asian; 61% had nonsquamous histology, 71% were male, and 5% had a history of brain metastases.1 There were 69% of patients that had a baseline ECOG performance status of 1; 87% of patients had metastatic disease, 13% had stage IIIA disease, and 11% had stage IIIB disease.1 There were 47% of patients with a PD-L1 tumor proportion score ≥50%; 53% had a tumor proportion score of 1 to 49%.1
In the KEYNOTE-042 study, compared to patients who received chemotherapy, patients who received pembrolizumab had a substantial improvement in overall survival but no improvement in median progression-free survival.1, 52 For patients with a PD-L1 tumor proportion score ≥1%, the median overall survival for patients in the pembrolizumab group was 16.7 months versus 12.1 months for patients in the chemotherapy group.1, 52 For patients with a PD-L1 tumor proportion score ≥50%, the median overall survival for patients in the pembrolizumab group was 20.0 months versus 12.2 months for patients in the chemotherapy group.1, 52 Patients with a PD-L1 tumor proportion score ≥50% had a median progression-free survival of 7.1 months for patients in the pembrolizumab group compared to 6.4 months for patients in the chemotherapy group.52 Patients with a tumor proportion score ≥1% had a median progression-free survival of 5.4 months and 6.5 months for pembrolizumab and chemotherapy, respectively.1, 52
Results of a subgroup analysis for patients with a tumor proportion score of 1—49% showed a median overall survival of 13.4 months for patients treated with pembrolizumab versus 12.1 months for patients treated with chemotherapy.1, 52
A 5-year analysis of the KEYNOTE-042 estimated the overall survival rates.54 For patients with a PD-L1 tumor proportion score ≥50%, the estimated 5-year overall survival rate for patients treated with pembrolizumab was 21.9% compared to 9.8% of patients treated with chemotherapy.54 For patients with a PD-L1 tumor proportion score ≥1%, the estimated 5-year overall survival rate was 16.6% and 8.5% for pembrolizumab and chemotherapy, respectively.54
Previously Treated Metastatic Non-small Cell Lung Cancer
The current indication for use of pembrolizumab as a single agent for the treatment of metastatic NSCLC in patients with disease progression during or following platinum-based chemotherapy is based principally on the results of an open-label, randomized phase 2/3 study (KEYNOTE-010).1, 15 Patients were enrolled in the study if PD-L1 expression of any intensity on at least 1% of tumor cells was detected by immunohistochemistry assay (PD-L1 IHC 22C3 pharmDx).1 In this study, 1033 patients were randomized (stratified by level of PD-L1 expression, ECOG performance status, and geographic region) in a 1:1:1 ratio to receive pembrolizumab 2 or 10 mg/kg by IV infusion every 3 weeks or docetaxel 75 mg/m2 by IV infusion every 3 weeks.1, 15 Treatment was continued for up to 24 months or until the occurrence of unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, associated with a decline in performance status, requiring urgent intervention, or confirmed in 4-6 weeks by repeat radiographic studies.1 The primary measures of efficacy were overall survival and progression-free survival (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ) in the total population (with PD-L1 tumor proportion score ≥1%) and in patients with high PD-L1 expression (defined as PD-L1 expression of any intensity on at least 50% of tumor cells); additional outcome measures were objective response rate and duration of response.1, 15
The median age of patients enrolled in the KEYNOTE-010 study was 63 years; 72% were white and 21% were Asian, 70% had nonsquamous histology, 66% had an ECOG performance status of 1, 61% were male, 43% had high PD-L1 expression, 21% had squamous histology, 15% had a history of brain metastases, 8% had EGFR genomic aberrations, and 1% had ALK genomic aberrations.1, 15 Most of the patients (91%) had metastatic disease;1 all patients enrolled in the study had received prior therapy with a platinum-containing, 2-drug combination regimen and 29% had received at least 2 prior therapies for metastatic disease.1, 15 This study excluded patients with active autoimmune disease requiring systemic corticosteroids, conditions requiring therapy with immunosuppressive agents, active brain metastases or carcinomatous meningitis; interstitial lung disease or a history of pneumonitis requiring corticosteroid therapy, or irradiation of the thoracic region at a dose exceeding 30 Gy within 26 weeks of enrollment.1, 15
In the total patient population (PD-L1 tumor proportion score ≥1%) of the KEYNOTE-010 study, median overall survival was substantially prolonged in patients receiving pembrolizumab 2 or 10 mg/kg compared with those receiving docetaxel (10.4 or 12.7 months, respectively, versus 8.5 months).1, 15 Among patients with high PD-L1 expression, median overall survival also was substantially prolonged in patients receiving pembrolizumab 2 or 10 mg/kg compared with those receiving docetaxel (14.9 or 17.3 months, respectively, versus 8.2 months, respectively).1, 15 In the total patient population, no difference in median progression-free survival was observed between patients receiving pembrolizumab 2 or 10 mg/kg and those receiving docetaxel; however, among those with high PD-L1 expression, median progression-free survival was prolonged in patients receiving pembrolizumab at either dosage compared with those receiving docetaxel (5.2 versus 4.1 months).1, 15 Patients receiving pembrolizumab at either dosage also had higher objective response rates compared with those receiving docetaxel in the total patient population (18-19 versus 9%) and in the cohort of patients with high PD-L1 expression (29-30% versus 8%).1, 15 Complete responses were not achieved in any treatment group.15 At a median follow-up of 13.1 months, the median duration of response had not been reached in patients receiving pembrolizumab.1, 15 The median time to response in the cohort of patients with high PD-L1 expression was similar in each treatment group (9 weeks).15 Results of a subgroup analysis (based on age, sex, ECOG performance status, PD-L1 expression, new or archival tumor sample, EGFR mutation status, and histology) suggested that the effect of pembrolizumab on overall survival was consistent across all subgroups.15 A follow-up study of long-term outcomes of the KEYNOTE-010 study provided estimated 36-month overall survival rates.55 For the total population, the 36-month overall survival rate for patients who received pembrolizumab at either dose was 22.9% versus 11.0% in patients who received docetaxel.55 For the high PD-L1 subgroup, the 36-month overall survival rate was 34.5% for pembrolizumab and 12.7% for docetaxel.55
Neoadjuvant and Adjuvant Treatment of Resectable Non-small Cell Lung Cancer
The current indication for use of pembrolizumab in combination with platinum-containing chemotherapy, followed by surgery and continued use of pembrolizumab as a single agent, for the treatment of patients with resectable NSCLC is based principally on the results of a double-blind, randomized, placebo controlled study (KEYNOTE-671).1, 56 Patients with previously untreated and resectable stage II, IIIA, or IIIB NSCLC, regardless of PD-L1 expression of tumor cells, were enrolled.1, 56 In this study, 797 patients were randomized (stratified by stage, level of PD-L1 expression, histology, and geographic region) in a 1:1 ratio to receive a neoadjuvant-adjuvant pembrolizumab regimen or placebo regimen.1, 56 Those randomized to the neoadjuvant-adjuvant pembrolizumab regimen received neoadjuvant pembrolizumab (200 mg by IV infusion) in combination with cisplatin (75 mg/m2) and either pemetrexed (500 mg/m2) on day 1 or gemcitabine (1 g/m2) on day 1 and 8 of each 21-day cycle for up to 4 cycles and adjuvant pembrolizumab (200 mg by IV infusion) every 3 weeks for up to 13 cycles within 4—12 weeks following surgery.1, 56 Those randomized to the placebo regimen received placebo in combination with cisplatin and either pemetrexed or gemcitabine at the same dosages for up to 4 cycles and placebo every 3 weeks for up to 13 cycles within 4—12 weeks following surgery.1, 56 Therapy was continued until disease progression, unacceptable toxicity, or the maximum number of administrations was reached.1, 56 The primary measures of efficacy were overall survival and event-free survival; additional efficacy measures included pathological complete response rate and major pathological response rate.1, 56
The median age of patients enrolled in the KEYNOTE-671 study was 64 years; 61% were white, 2% were Black, and 31% were Asian; 9% were Hispanic or Latino; 57% had nonsquamous histology; 71% were male, 33% had PD-L1 expression ≥50%, 67% had PD-L1 expression <50%.1 All patients enrolled had an ECOG performance status of 0 or 1.1 Most of the patients (70%) had stage III disease and 30% had stage II disease; 81% in the pembrolizumab with chemotherapy group had definitive surgery versus 76% in the placebo with chemotherapy group.1 This study excluded patients with active autoimmune disease requiring systemic corticosteroids, conditions requiring therapy with immunosuppressive agents, or interstitial lung disease or a history of pneumonitis requiring corticosteroid therapy.1
In the KEYNOTE-671 study, there were substantial improvements in overall survival and event-free survival in patients who received the pembrolizumab-containing regimen compared with those receiving the placebo regimen.1 The median overall survival had not been reached for the pembrolizumab with chemotherapy regimen and was 52.4 months for the placebo with chemotherapy regimen.1, 56 The estimated 36-month overall survival rate was 71% and 64% for the pembrolizumab and placebo group, respectively.56 The median event-free survival for the pembrolizumab plus chemotherapy regimen was 47.2 months versus 18.3 months for the placebo regimen group.56 For the outcome of pathological complete response, the rate was 18.1% for the pembrolizumab with chemotherapy group and 4.0% for the placebo with chemotherapy group; for the outcome of major pathological response, the rates were 30.2% and 11.0% for each group respectively.1 Results of a subgroup analysis (based on sex, clinical disease and nodal stages, histology, EGFR mutation status, and ALK translocation status) suggested that the effect of pembrolizumab on overall survival was consistent across these subgroups.56
Adjuvant Treatment of Resected Non-small Cell Lung Cancer
The current indication for use of pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for adults with stage IB, II, or IIIA NSCLC is based principally on the results of a triple-blind, randomized, placebo controlled study (KEYNOTE-091).1, 57 Patients with completely resected stage IB (tumors ≥4 cm in diameter), II, or IIIA NSCLC, regardless of PD-L1 expression of tumor cells, were enrolled.1, 57 In this study, 1177 patients were randomized (stratified by stage, receipt of adjuvant chemotherapy, level of PD-L1 expression, and geographic region) in a 1:1 ratio to receive pembrolizumab (200 mg by IV infusion) or placebo every 3 weeks.1, 57 Adjuvant chemotherapy was optional for up to 4 cycles; patients had not received neoadjuvant radiotherapy or chemotherapy.1, 57 Therapy was continued for up to 1 year or until disease progression or unacceptable toxicity occurred; crossover from the placebo group to the pembrolizumab group was not permitted.1, 57 The primary measure of efficacy was disease-free survival for both the overall population and in patients with a PD-L1 expression tumor proportion score ≥50%; an additional efficacy measure was overall survival.1, 57
The median age of patients enrolled in the KEYNOTE-091 study was 64 years; 77% were white, and 18% were Asian; 86% were current or former smokers; 68% were male, 28% had PD-L1 expression ≥50%, 39% had PD-L1 expression <1%.1 All patients enrolled had an ECOG performance status of 0 or 1.57 Most of the patients (57%) had stage II disease, 31% had stage IIIA disease, and 11% had stage IB disease.1 Of the patients randomized, 86% received adjuvant platinum-based chemotherapy following surgical resection.1 This study excluded patients with active autoimmune disease requiring treatment, active HBV or HCV infection, or history of HIV.57
In the KEYNOTE-091 study, there was a substantial improvement in disease-free survival in the overall population with a median of 53.6 months for patients who received pembrolizumab compared with 42.0 months for patients who received placebo.57 The median disease-free survival had not been reached for either group for patients with PD-L1 expression ≥50%.57 For the overall population, median overall survival has not been reached for either group.1, 57 Results of a protocol-specified subgroup analysis (based on stratification factors, histology, smoking status, sex, age, ECOG status, race, and EGFR mutation) suggested that the effect of pembrolizumab on disease-free survival was consistent across subgroups.57
Malignant Pleural Mesothelioma
Pembrolizumab is used in combination with pemetrexed and platinum chemotherapy for the first-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma (MPM) in adults.1
The current indication for pembrolizumab, in combination with pemetrexed and platinum chemotherapy, for first-line treatment of unresectable advanced or metastatic MPM is based principally on the results of an open-label, randomized, phase 3 study (KEYNOTE-483).1, 58 Adults with unresectable advanced or metastatic MPM, with no prior systemic therapy for advanced/metastatic disease and regardless of PD-L1 expression, were enrolled.1, 58 In this study, 440 patients were randomized (stratified by histology) in a 1:1 ratio to receive a pembrolizumab (200 mg by IV infusion) plus chemotherapy regimen or a chemotherapy regimen.1, 58 The chemotherapy regimen for both the treatment group and control group was pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or carboplatin (at the dose required to obtain an AUC of 5-6 mg/mL per minute) on day 1 of each 3-week cycle for up to 6 cycles.1, 58 For patients randomized to receive pembrolizumab, pembrolizumab was administered every 3 weeks for up to 2 years.1, 58 Therapy was continued until treatment completion, disease progression, or unacceptable toxicity.1, 58 The primary measure of efficacy was overall survival; additional efficacy measures included progression-free survival, overall response rate, and duration of response, as assessed by blinded independent central review committee according to modified RECIST for mesothelioma.1, 58
The median age of patients enrolled in the KEYNOTE-483 study was 70 years; 79% were white; 2% were Hispanic or Latino; 76% were male; 78% had epithelioid and 22% had non-epithelioid histology; 60% had PD-L1 expression ≥1%, 30% had PD-L1 expression <1%.1 All patients enrolled had an ECOG performance status of 0 or 1.58 This study excluded patients with active autoimmune disease requiring systemic corticosteroids, conditions requiring therapy with immunosuppressive agents, untreated CNS metastases, pneumonitis, or with concurrent serious illness or cancer.1, 58
In the KEYNOTE-583 study, there was a substantial improvement in overall survival for patients who received pembrolizumab with chemotherapy compared with patients who received chemotherapy alone.1, 58 The median overall survival was 17.3 months for pembrolizumab plus chemotherapy versus 16.1 months for chemotherapy alone.1, 58 The median progression-free survival was 7.1 months for both groups.1, 58 Patients treated with pembrolizumab with chemotherapy had an objective response rate of 62% versus 38% for patients treated with only chemotherapy.58 The duration of response was 5.5 months and 5.8 months for pembrolizumab with chemotherapy and chemotherapy alone, respectively.58 Results of a subgroup analysis (based on age, sex, histology, European Organization for Research and Treatment of Cancer [EORTC] score, PD-L1 expression) suggested benefit in most subgroups.58
Head and Neck Squamous Cell Cancer
Pembrolizumab is used in combination with platinum and fluorouracil for the first-line treatment of metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).1
Pembrolizumab is also used as a single agent for the first-line treatment of patients with metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 (i.e., combined positive score ≥1%).1 An FDA-approved diagnostic test is required to confirm the presence of PD-L1 expression prior to initiation of therapy.1
Pembrolizumab is also used as a single agent for the treatment of recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.1
First-line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma
The current indications for pembrolizumab in the treatment of recurrent or metastatic HNSCC are based principally on the results of an open-label, multicenter, randomized, multicohort phase 3 study (KEYNOTE-048).1, 59 Patients with metastatic HNSCC, who had not previously received systemic therapy, or recurrent disease, considered incurable by local therapies, were enrolled.1 There were 882 patients randomized (stratified by PD-L1 expression, human papillomavirus [HPV] status, and ECOG performance status) in a 1:1:1 ratio to receive pembrolizumab alone (200 mg by IV infusion) every 3 weeks, pembrolizumab (200 mg by IV infusion) in combination with carboplatin (at the dose required to obtain an AUC of 5 mg/mL per minute) or cisplatin (100 mg/m2) and fluorouracil (1 g/m2 per day as a continuous IV infusion over 96 hours) every 3 weeks, or cetuximab (400 mg/m2IV initially and then 250 mg/m2 IV once weekly) in combination with carboplatin or cisplatin and fluorouracil (at same dosages) every 3 weeks.1 The platinum-fluorouracil chemotherapy regimens were administered for a maximum of 6 cycles; treatment with pembrolizumab continued until disease progression, unacceptable toxicity, or up to 24 months.1, 59 Treatment with cetuximab continued until disease progression or intolerable toxicity.59 Patients receiving pembrolizumab with disease progression that were clinically stable and considered to be deriving clinical benefit could continue receiving pembrolizumab.1, 59 The primary measures of efficacy included overall survival and progression-free survival, as assessed by blinded independent central review according to RECIST (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ), tested in the overall population and patients with a PD-L1 expression score of ≥1%.1, 59
The median age of patients enrolled in the KEYNOTE-048 study was 61 years; 73% were white, 2.4% were Black, and 20% were Asian; 83% were male; 79% were former or current smokers; 22% of tumors were HPV-positive.1 There were 95% of patients that had stage IV disease; 23% of patients had a PD-L1 expression ≥50%, and 85% of patients had a PD-L1 expression ≥1%.1 All patients enrolled had an ECOG performance status of 0 or 1.59 This study excluded patients with active autoimmune disease requiring systemic therapy, conditions requiring therapy with immunosuppressive agents, symptomatic CNS metastases, pneumonitis, or with progressive disease within 6 months of curatively intended systemic treatment for locoregionally advanced disease.1, 59
In the KEYNOTE-048 study, there was a substantial improvement in overall survival for patients with PD-L1 expression ≥1% who received pembrolizumab alone compared with patients who received cetuximab with platinum-fluorouracil chemotherapy and for the overall population who received pembrolizumab plus chemotherapy compared with patients who received cetuximab with chemotherapy.1, 59 For the overall population, the medical overall survival was 13.0 months for patients in the pembrolizumab with chemotherapy group versus 10.7 months for patients in the cetuximab with chemotherapy group.1, 59 The median progression-free survival was 4.9 months for pembrolizumab with chemotherapy and 5.1 months for cetuximab with chemotherapy.1 For the patient population with PD-L1 expression ≥1%, the median overall survival was 12.3 months for patients who received pembrolizumab alone compared to 10.3 months for patients who received cetuximab plus chemotherapy.1, 59 The median progression-free survival for this population was 3.2 months for patients in the pembrolizumab-only group versus 5.0 months for patients in the cetuximab plus chemotherapy group.1, 59 In the overall population, there was no substantial difference in overall survival in patients treated only with pembrolizumab compared to patients treated with cetuximab plus chemotherapy.1, 59
Previously Treated Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
The current indication for pembrolizumab in the treatment of recurrent or metastatic HNSCC is based principally on the results for a cohort of patients with head and neck squamous cell carcinoma in an open-label, multicenter, nonrandomized, phase 1b study (KEYNOTE-012);1, 16 the cohort of patients with HNSCC included 174 adults with head and neck squamous cell carcinoma that had progressed during or following platinum-containing therapy for recurrent or metastatic disease or following platinum-containing therapy as part of induction, concurrent, or adjuvant therapy.1 Patients were enrolled in the study if PD-L1 expression of any intensity on at least 1% of tumor cells was detected by immunohistochemistry assay.16 Patients were eligible for enrollment in the study regardless of their HPV status.16 Patients received pembrolizumab 10 mg/kg administered as an IV infusion every 2 weeks or 200 mg administered as an IV infusion every 3 weeks for up to 24 months or until the occurrence of unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, associated with a decline in performance status, requiring urgent intervention, or confirmed after at least 4 weeks by repeat radiographic studies.16 Reinitiation of pembrolizumab was permitted for subsequent disease progression for up to one additional year.1
The median age of patients enrolled in the HSNCC cohort of the KEYNOTE-012 study was 60 years; 87% had metastatic disease, 82% were male, 75% were white, 6% were Black, 16% were Asian, 63% previously had received cetuximab therapy, and 33% had HPV-positive tumors.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 In the cohort of patients with HNSCC, the median number of prior therapies was 2.1 This study excluded patients with active autoimmune disease, conditions requiring therapy with immunosuppressive agents, interstitial lung disease, brain metastases, infections requiring systemic therapy, HIV infection, or HBV or HCV infection.1, 16
At a median follow-up of 8.9 months, the objective response rate for patients in the HNSCC cohort of the KEYNOTE-012 study was 16%; complete response was achieved in 5% of patients.1 At the time of analysis, the median duration of response had not been reached.1 Objective response rates and duration of response were similar in both dosage groups and those with HPV-negative or HPV-positive disease.1 Objective response rate was similar in an expansion cohort of patients who received a fixed dosage of pembrolizumab (200 mg administered by IV infusion every 3 weeks).17 Also, in the expansion study, the 6-month progression-free survival rate for pembrolizumab-treated patients was 23% (37% in those with HPV-positive disease and 20% in those with HPV-negative disease); the median overall survival was 8 months.17
Pembrolizumab is used for the treatment of relapsed or refractory classical Hodgkin lymphoma (cHL) in adults; pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.1, 4
Pembrolizumab is used in pediatric patients for the treatment of refractory cHL, or cHL that has relapsed after 2 or more lines of therapy; pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.1, 4
Pembrolizumab is also used for cHL in adults at an additional dosing regimen of 400 mg every 6 weeks.1 The accelerated approval of pembrolizumab for this indication is based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety.1 Continued approval for this dosing may be contingent on verification and description of clinical benefit in confirmatory studies.1
The current indication for use of pembrolizumab for the treatment of relapsed or refractory cHL is based principally on the results of an open-label, multicenter, noncomparative phase 2 study (KEYNOTE-087) and an open-label, active-controlled study (KEYNOTE-204).1, 18, 60
In KEYNOTE-087, patients were enrolled in 3 cohorts: those with disease progression following autologous stem cell transplantation and subsequent therapy with brentuximab vedotin, those with disease progression following salvage chemotherapy and brentuximab vedotin, and those with disease progression following autologous transplantation only.18 In this study, 210 patients received pembrolizumab 200 mg by IV infusion every 3 weeks for up to 24 months or until disease progression or unacceptable toxicity occurred;1, 18 however, clinically stable patients were permitted to continue pembrolizumab therapy despite disease progression at the time of the initial assessment.18 The primary measure of efficacy was objective response rate (as evaluated by a blinded independent central review committee according to revised International Working Group [IWG] criteria).1, 18
The median age of patients enrolled in the KEYNOTE-087 study was 35 years;1, 18 88% were white and 9% were 65 years of age or older.1 With one exception, all patients had a baseline ECOG performance status of 0 or 1.18 Patients in this study had received a median of 4 prior therapies for cHL;1, 18 58% of patients were refractory to their most recent therapy (35% of these patients had primary refractory disease and 14% were refractory to all prior therapies), 61% had undergone prior autologous stem cell transplantation, 83% previously had received brentuximab vedotin, and 36% had received prior radiation therapy.1 This study excluded patients with active noninfectious pneumonitis; those who had received an allogeneic stem cell transplant within the past 5 years; those who had received an allogeneic stem cell transplant and experienced symptoms of graft-versus-host disease (GVHD); and those with CNS involvement, active autoimmune disease that required systemic therapy in the past 2 years, conditions requiring therapy with immunosuppressive agents, active infection requiring systemic therapy, HIV infection, or active HBV or HCV infection.1, 18
At a median follow-up of 9.4 months in the KEYNOTE-087 study, the objective response rate was 69% with a median response duration of 11.1 months; complete response was achieved in 22% of patients.1, 18 Objective response rates were similar in each cohort.18 A 5-year follow-up study of KEYNOTE-087 reported results at a median follow-up of 63.7 months.61 The objective response rate at this time point for the overall population was 71.4%, with a complete response rate of 27.6%.61
In KEYNOTE-204, 304 adults with relapsed or refractory cHL after at least one multi-agent chemotherapy regimen were randomized 1:1 (stratified by prior autologous stem cell transplant and disease status after frontline therapy) to receive pembrolizumab (200 mg by IV infusion) or brentuximab vedotin (1.8 mg/kg by IV infusion) every 3 weeks.1, 60 Treatment continued until unacceptable toxicity, disease progression, or a maximum of 35 cycles (approximately 2 years) was reached.1, 60 The primary measure of efficacy was progression-free survival (as evaluated by a blinded independent central view committee according to revised IWG criteria).1, 60
The median age of patients enrolled in the KEYNOTE-204 study was 35 years; 77% were white, 9% Asian, and 3.9% Black.1 With one exception, all patients had a baseline ECOG performance status of 0 or 1.60 Patients in this study had received a median of 2 prior therapies for cHL in the pembrolizumab group and 3 prior therapies in the brentuximab vedotin group.1 There were 42% of patients who were refractory to their most recent therapy, 29% had primary refractory disease, 37% had prior autologous stem cell transplant, 5% had received prior brentuximab vedotin, and 39% had prior radiation therapy.1 This study excluded patients with current or historical immunosuppressive therapy; those who had received an allogeneic stem cell transplant within the past 5 years; those with ongoing GVHD from a transplantation more than 5 years ago; an additional malignancy that progressed or that required active treatment in the past 3 years; known active CNS metastases or carcinomatous meningitis; active autoimmune disease requiring systemic treatment; history of pneumonitis; active infection requiring systemic therapy; known history of HIV; active HBV or HCV; or known history of active tuberculosis.60
In the KEYNOTE-204 study, there was substantial improvement in progression-free survival for patients who received pembrolizumab compared with patients who received brentuximab vedotin.1, 60 The median progression-free survival for patients who received pembrolizumab was 13.2 months versus 8.3 months for patients who received brentuximab vedotin.1, 60 The objective response rate was 66% and 54% for the pembrolizumab and brentuximab vedotin groups, respectively; the median duration of response was 20.7 months and 13.8 months, respectively.1, 60 Results of a subgroup analysis suggested similar benefits in progression-free survival across subgroups.60
The current indication for use of pembrolizumab in pediatric patients for the treatment of refractory cHL, or cHL that has relapsed after 2 or more lines of therapy, is based on evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data for pediatric patients.1
A multicenter, nonrandomized, open-label, single-arm study has been conducted in pediatric patients with advanced melanoma or a PD-L1 positive, advanced, relapsed, or refractory solid tumor or lymphoma (KEYNOTE-051).62 The KEYNOTE-051 study enrolled 173 pediatric patients from 6 months to 17 years of age with advanced melanoma, lymphoma, or PD-L1 or microsatellite instability-high (MSI-H) solid tumors.1 The median time of follow-up was 8.6 months.62 There were 15 patients with relapsed or refractory Hodgkin lymphoma in KEYNOTE-051, in which 9 patients (60%) achieved an objective response.62
The current indication for use of pembrolizumab at a dosage of 400 mg every 6 weeks for cHL for adults was primarily based on dose-exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma.1
Primary Mediastinal Large B-cell Lymphoma
Pembrolizumab is used for the treatment of refractory primary mediastinal large B-cell lymphoma (PMBCL) and PMBCL that has relapsed following at least 2 prior therapies in adult and pediatric patients; pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.1, 4 Pembrolizumab is not recommended for patients with PMBCL who require urgent cytoreductive therapy.1
Pembrolizumab is also used for PMBCL in adults at an additional dosing regimen of 400 mg every 6 weeks.1 The accelerated approval of pembrolizumab for this indication is based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety.1 Continued approval for this dosing may be contingent on verification and description of clinical benefit in confirmatory studies.1
The current indication for use of pembrolizumab for the treatment of relapsed or refractory PMBCL in adults and pediatric patients is based principally on the results of an open-label, multicenter, noncomparative phase 2 study (KEYNOTE-170).1, 63, 64 In this study, 53 patients received pembrolizumab 200 mg by IV infusion every 3 weeks for up to 24 months or until disease progression or unacceptable toxicity occurred.1, 63 The primary measure of efficacy was objective response rate (as evaluated by a blinded independent central review committee according to revised IWG criteria); additional efficacy measures included duration of response, progression-free survival, and overall survival.1, 63, 64
The median age of patients enrolled in the KEYNOTE-170 study was 33 years;1 92% were white and 43% were male.1 All patients had a baseline ECOG performance status of 0 or 1.1, 63 Patients in this study had received a median of 3 prior therapies for PMBCL; 49% of patients had relapsed disease refractory to their most recent therapy, 36% had primary refractory disease, 32% had received prior radiation therapy, 26% had undergone prior autologous stem cell transplantation, and 15% had untreated relapsed disease.1 All patients had received prior therapy with rituximab.1 This study excluded patients with active noninfectious pneumonitis; those who had received an allogeneic stem cell transplant within the past 5 years; those who had received an allogeneic stem cell transplant and experienced symptoms of GVHD; those with active autoimmune disease; those with active CNS involvement; and those with conditions requiring therapy with immunosuppressive agents or active infection requiring systemic therapy.1, 63
At a median follow-up of 9.7 months, the objective response rate was 45%, with a median time to response of 2.9 months; complete response was achieved in 13% of patients.1, 63 At the time of this analysis, median duration of response had not been reached.1, 63 Median progression-free survival was 5.5 months.63 An additional analysis of KEYNOTE-170 reported results with a median duration of follow-up of 48.7 months.64 At this time point, the objective response rate was 41.5%, 7 patients improved to complete response, the median progression-free survival was 4.3 months, and the median overall survival was 22.3 months.64 The median duration of response had not been reached.64
The current indication for use of pembrolizumab at a dosage of 400 mg every 6 weeks for PMBCL for adults was primarily based on dose-exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma.1
Pembrolizumab is used in combination with enfortumab vedotin for the treatment of adults with locally advanced or metastatic urothelial cancer.1
Pembrolizumab is used as a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy or who have disease progression during or following platinum-containing therapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.1
Pembrolizumab is also used as a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.1
Combination Therapy for Locally Advanced or Metastatic Urothelial Cancer
The efficacy and safety of pembrolizumab in combination with enfortumab vedotin for the treatment of adults with locally advanced or metastatic urothelial cancer are based principally on the results of a phase 3, open-label, randomized, multicenter trial (KEYNOTE-A39) and an open-label, multi-cohort, phase 1b/2 study (KEYNOTE-869).1, 200, 201, 202
The KEYNOTE-A39 study enrolled 886 patients with locally advanced or metastatic urothelial cancer who had received no previous systemic therapy for locally advanced or metastatic disease.1, 200 Patients were randomized (stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases) in a 1:1 ratio to receive pembrolizumab plus enfortumab vedotin or chemotherapy with gemcitabine and cisplatin or carboplatin.1, 200 Patients randomized to the pembrolizumab plus enfortumab vedotin group received pembrolizumab 200 mg over 30 minutes on day 1 and enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle; pembrolizumab was given approximately 30 minutes after enfortumab vedotin, and treatment continued for up to 2 years (or until disease progression or unacceptable toxicity).1, 200 Patients randomized to the chemotherapy group received gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle and cisplatin 70 mg/m2 or carboplatin (AUC of 4.5 or 5) on day 1 of a 21-day cycle; treatment was continued for up to 6 cycles or until disease progression or unacceptable toxicity.1, 200 The primary measures of efficacy were overall survival and progression-free survival (as evaluated by a blinded independent central review committee according to RECIST).1, 200 Additional efficacy outcome measures included objective response rate as assessed by a blinded independent central review committee.1, 200
The median age of patients enrolled in KEYNOTE-A39 was 69 years; 76.7% were male, 67.5% were white, and 21.6% were Asian.1, 200 Baseline ECOG performance status was 0, 1, or 2 in 49, 47, and 3% of patients, respectively.1 Most patients (95%) had metastatic urothelial cancer at baseline; 72% had visceral metastases and 22% had liver metastases.1 Cisplatin-ineligible patients accounted for 46% of the trial population.1 Patients with active CNS metastases, ongoing sensory or motor neuropathy (grade 2 or higher), or uncontrolled diabetes (hemoglobin A1c [HbA1c] ≥8% or HbA1c≥7% with symptoms) were excluded from the trial.1
In the KEYNOTE-A39 study, median overall survival was prolonged in patients receiving pembrolizumab plus enfortumab vedotin compared with those receiving chemotherapy (31.5 versus 16.1 months; hazard ratio: 0.47).1, 200 Median progression-free survival was also prolonged in patients receiving pembrolizumab plus enfortumab vedotin (12.5 versus 6.3 months; hazard ratio: 0.45).1, 200 Patients receiving pembrolizumab plus enfortumab vedotin also had higher objective response rates compared with those receiving chemotherapy (67.7 versus 44.4%); complete responses were achieved in 29.1 or 12.5% of patients receiving pembrolizumab plus enfortumab vedotin or chemotherapy, respectively.1, 69
The KEYNOTE-869 study enrolled a total of 121 patients with locally advanced or metastatic urothelial cancer who had received no prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy.1, 200, 201 Patients received pembrolizumab 200 mg IV on day 1 and enfortumab vedotin 1.25 mg/kg IV on days 1 and 8 of a 21-day cycle; pembrolizumab was administered approximately 30 minutes after enfortumab vedotin, and treatment was continued until disease progression or unacceptable toxicity occurred.1 The primary measures of efficacy were objective response rate and duration of response (as evaluated by a blinded independent central review committee according to RECIST).1
The median age of patients enrolled in KEYNOTE-869 was 71 years; 74% were male, 85% were white, and 10% were Hispanic or Latino.1 Baseline ECOG performance status was 1 or 2 in 45 and 15% of patients, respectively.1 Most patients (97.5%) had metastatic urothelial cancer at baseline; 37% had upper urinary tract disease, 84% had visceral metastases, and 22% had liver metastases.1 Reasons for cisplatin ineligibility included baseline renal impairment (creatinine clearance 30-59 mL/minute), poor performance status (ECOG performance status of 2), hearing loss of grade 2 or greater severity, and multiple reasons for cisplatin ineligibility in 60, 10, 13, and 16% of patients, respectively.1 Patients with active CNS metastases, ongoing sensory or motor neuropathy (grade 2 or higher), or uncontrolled diabetes (HbA1c≥8% or HbA1c≥7% with symptoms) were excluded from the trial.1
Patients in KEYNOTE-869 were enrolled in either the dose-escalation cohort (5 patients), Cohort A (40 patients), or Cohort K (76 patients); the median follow-up time for the dose escalation cohort and Cohort A was 44.7 months, while the median follow-up time for Cohort K was 14.8 months.1 The confirmed objective response rate in the 3 cohorts combined was 68%, with a complete response rate of 12%.1 The median duration of response for the dose escalation cohort and Cohort A was 22.1 months, and the median duration of response for Cohort K was not reached.1
Monotherapy for Locally Advanced or Metastatic Urothelial Carcinoma
The efficacy and safety of pembrolizumab in the treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing therapy or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting are based principally on the results of an open-label, multicenter, randomized, phase 3 study (KEYNOTE-045).1, 20 In this study, 542 patients with locally advanced or metastatic urothelial carcinoma that had progressed following platinum-containing therapy or within 12 months following platinum-containing therapy in the neoadjuvant or adjuvant setting were randomized (stratified by ECOG performance status, presence of liver metastases, baseline hemoglobin concentration, and time elapsed since last dose of chemotherapy) in a 1:1 ratio to receive either pembrolizumab (200 mg by IV infusion) or investigator's choice of chemotherapy (paclitaxel 175 mg/m2 IV, docetaxel 75 mg/m2 IV, or vinflunine 320 mg/m2 IV [not commercially available in the US]) every 3 weeks.1, 20 Treatment was continued for up to 24 months or until the occurrence of unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, associated with a decline in performance status, requiring urgent intervention, or confirmed by repeat radiographic studies.1, 20 The primary measures of efficacy were overall survival and progression-free survival (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ); additional outcome measures were objective response rate (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ) and duration of response.1, 20
The median age of patients enrolled in the KEYNOTE-045 study was 66 years; 98% had an ECOG performance status of 0 or 1, 96% had metastatic disease, 87% had visceral metastases (including 34% with metastases to the liver), 74% were male, 72% were white, 23% were of Asian ancestry, and 21% had received at least 2 prior systemic therapies for metastatic disease.1, 20 The lower or upper urinary tract was the primary site of the tumor in 86 or 14% of patients, respectively.1, 20 Most patients (76%) had received prior therapy with cisplatin, 23% had received carboplatin, and 1% had received therapy containing other platinum agents; 15% of patients had disease progression following platinum-containing therapy in the neoadjuvant or adjuvant setting.1 Patients with active brain metastases or carcinomatous meningitis, autoimmune disease, interstitial lung disease, conditions requiring therapy with immunosuppressive agents, active infection requiring systemic therapy, a history of HIV infection, active HBV or HCV infection, or at least one poor prognostic factor for second-line therapy (i.e., hemoglobin concentration less than 10 g/dL, liver metastases, last dose of chemotherapy less than 3 months prior to enrollment) were excluded from the study.1, 20
In the KEYNOTE-045 study, median overall survival was prolonged in patients receiving pembrolizumab compared with those receiving chemotherapy (10.3 versus 7.4 months; hazard ratio: 0.73); however, a difference in median progression-free survival was not observed between the treatment groups.1, 20 Patients receiving pembrolizumab also had higher objective response rates compared with those receiving chemotherapy (21 versus 11%); complete responses were achieved in 7 or 3% of patients receiving pembrolizumab or chemotherapy, respectively.1, 20 Median duration of response had not been reached in patients receiving pembrolizumab.1, 20 The median follow-up period at the time of the analysis was 9 months.1 Results of a subgroup analysis (based on age, sex, ECOG performance status, smoking status, histology, PD-L1 expression, site of primary tumor, site of metastases, presence of liver metastases, baseline hemoglobin concentration, number of risk factors, setting of most recent therapy, time elapsed since most recent therapy, previous platinum therapy, and investigator's choice of chemotherapy) suggested that the effect of pembrolizumab on overall survival was consistent across all subgroups; however, an overall survival benefit for the drug compared with chemotherapy was not apparent in the subgroup of patients who had never smoked (hazard ratio: 1.06).20
Patients in KEYNOTE-045 were followed for up to 5 years; at a median follow-up of 62.9 months, median overall survival was 10.1 months with pembrolizumab and 7.2 months with chemotherapy.203 Overall survival rates at 48 months were 16.7 and 10.1% for pembrolizumab and chemotherapy, respectively, while progression-free survival rates were 9.5 and 2.7%, respectively.203 The median duration of response was 29.7 months for pembrolizumab and 4.4 months for chemotherapy.203
The efficacy and safety of pembrolizumab in the treatment of locally advanced or metastatic urothelial carcinoma in patients who are not candidates for cisplatin-containing therapy are based principally on the results of an open-label, multicenter, noncomparative, phase 2 study (KEYNOTE-052).1, 19 In this study, 370 patients with locally advanced or metastatic urothelial carcinoma who were not candidates for cisplatin-containing therapy received pembrolizumab 200 mg by IV infusion every 3 weeks.1, 19 Treatment was continued for up to 24 months or until the occurrence of unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, associated with a decline in performance status, requiring urgent intervention, or confirmed by repeat radiographic studies.1, 19 The primary measures of efficacy were objective response rate (as evaluated by an independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ) and duration of response.1, 19
The median age of patients enrolled in the KEYNOTE-052 study was 74 years; 89% were white, 87% had metastatic disease, 85% had visceral metastases (including 21% with metastases to the liver), and 77% were male.1, 19 The lower or upper urinary tract was the primary site of the tumor in 81 or 19% of patients, respectively.1, 19 Most patients (90%) were treatment-naive and 10% had received platinum-containing therapy in the neoadjuvant or adjuvant setting.1, 19 Reasons for cisplatin ineligibility included baseline renal impairment (creatinine clearance <60 mL/minute), poor performance status (ECOG performance status of 2), poor performance status and baseline renal impairment, or other reasons (i.e., New York Heart Association [NYHA] class III heart failure, peripheral neuropathy or hearing loss of grade 2 or greater severity) in 50, 32, 9, or 9% of patients, respectively.1, 19 Patients with active brain metastases and/or carcinomatous meningitis, autoimmune disease, interstitial lung disease, conditions requiring therapy with immunosuppressive agents, active infection requiring systemic therapy, a history of HIV infection, or active HBV or HCV infection were excluded from the study.1, 19
In the KEYNOTE-052 study, the objective response rate was 29%; complete response was achieved in 10% of patients.1 At a median follow-up of 11.4 months, median duration of response was 33.4 months.1 Patients in KEYNOTE-052 were followed for up to 5 years; at a median follow-up of 56.3 months, median overall survival was 11.3 months.203 The overall survival rate at 48 months was 19%, and the progression-free survival rate was 10.3%.203 The median duration of response was 33.4 months.203
Monotherapy for BCG-unresponsive, High-risk NMIBC
The efficacy and safety of pembrolizumab for the treatment of BCG-unresponsive, high-risk NMIBC is based principally on the results of a phase 2, open-label, single-arm trial (KEYNOTE-057).1, 204 The KEYNOTE-057 trial enrolled 96 patients with BCG-unresponsive, high-risk NMIBC with CIS (with or without papillary tumors) who were ineligible for or had elected not to undergo cystectomy; BCG-unresponsive, high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG.1 Prior to treatment, all patients underwent transurethral resection of bladder tumor (TURBT) to remove all resectable disease; residual CIS not amenable to complete resection was allowed.1, 204 All patients received pembrolizumab 200 mg IV every 3 weeks for up to 24 months or until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease occurred.1, 204 The major efficacy outcomes were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography imaging) and duration of response.1
The median age of patients enrolled in KEYNOTE-057 was 73 years; 84% were male, and 67% were white.1, 204 Baseline ECOG performance status was 0 or 1 in 73 and 27% of patients, respectively.1, 204 Tumor pattern at study entry was CIS with T1, CIS with high grade Ta, or CIS in 12, 25, and 63% of patients, respectively.204 Baseline high-risk NMIBC disease status was persistent in 27% of patients and recurrent in 73% of patients.1 The median number of prior BCG instillations was 12.1 Patients with muscle-invasive locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extravesical non-muscle invasive transitional cell carcinoma of the urothelium, autoimmune disease, or a medical condition requiring immunosuppression were excluded from the trial.1
In the KEYNOTE-057 study, the complete response rate was 41%.1, 204 At a median follow-up of 28 months, median duration of response was 16.2 months.1
The randomized, open-label, multicenter KEYNOTE-361 study examined the efficacy of pembrolizumab in platinum-eligible patients with previously untreated, locally advanced or metastatic urothelial carcinoma;1, 205 pembrolizumab in combination with platinum-based chemotherapy is not currently FDA-labeled for use in such patients.1 In this trial, patients were randomized to receive pembrolizumab monotherapy, pembrolizumab in combination with platinum-based therapy (cisplatin or carboplatin in combination with gemcitabine), or platinum-based therapy alone.1, 205 The study did not meet its major efficacy outcome of improved progression-free survival or overall survival in the pembrolizumab plus chemotherapy arm compared to the chemotherapy alone arm.1, 205 Additional efficacy endpoints, including overall survival in the pembrolizumab monotherapy arm, could not be formally tested.1, 205
Microsatellite Instability-high or Mismatch Repair Deficient Cancer
Pembrolizumab is used for the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior therapy in adult and pediatric patients who are not candidates for other satisfactory treatment options.1
The current indication for pembrolizumab in the treatment of unresectable or metastatic MSI-H or dMMR solid tumors is based principally on pooled results for 504 patients with MSI-H or dMMR solid tumors across 3 open-label, multicenter, noncomparative trials (KEYNOTE-164, KEYNOTE-158, and KEYNOTE-051).1, 206, 207, 208 KEYNOTE-164 enrolled 124 patients with advanced MSI-H or dMMR colorectal cancer that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan (with or without monoclonal antibody therapy targeting vascular endothelial growth factor [VEGF] or epidermal growth factor receptor [EGFR]).1, 206 KEYNOTE-158 enrolled 373 patients with advanced MSI-H or dMMR non-colorectal cancers who had disease progression following prior therapy.1, 208 KEYNOTE-051 enrolled 7 pediatric patients with MSI-H or dMMR cancers.1 In these trials, adult patients received pembrolizumab 200 mg IV every 3 weeks and pediatric patients received pembrolizumab 2 mg/kg IV every 3 weeks; treatment was continued for up to 24 months or until the occurrence of unacceptable toxicity or disease progression.1 The primary measures of efficacy were objective response rate and duration of response; outcomes were evaluated by a blinded independent central review committee according to RECIST (modified to follow no more than 10 target lesions and no more than 5 target lesions per organ in KEYNOTE-158), or by the investigator according to RECIST in KEYNOTE-051.1
The median age of patients in KEYNOTE-164 and KEYNOTE-158 was 60 years; 92% had metastatic disease, 78% were white, 14% were Asian, 4% were American Indian or Alaska Native, and 3% were Black.1 The majority of patients (61%) had received 2 or more prior lines of therapy.1 The median age of patients in KEYNOTE-051 was 11 years; 71% of patients had stage IV disease, 86% were white, and 14% were Asian.1 The majority of patients (57%) had received 1 prior line of therapy; 29% had received 2 prior lines of therapy.1 Patients with active autoimmune disease or conditions requiring therapy with immunosuppressive agents were excluded from all 3 trials.1
In the pooled cohort of patients with MSI-H or dMMR solid tumors, the objective response rate was 33.3%; complete response was achieved in 10.3% of patients.1 At a median follow-up time of 20.1 months, the median duration of response was 63.2 months, with 77% demonstrating a ≥12-month duration of response and 39% demonstrating a ≥36-month duration of response.1 Objective response rates were similar for patients with colorectal cancer (34%) and non-colorectal cancer (33%).1
Microsatellite Instability-high or Mismatch Repair Deficient Colorectal Cancer
Pembrolizumab is used for the treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer (as determined by an FDA-approved test).1
The current indication for pembrolizumab in the treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer is based principally on the results of a phase 3, multicenter, randomized, open-label trial (KEYNOTE-177).1, 209, 210, 211 KEYNOTE-177 enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR colorectal cancer.1, 209, 210 Patients were randomized in a 1:1 ratio to receive pembrolizumab 200 mg IV every 3 weeks or investigator's choice of chemotherapy given IV every 2 weeks.1, 209, 210 Chemotherapy regimens could include mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 or levoleucovorin 200 mg/m2, and fluorouracil 400 mg/m2 on day 1, then fluorouracil 2400 mg/m2 over 46-48 hours) or FOLFIRI (irinotecan 180 mg/m2, leucovorin 400 mg/m2 or levoleucovorin 200 mg/m2, and fluorouracil 400 mg/m2on day 1, then fluorouracil 2400 mg/m2 over 46-48 hours); chemotherapy regimens could be given alone or in combination with bevacizumab (5 mg/kg on day 1) or cetuximab (400 mg/m2 on first infusion, then 250 mg/m2 weekly).1, 209 Treatment was continued for up to 24 months, or until disease progression or unacceptable toxicity occurred.1 The main efficacy outcome measures were overall survival and progression-free survival (evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1 Additional measures of efficacy included objective response rate and duration of response.1
The median age of patients in the KEYNOTE-177 trial was 63 years; 50% were male, 75% were white, 16% were Asian, and 27% had received prior adjuvant or neoadjuvant chemotherapy.1 Among the patients receiving chemotherapy, 56% received mFOLFOX6 and 44% received FOLFIRI; 70% received bevacizumab in addition to mFOLFOX6 or FOLFIRI, and 11% received cetuximab in addition to mFOLFOX6 or FOLFIRI.1
In the KEYNOTE-177 trial, progression-free survival was improved with pembrolizumab compared to chemotherapy; however, overall survival was not substantially improved with pembrolizumab at the time of prespecified final analysis.1, 210 At a median follow-up time of 38.1 months, median progression-free survival was 16.5 months with pembrolizumab and 8.2 months with chemotherapy.1, 210 At the time of the prespecified final analysis, median overall survival was not reached in the pembrolizumab group and 36.7 months in the chemotherapy group.1, 210 The objective response rate was 44 and 33% in the pembrolizumab and chemotherapy groups, respectively; complete responses were achieved in 11 and 4% of patients in each group, respectively.1 Median duration of response was not reached in the pembrolizumab group and 10.6 months in the chemotherapy group; 43 and 18% of patients in the pembrolizumab and chemotherapy groups, respectively, achieved a duration of response ≥24 months.1
An exploratory 5-year analysis of data from the KEYNOTE-177 trial found that, at a median follow-up time of 73.3 months, the median overall survival was 77.5 months with pembrolizumab and 36.7 months with chemotherapy.211 Five-year overall survival rates were 54.8 and 44.2% for pembrolizumab and chemotherapy, respectively.211 Median duration of response was 75.4 months with pembrolizumab versus 10.6 months with chemotherapy.211
Pembrolizumab is used in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor type 2 (HER2)-positive gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (combined positive score ≥1) as determined by an FDA-approved test.1 The accelerated approval of pembrolizumab for this indication is based on tumor response rate and durability of response.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of pembrolizumab in confirmatory studies.1
Pembrolizumab is also used in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma.1
Pembrolizumab has been designated an orphan drug by FDA for the treatment of gastric cancer, including gastroesophageal junction adenocarcinoma.4
The current indication for pembrolizumab in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy in the treatment of advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (KEYNOTE-811).1, 212, 213 The KEYNOTE-811 trial enrolled 698 patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma who had not previously received systemic therapy for metastatic disease.1, 213 Patients were randomized (stratified by PD-L1 expression [combined positive score ≥1 or <1], chemotherapy regimen [5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin], and geographic region) in a 1:1 ratio to receive pembrolizumab 200 mg IV or placebo in conjunction with trastuzumab (8 mg/kg on first infusion and 6 mg/kg in subsequent cycles) and investigator's choice of chemotherapy.1, 212, 213 Pembrolizumab was administered prior to trastuzumab and chemotherapy on day 1 of each 3-week cycle.1 For chemotherapy, patients could receive either FP (cisplatin 80 mg/m2 for up to 6 cycles plus 5-fluorouracil 800 mg/m2 per day for 5 days) or CAPOX (oxaliplatin 130 mg/m2 for up to 6-8 cycles plus capecitabine 1000 mg/m2 twice daily for 14 days).1, 212, 213 Treatment with pembrolizumab or placebo was continued for up to 24 months, or until disease progression or unacceptable toxicity occurred.1, 212, 213 In the first interim efficacy analysis, the major outcome measures assessed were objective response rate and duration of response (evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1
Data from the first 264 patients randomized into the KEYNOTE-811 trial were included in the first interim analysis.1, 212 Among these 264 patients, the median age was 62 years; 82% were male, 63% were white, 31% were Asian, 0.8% were Black, and 97% had metastatic disease.1 The majority of patients (87%) received CAPOX as their chemotherapy regimen.1 Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition requiring immunosuppression were excluded from the trial.1
Patients receiving pembrolizumab demonstrated higher objective response rates in the first interim analysis than patients who received placebo.1, 212 Objective response rates were 74.4 and 51.9% in the pembrolizumab and placebo groups, respectively; complete responses were observed in 11.3 and 3.1% of patients in each group respectively.1, 212 The median duration of response was 10.6 months in the pembrolizumab group and 9.5 months in the placebo group.1, 212 In a prespecified subgroup analysis based on PD-L1 status, the objective response rate in patients with PD-L1-positive disease was 76% in the pembrolizumab group and 51% in the placebo group.1 In patients with PD-L1-negative disease, the objective response rates were 63 and 58% in the pembrolizumab and placebo arms, respectively.1
Subsequent interim analyses were performed in the full trial population of 698 patients.213 Among these patients, the median age was 63 years; 98% had metastatic disease, 85% had tumors with a PD-L1 combined positive score ≥1, and 85% received CAPOX as their chemotherapy regimen.213 At the time of the second interim analysis (median follow-up of 28.3 months in the pembrolizumab group and 28.5 months in the placebo group), median progression-free survival was 10 months in the pembrolizumab group and 8.1 months in the placebo group; median overall survival was 20 and 16.9 months in the pembrolizumab and placebo groups, respectively.213 At the time of the third interim analysis (median follow-up of 38.4 months in the pembrolizumab group and 38.6 months in the placebo group), median progression-free survival was 10 and 8.1 months with pembrolizumab and placebo respectively, while median overall survival was 20 and 16.8 months for pembrolizumab and placebo respectively.213 Prespecified subgroup analyses found a progression-free survival benefit for pembrolizumab over placebo among patients with a PD-L1 combined positive score ≥1, but not among patients with a PD-L1 combined positive score <1.213
The current indication for pembrolizumab in combination with fluoropyrimidine- and platinum-containing chemotherapy in the treatment of advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (KEYNOTE-859).1, 214 The KEYNOTE-859 trial enrolled 1579 patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma who had not previously received systemic therapy for metastatic disease.1, 214 Patients were randomized (stratified by PD-L1 expression [combined positive score ≥1 or <1], chemotherapy regimen [5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin], and geographic region) in a 1:1 ratio to receive pembrolizumab 200 mg IV or placebo in conjunction with investigator's choice of chemotherapy.1, 214 Pembrolizumab was administered prior to chemotherapy on day 1 of each 3-week cycle.1 For chemotherapy, patients could receive either FP (cisplatin 80 mg/m2 plus 5-fluorouracil 800 mg/m2 per day for 5 days) or CAPOX (oxaliplatin 130 mg/m2 plus capecitabine 1000 mg/m2 twice daily for 14 days); platinum agents could be administered for ≥6 cycles following local guidelines.1, 214 Treatment with pembrolizumab or placebo continued for up to 24 months, or until disease progression or unacceptable toxicity occurred.1, 214 The major efficacy outcome measure was overall survival; other efficacy outcome measures included progression-free survival, objective response rate, and duration of response (evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1, 214
The median age of patients in the KEYNOTE-859 trial was 62 years; 68% were male, 55% were white, 34% were Asian, 4.2% were American Indian or Alaskan Native, 1.3% were Black, 97% had metastatic disease, and 78% had tumors that expressed PD-L1 with a combined positive score ≥1.1 The majority of patients (86%) received CAPOX as their chemotherapy regimen.1 Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition requiring immunosuppression were excluded from the trial.1
In a prespecified interim analysis of the KEYNOTE-859 trial, pembrolizumab improved overall survival, progression-free survival, and objective response rate compared to placebo.1 Median overall survival was 12.9 months with pembrolizumab and 11.5 months with placebo; median progression-free survival was 6.9 months with pembrolizumab and 5.6 months with placebo.1, 214 The objective response rate was 51 and 42% for pembrolizumab and placebo, respectively.1 Complete responses were observed in 9 and 6% of patients in the pembrolizumab and placebo groups, respectively.1, 214 The median duration of response was 8 months in the pembrolizumab group and 5.7 months in the placebo group.1, 214 In an exploratory subgroup analysis of patients with PD-L1 combined positive score <1, the median overall survival was 12.7 months with pembrolizumab and 12.2 months with placebo.1
Pembrolizumab is used for the treatment of locally advanced or metastatic esophageal carcinoma or gastroesophageal junction carcinoma (tumors with epicenter 1-5 cm above the gastroesophageal junction) that is not amenable to surgical resection or definitive chemoradiation.1 Pembrolizumab may be used in combination with platinum- and fluoropyrimidine-based chemotherapy or as a single agent after 1 or more prior lines of systemic therapy in patients with tumors of squamous cell histology that express PD-L1 (combined positive score ≥10) as determined by an FDA-approved test.1 Pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.4
Combination Therapy for First-line Treatment
The current indication for pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy for the treatment of locally advanced or metastatic esophageal or gastroesophageal junction carcinoma is based principally on the results of a multicenter, randomized, placebo-controlled, phase 3 study (KEYNOTE-590).1, 215 The KEYNOTE-590 study enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction carcinoma who were not candidates for surgical resection or definitive chemoradiation; patients with gastroesophageal junction carcinoma had tumors with an epicenter 1-5 cm above the gastroesophageal junction.1, 215 Patients were ineligible for enrollment if they had received prior systemic therapy in the locally advanced or metastatic setting.1, 215 Patients were randomized (stratified by tumor histology, geographic region, and ECOG performance status) in a 1:1 ratio to receive pembrolizumab 200 mg IV or placebo on day 1 of each 3-week cycle.1, 215 Pembrolizumab or placebo was given in conjunction with cisplatin 80 mg/m2 IV on day 1 of each 3-week cycle for up to 6 cycles and 5-fluorouracil 800 mg/m2 IV daily on days 1-5 of each 3-week cycle.1, 215 Treatment continued for 24 months or until unacceptable toxicity or disease progression occurred.1 The major efficacy outcomes were overall survival and progression-free survival (evaluated by the investigator according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ); additional efficacy outcome measures included objective response rate and duration of response, as evaluated by the investigator according to modified RECIST.1, 215
The median age of patients in the KEYNOTE-590 study was 63 years; 83% were male, 37% were white, 53% were Asian, 1% were Black, 91% had metastatic disease, 73% had a tumor histology of squamous cell carcinoma, and 27% had a tumor histology of adenocarcinoma.1 Patients with active autoimmune disease or a medical condition requiring immunosuppression were excluded from the study.1
In the KEYNOTE-590 study, pembrolizumab plus chemotherapy substantially improved overall survival and progression-free survival compared to placebo plus chemotherapy.1, 215 Median overall survival was 12.4 months in the pembrolizumab group and 9.8 months in the placebo group.1, 215 Median progression-free survival was 6.3 and 5.8 months in the pembrolizumab and placebo groups, respectively.1, 215 The objective response rates in the pembrolizumab and placebo groups were 45 and 29%, respectively, with 6 and 2.4% of patients achieving a complete response.1 The median duration of response was 8.3 months with pembrolizumab and 6 months with placebo.1, 215 In a pre-specified subgroup analysis of 383 patients with a PD-L1 combined positive score ≥10, median overall survival was 13.5 months with pembrolizumab and 9.4 months with placebo.1, 215 In an exploratory analysis of 347 patients with a PD-L1 combined positive score <10, median overall survival was 10.5 months with pembrolizumab and 10.6 months with placebo.1, 215
Monotherapy for Treatment of Recurrent Disease
The current indication for pembrolizumab as a single agent for the treatment of recurrent locally advanced or metastatic esophageal or gastroesophageal junction carcinoma is based principally on the results of a multicenter, randomized, open-label, phase 3 trial (KEYNOTE-181).1, 216 The KEYNOTE-181 trial enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who had progressed on or after 1 prior line of systemic treatment for advanced disease.1, 216 Patients with HER2-positive esophageal cancer were required to have received treatment with approved HER2-targeted therapy.1 Patients were randomized (stratified by tumor histology and geographic region) in a 1:1 ratio to receive pembrolizumab 200 mg IV every 3 weeks or investigator's choice of chemotherapy (paclitaxel 80-100 mg/m2 on days 1, 8, and 15 of every 4-week cycle; docetaxel 75 mg/m2 every 3 weeks; or irinotecan 180 mg/m2 every 2 weeks).1, 216 Treatment was continued for up to 24 months or until unacceptable toxicity or disease progression occurred.1, 216 The major efficacy outcome measure was overall survival, evaluated in the following co-primary populations: patients with esophageal squamous cell carcinoma, patients with tumors expressing PD-L1 with a combined positive score ≥10, and all randomized patients.1, 216 Other efficacy outcome measures included progression-free survival, objective response rate, and duration of response (evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1
Of the 628 patients enrolled in KEYNOTE-181, 167 patients had esophageal squamous cell carcinoma that expressed PD-L1 with a combined positive score ≥10.1, 216 The median age of these 167 patients was 65 years; 84% were male, 32% were white, 68% were Asian, and 90% had metastatic disease.1 Prior to enrollment, 99% of patients had received platinum-based treatment and 84% had also received treatment with a fluoropyrimidine; 33% had received prior therapy with a taxane.1 Patients with a history of noninfectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition requiring immunosuppression were excluded from the study.1
In the KEYNOTE-181 trial, an overall survival benefit with pembrolizumab was observed in patients with esophageal squamous cell carcinoma whose tumors expressed PD-L1 (combined positive score ≥10).1, 216 Among these patients, the median overall survival was 10.3 months with pembrolizumab versus 6.7 months with chemotherapy.1, 216 Progression-free survival was 3.2 months with pembrolizumab and 2.3 months with chemotherapy.1 The objective response rate was 22 and 7% in the pembrolizumab and chemotherapy arms, respectively, with 5 and 1% of patients achieving a complete response.1 Median duration of response was 9.3 months in the pembrolizumab group and 7.7 months in the chemotherapy group.1
An additional multicenter, non-randomized, open-label, phase 2 trial (KEYNOTE-180) examined the efficacy of pembrolizumab in 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease.1, 217 All patients received pembrolizumab, using the same dosage regimen as KEYNOTE-181.1, 217 The major efficacy outcome measures were objective response rate and duration of response (evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1
Among the 121 patients enrolled in KEYNOTE-180, 35 patients had esophageal squamous cell carcinoma that expressed PD-L1 (combined positive score ≥10).1 Among these 35 patients, the median age was 65 years; 71% were male, 26% were white, 69% were Asian, and all had metastatic disease.1 The objective response rate among these patients was 20%, with a duration of response ranging from 4.2 to 25.1+ months.1
Pembrolizumab is used in combination with chemoradiotherapy for the treatment of patients with International Federation of Gynecology and Obstetrics (FIGO) stage III-IVA cervical cancer.1
Pembrolizumab is also used in combination with chemotherapy (with or without bevacizumab) for the treatment of persistent, recurrent, or metastatic cervical cancer in patients whose tumors express PD-L1 (combined positive score ≥1) as determined by an FDA-approved test.1
Pembrolizumab is used as a single agent for the treatment of recurrent or metastatic cervical cancer that has progressed during or following chemotherapy in patients whose tumors express PD-L1 (combined positive score ≥1) as determined by an FDA-approved test.1
Combination with Chemoradiotherapy for FIGO Stage III-IVA Cervical Cancer
The current indication for pembrolizumab in combination with chemoradiotherapy for the treatment of FIGO stage III-IVA cervical cancer is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (KEYNOTE-A18).1, 218, 219 The KEYNOTE-A18 trial enrolled 1060 patients with cervical cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer.1, 218 Patients were randomized (stratified by planned type of external beam radiation therapy, stage of cervical cancer at screening, and planned total radiotherapy dose) in a 1:1 ratio to receive pembrolizumab or placebo, both in conjunction with chemoradiotherapy.1, 218 Patients assigned to the pembrolizumab group received pembrolizumab 200 mg IV every 3 weeks for 5 cycles in conjunction with radiotherapy (external beam radiation therapy followed by brachytherapy) and cisplatin 40 mg/m2 IV weekly (5 cycles with an optional sixth infusion depending on local practice); this was followed by pembrolizumab 400 mg IV every 6 weeks for 15 cycles.1, 218 Patients assigned to the placebo group received the same regimen with placebo infusions administered in place of pembrolizumab infusions.1, 218 Treatment was continued until disease progression or unacceptable toxicity.1, 218 The major efficacy outcomes were overall survival and progression-free survival (as confirmed by histopathology or as evaluated by the investigator according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1
Among the patients enrolled in KEYNOTE-A18, 596 patients had FIGO stage III-IVA disease.1 The median age of these patients was 52 years; 36% were white, 34% were Asian, 1% were Black, 38% were Hispanic or Latino, 93% had a combined positive score ≥1, 83% had squamous cell carcinoma, and 70% had positive pelvic and/or para-aortic lymph nodes.1 For external beam radiation therapy, most patients (85%) received intensity-modulated radiation therapy or volumetric modulated arc therapy.1 An additional 462 patients with FIGO stage IB2-IIB disease and 2 patients with FIGO stage IVB disease were also enrolled in KEYNOTE-A18.1
The KEYNOTE-A18 trial found substantial improvements in progression-free survival with pembrolizumab compared to placebo in the overall trial population.1 However, in an exploratory subgroup analysis, progression-free survival was not substantially improved in patients with FIGO stage IB2-IIB disease, indicating that the improvement observed in the overall trial population was primarily attributable to improvements in the subgroup of patients with FIGO stage III-IVA disease.1 Among patients with FIGO stage III-IVA disease, the 12-month progression-free survival rate was 81% in patients who received pembrolizumab and 70% among patients who received placebo; median progression-free survival was not reached at the time of analysis for either group.1 Overall survival data were not mature at the time of the progression-free survival analysis.1
Combination with Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer
The current indication for pembrolizumab in combination with chemotherapy for the treatment of persistent, recurrent, or metastatic cervical cancer is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (KEYNOTE-826).1, 220, 221 The KEYNOTE-826 trial enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent.1, 220 Patients were randomized (stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab, and PD-L1 status) in a 1:1 ratio to receive pembrolizumab 200 mg IV or placebo in conjunction with investigator's choice of chemotherapy.1, 220 Options for chemotherapy included the following: paclitaxel 175 mg/m2 plus cisplatin 50 mg/m2; paclitaxel 175 mg/m2 and cisplatin 50 mg/m2plus bevacizumab 15 mg/kg; paclitaxel 175 mg/m2 plus carboplatin AUC 5 mg/mL per minute; or paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL per minute plus bevacizumab 15 mg/kg.1, 220 All medications were administered IV on day 1 of each 3-week treatment cycle; cisplatin could be administered on day 2 of each 3-week treatment cycle.1 Treatment with pembrolizumab continued for 24 months or until disease progression or unacceptable toxicity.1 Pembrolizumab could be continued after disease progression if the patient was clinically stable and continued to derive benefit from the medication (as assessed by the investigator).1 The major efficacy outcomes were overall survival and progression-free survival (as evaluated by the investigator according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1 Additional efficacy outcome measures included objective response rate and duration of response (as evaluated by the investigator according to RECIST).1
Among the 617 patients enrolled in KEYNOTE-826, 548 patients had tumors that expressed PD-L1 with a combined positive score ≥1.1, 220 Among these patients, the median age was 51 years; 59% were white, 18% were Asian, 6% were American Indian or Alaska Native, 1% were Black, and 37% were Hispanic or Latino.1 Most patients (75%) had squamous cell carcinoma, and 32% had metastatic disease at diagnosis.1 At study entry, 21% of patients had metastatic disease only and 79% of patients had persistent or recurrent disease with or without distant metastases; of the patients with persistent or recurrent disease, 39% had received prior chemoradiation only and 17% had received prior chemoradiation plus surgery.1 Bevacizumab was administered to 63% of patients during the study.1 Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition requiring immunosuppression were excluded from the trial.1
In KEYNOTE-826, pembrolizumab substantially improved overall survival and progression-free survival compared with placebo.1, 220 Among the patients with tumors that expressed PD-L1 (combined positive score ≥1), median overall survival at the time of interim analysis was not reached with pembrolizumab and was 16.3 months with placebo;1, 220 a final analysis of overall survival found a median overall survival of 28.6 months among patients who received pembrolizumab and 16.5 months among patients who received placebo.1, 221 Median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group.1, 220 Objective response rates were 68.1 and 50.2% for patients receiving pembrolizumab and placebo, respectively, with complete response rates of 22.7 and 13.1%.1, 220 The median duration of response was 18 months for patients receiving pembrolizumab and 10.4 months for patients receiving placebo.1, 220
Monotherapy for Previously Treated Recurrent or Metastatic Cervical Cancer
The current indication for pembrolizumab in the treatment of recurrent or metastatic cervical cancer is based principally on the results for a subset of 77 patients with PD-L1-positive cervical cancer (part of a cohort of 98 patients with cervical cancer) in an open-label, multicenter, nonrandomized, phase 2 study (KEYNOTE-158).1, 222 These 77 patients had a PD-L1 combined positive score ≥1 as detected by an immunohistochemistry assay (PD-L1 IHC 22C3 pharmDx) and had received at least one prior chemotherapy regimen in the metastatic setting.1, 222 Patients received pembrolizumab 200 mg administered as an IV infusion every 3 weeks.1, 222 Treatment was continued for up to 24 months or until unacceptable toxicity or disease progression occurred; however, patients with disease progression could receive additional doses of the drug until disease progression was confirmed, unless disease progression was symptomatic, rapidly progressive, associated with a decline in performance status, or requiring urgent intervention.1
The median age of the 77 patients in the KEYNOTE-158 study with PD-L1-positive cervical cancer was 45 years; 81% were white, 14% were Asian, 3% were Black, 92% had squamous cell carcinoma, 6% had adenocarcinoma, and 1% had adenosquamous histology.1 Of these 77 patients, 95% had metastatic disease and 65% had received at least 2 prior therapies for recurrent or metastatic disease.1 All of the patients had an ECOG performance status of 0 or 1.1 The study excluded patients with autoimmune disease or conditions requiring therapy with immunosuppressive agents.1
At a median follow-up of 11.7 months, the objective response rate in the KEYNOTE-158 study for patients with PD-L1-positive cervical cancer who had received at least one prior chemotherapy regimen for metastatic disease was 14.3%; complete response was achieved in 2.6% of patients.1, 222 At the time of analysis, the median duration of response had not been reached; however, 90.9% of patients who responded to pembrolizumab had durable responses of 6 months or more.1, 222 Objective responses were not observed in patients with a PD-L1 combined positive score <1.1, 222
Pembrolizumab is used for the treatment of hepatocellular carcinoma secondary to hepatitis B in patients who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen;1 pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.4
The current indication for pembrolizumab in the treatment of previously treated hepatocellular carcinoma is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled, phase 3 study conducted in Asia (KEYNOTE-394).1, 223 The KEYNOTE-394 trial enrolled 453 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma and Child-Pugh class A liver function who were previously treated with sorafenib or oxaliplatin-based chemotherapy and not amenable to or refractory to local-regional therapy.1, 223 Patients with hepatitis B were required to have a viral load <2000 IU/mL or <104 copies/mL.1 Patients were excluded from the trial if they had hepatic encephalopathy, main branch portal venous invasion, clinically apparent ascites, esophageal or gastric variceal bleeding within the preceding 6 months, autoimmune disease requiring systemic therapy within 2 years of treatment, or any medical condition requiring immunosuppression.1 Patients enrolled in KEYNOTE-394 were randomized (stratified by prior treatment, macrovascular invasion, and etiology) in a 2:1 ratio to receive pembrolizumab 200 mg IV every 3 weeks or placebo.1, 223 Treatment continued for 24 months, or until disease progression or unacceptable toxicity occurred.1 The major efficacy outcome was overall survival; other efficacy outcomes included progression-free survival, objective response rate, and duration of response (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1
The KEYNOTE-394 trial enrolled a total of 453 patients; 360 patients had active hepatitis B infections.1, 223 Among the patients with hepatitis B, the median age was 52 years; 86% were male, all patients were Asian, 90% had received prior sorafenib therapy, and 10% had received prior oxaliplatin-based chemotherapy.1 Most patients (93%) had BCLC stage C disease; 77% had extrahepatic disease, and 10% had macrovascular invasion.1
In KEYNOTE-394, pembrolizumab improved overall survival compared to placebo in patients with hepatocellular carcinoma secondary to hepatitis B.1 Median overall survival in this patient population at the time of prespecified final analysis was 13.9 months with pembrolizumab and 13 months with placebo.1 Median progression-free survival at the time of prespecified interim analysis was 2 months with pembrolizumab and 2.3 months with placebo.1 Objective response rates were 11 and 1.6% in the pembrolizumab and placebo groups, respectively, with only 0.9 and 0.8% of patients achieving complete response, respectively.1 Median duration of response was 23.9 months with pembrolizumab and 5.6 months with placebo.1
Pembrolizumab is used in combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer;1 pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.4
The current indication for pembrolizumab in combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled trial (KEYNOTE-966) in 1069 patients with locally advanced unresectable or metastatic biliary tract cancer who had not received prior systemic therapy in the setting of advanced disease.1, 67 The study excluded patients with autoimmune disease who required systemic therapy within 2 years of treatment or any condition requiring immunosuppressive therapy.1, 67 Patients were randomized (stratified by geographic region, site of origin, and presence of metastases) in a 1:1 ratio to receive pembrolizumab 200 mg IV or placebo on day 1 of each 3-week cycle for a maximum of 35 cycles (about 24 months).1, 67 Pembrolizumab or placebo was given in conjunction with IV gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on day 1 and day 8 of each 3-week cycle.1, 67 Treatment with cisplatin could be administered for a maximum of 8 cycles; treatment with gemcitabine could be continued beyond 8 cycles.1, 67 Treatment was continued until unacceptable toxicity or disease progression occurred.1, 67 The major efficacy outcome was overall survival; additional efficacy outcome measures included progression-free survival, objective response rate, and duration of response, as evaluated by the investigator according to modified RECIST.1, 67
The median age of patients in the KEYNOTE-966 study was 64 years; 52% were male, 49% were white, 46% were Asian, 1.3% were Black or African American, and all patients had an ECOG performance status of 0 or 1.1 At baseline, 31 and 3% of patients had a history of hepatitis B and C infection, respectively.1
In the KEYNOTE-966 study, pembrolizumab plus chemotherapy substantially improved overall survival compared to placebo plus chemotherapy.1, 67 Median overall survival was 12.7 months in the pembrolizumab group and 10.9 months in the placebo group.1, 67 Median progression-free survival was 6.5 and 5.6 months in the pembrolizumab and placebo groups, respectively.1, 67 The objective response rates in the pembrolizumab and placebo groups were 29 and 29%, respectively, with 2.1 and 1.3% of patients achieving a complete response.1 The median duration of response was 8.3 months with pembrolizumab and 6.8 months with placebo.1
Pembrolizumab is used for the treatment of adults and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma;1 pembrolizumab has been designated an orphan drug by FDA for the treatment of this cancer.4
The current indication for pembrolizumab in the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma is based principally on the results of 2 noncomparative, nonrandomized studies (KEYNOTE-017 and KEYNOTE-913) in 105 patients with recurrent locally advanced or metastatic Merkel cell carcinoma who had not received prior systemic therapy for advanced disease.1, 41 The primary measures of efficacy were objective response rate (as evaluated by a blinded independent central review committee according to RECIST) and duration of response.1 The studies excluded patients with active autoimmune disease or any condition requiring immunosuppressive therapy.1 The median age of patients enrolled in these studies was 73 years (79% were 65 years of age or older); 62% were male and 80% were white.1 All patients had an ECOG performance status of 0 or 1.1 Most patients (84%) had stage IV disease; 13% had stage IIIB disease.1 Prior therapies included surgery or radiation therapy in 76 or 51% of patients, respectively.1
In KEYNOTE-017, 50 patients received pembrolizumab 2 mg/kg administered as an IV infusion every 3 weeks for up to 24 months or until the occurrence of unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, associated with a decline in performance status, requiring urgent intervention, or confirmed in at least 4 weeks with repeat radiographic studies.1, 41 At a median follow-up of 14.9 months, the objective response rate was 56%; complete response was achieved in 24% of patients.1, 41 The median duration of response had not been reached at the time of analysis;1, 41 however, 96% of patients who responded to the drug had durable responses of 6 months or more and 54% had durable responses of 12 months or more.1 In a later analysis conducted at a median follow-up of 31.8 months, the objective response rate was 58%, with complete responses achieved in 30% of patients.65 The median duration of response was not reached at 3 years.65
In KEYNOTE-913, 55 patients received pembrolizumab 200 mg (or 2 mg/kg up to a maximum of 200 mg in pediatric patients) administered as an IV infusion every 3 weeks for up to 35 cycles (about 2 years) or until unacceptable toxicity or disease progression occurred or the investigator decided to stop treatment.1, 66 At a median follow-up of 50.3 months, the objective response rate was 49%; complete response was achieved in 22% of patients.66 At the time of data cutoff, the median duration of response was 39.8 months, the median progression-free survival was 9.3 months, and the median overall survival was 24.3 months.66
Pembrolizumab is used in combination with axitinib or lenvatinib for the first-line treatment of adults with advanced renal cell carcinoma.1
Pembrolizumab is also used as adjuvant treatment for patients with renal cell carcinoma who are at an intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.1
Combination Therapy with Axitinib
The current indication for pembrolizumab in combination with axitinib for the treatment of advanced renal cell carcinoma is based principally on the results of an open-label, randomized, controlled trial (KEYNOTE-426) in 861 patients who had not received systemic therapy for advanced renal cell carcinoma.1, 68 Patients were enrolled regardless of PD-L1 tumor expression status.1 Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were excluded.1 Patients were randomized to receive pembrolizumab in combination with axitinib or sunitinib monotherapy.1 Axitinib and sunitinib were continued until disease progression or unacceptable toxicity occurred.1 Pembrolizumab was continued for up to 24 months or until disease progression or unacceptable toxicity occurred.1 Patients randomized to axitinib received a dosage of 5 mg orally twice daily in combination with pembrolizumab 200 mg IV every 3 weeks; the dosage of axitinib was increased to 7 mg twice daily, followed by an increase to 10 mg twice daily if the initial 5-mg dosage was tolerated for 2 consecutive cycles.1 Patients randomized to sunitinib received a dosage of 50 mg orally once daily for 4 consecutive weeks followed by 2 weeks without therapy.1 The median age of patients enrolled in the study was 62 years; 73% were male, 79% were white, 20% were Asian, and 80% of patients had a baseline Karnofsky performance status of 90-100.1 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group status was favorable, intermediate, or poor in 31, 56, or 13% of patients, respectively.1
The primary measures of efficacy were overall survival and progression-free survival.1 At a median follow-up duration of 12.8 months, overall survival was substantially prolonged in patients treated with pembrolizumab in combination with axitinib compared with those treated with sunitinib.1 An updated analysis was conducted at the time of 418 observed deaths; patients treated with pembrolizumab in combination with axitinib were reported to have an overall survival of 45.7 months compared with 40.1 months in those treated with sunitinib.1 Median progression-free survival was prolonged (15.1 versus 11 months) and objective response rate was higher (59 versus 36%) in patients treated with pembrolizumab in combination with axitinib compared with those treated with sunitinib.1 Consistent results were observed across prespecified subgroups, IMDC risk categories, and PD-L1 tumor expression status.1
Long-term follow-up of the KEYNOTE-426 study demonstrated continued clinical benefit in patients treated with pembrolizumab in combination with axitinib compared with those treated with sunitinib.69 At a median duration of follow-up of 30.6 months, median progression-free survival was 15.4 or 11.1 months in patients treated with pembrolizumab in combination with axitinib compared with those treated with sunitinib; at the time of analysis, median overall survival had not been reached in patients treated with pembrolizumab in combination with axitinib.69
Combination Therapy with Lenvatinib
The current indication for pembrolizumab in combination with lenvatinib for the treatment of advanced renal cell carcinoma is based principally on the results of the multicenter, open-label, randomized, phase 3 KEYNOTE-581 trial (also referred to as CLEAR).1, 70 Patients enrolled in the study were adults with treatment-naive advanced renal cell carcinoma with clear-cell histology and at least one measurable lesion.70 Patients were enrolled regardless of PD-L1 tumor expression; however, patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.1 In this study, 1069 patients were randomized in a 1:1:1 ratio (stratified by geographic region and prognostic risk group) to receive lenvatinib 20 mg orally once daily on days 1-21 and pembrolizumab 200 mg IV on day 1 of each 21-day cycle, lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily of each 21-day cycle, or sunitinib 50 mg orally once daily for 4 consecutive weeks followed by a 2-week period without treatment.1, 70 Treatment was continued until disease progression or unacceptable toxicity occurred; however, clinically stable patients with disease progression receiving pembrolizumab in combination with lenvatinib could continue treatment if they were considered to be deriving clinical benefit.1 The maximum duration of therapy for pembrolizumab was 24 months; however, lenvatinib therapy could continue beyond 24 months.1 The primary endpoint of the trial was progression-free survival (as determined by an independent review committee); overall survival and objective response rate were key secondary endpoints.1, 70 All of these endpoints were evaluated by an independent review committee.1, 70
The median age of patients enrolled in the study was 62 years; 75% were male, 74% were white, 21% were Asian, 1% were Black, and 82% had a baseline Karnofsky performance status score of 90 to 100.1 Memorial Sloan Kettering Cancer Center (MSKCC) risk categories were favorable, intermediate, and poor risk in 27, 64, and 9% of patients, respectively.1 Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).1 At the protocol-specified interim analysis, median progression-free survival was substantially longer in patients receiving pembrolizumab in combination with lenvatinib (23.9 months) and those receiving lenvatinib in combination with everolimus (14.7 months) compared with those receiving sunitinib alone (9.2 months).1, 70 Results of a subgroup analysis (based on age, sex, geographic region, MSKCC prognostic risk group, IMDC risk group, baseline Karnofsky performance status score, number of organs with metastases, and PD-L1 combined positive score) suggested that the effect of pembrolizumab on progression-free survival was evident across all subgroups.70 Median overall survival had not been reached at the time of interim analysis; however, the risk of death was decreased by 34% in patients receiving pembrolizumab in combination with lenvatinib compared with those receiving sunitinib.1, 70 Overall survival was not substantially longer in patients receiving lenvatinib in combination with everolimus compared with those receiving sunitinib.1, 70 Objective response was observed in 71, 53.5, or 36.1% of patients receiving pembrolizumab in combination with lenvatinib, lenvatinib in combination with everolimus, or sunitinib alone, respectively.1, 70
A final overall survival analysis was performed after approximately 304 deaths had been observed.1, 71 The median follow-up at the time of final overall survival analysis was 49.8 months in the pembrolizumab plus lenvatinib group and 49.4 months in the sunitinib group.71 Median overall survival was 53.7 months in the pembrolizumab plus lenvatinib group and 54.3 months in the sunitinib group (hazard ratio 0.79).1, 71
In a separate multicenter, single-arm, phase 2 study (KEYNOTE-B61), 160 adults with treatment-naïve advanced renal cell carcinoma with non-clear-cell histology were treated with IV pembrolizumab 400 mg every 6 weeks in combination with oral lenvatinib 20 mg once daily.1, 72 Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.1, 72 Treatment was continued until disease progression or unacceptable toxicity occurred; however, patients with disease progression could continue treatment if they were considered to be deriving clinical benefit.1, 72 The maximum duration of therapy for pembrolizumab was 24 months; lenvatinib therapy could continue beyond 24 months.1, 72 The primary endpoint of KEYNOTE-B61 was objective response rate (as evaluated by a blinded independent central review committee according to RECIST); duration of response was also evaluated as a secondary endpoint.1, 72
The median age of patients enrolled in the study was 60 years; 71% were male, 86% were white, 8% were Asian, 3% were Black, and 78% had a baseline Karnofsky performance status score of 90-100.1 IMDC risk categories were favorable, intermediate, and poor risk in 35, 54, and 10% of patients, respectively.1 Common sites of metastases in patients were lymph node (65%), lung (35%), bone (30%), and liver (21%).1 At the time of data analysis, the objective response rate was 51%; complete response was achieved in 8% of patients.1 The median duration of response was 19.5 months.1
Adjuvant Treatment of Renal Cell Carcinoma
The current indication for pembrolizumab as adjuvant therapy for renal cell carcinoma is based principally on the results of a phase 3 randomized, double-blind, placebo-controlled study (KEYNOTE-564) of 994 adults with renal cell carcinoma with a clear-cell component and a high risk of disease recurrence (defined as tumor stage 2 with nuclear grade 4 or sarcomatoid differentiation; tumor stage 3 or higher; regional lymph node metastasis; or stage M1 with no evidence of disease [NED]).1, 73 Eligible patients were required to have undergone a partial nephroprotective or radical complete nephrectomy with negative surgical margins within ≥4 weeks prior to screening and could not have previously received systemic therapy for renal cell carcinoma.1 Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.1, 73 Patients in KEYNOTE-564 were randomized (stratified by metastasis status with those with no distant metastasis further stratified by ECOG performance status and region) in a 1:1 ratio to receive adjuvant treatment with pembrolizumab (200 mg by IV infusion every 3 weeks) or placebo for up to 1 year or until disease progression or unacceptable toxicity occurred.1, 73 The primary measure of efficacy was investigator-assessed disease-free survival, which was defined as time to recurrence, metastasis, or death.1, 73 Overall survival was also assessed.1, 73
The median age of patients enrolled in the KEYNOTE-564 study was 60 years; 71% were male, 75% were white, 14% were Asian, 9% were of unknown race, and 1% each were Black or African American, American Indian or Alaska Native, or multiracial.1 All patients had an ECOG performance status of 0 or 1.1 Most patients had disease without nodal involvement (94%), were considered intermediate-high risk (86%), and had undergone a radical nephrectomy (92%).1
At a median follow-up of 24.1 months in the KEYNOTE-564 study, median disease-free survival was not reached in either group; however, the risk of these events was substantially lower in the pembrolizumab group compared to the placebo group.1, 73 Median overall survival was also not reached in either group, but the risk of death was substantially lower with pembrolizumab compared to placebo.1, 73 At a median follow-up of 57.2 months, disease-free survival and overall survival findings remained consistently improved with pembrolizumab compared to placebo; the estimated overall survival at 48 months was 91.2% with pembrolizumab compared to 86% with placebo.74
Pembrolizumab is used first in combination with carboplatin and paclitaxel, then as a single agent for the treatment of adults with primary advanced or recurrent endometrial carcinoma.1
Pembrolizumab is also used in combination with lenvatinib for the treatment of adults with advanced endometrial carcinoma that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not MSI-H, who have disease progression following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation.1
Pembrolizumab is used as a single agent for the treatment of adults with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation.1
Combination Therapy with Paclitaxel and Carboplatin for Treatment of Primary Advanced or Recurrent Endometrial Carcinoma
The current indication for pembrolizumab in combination with paclitaxel and carboplatin for the treatment of advanced or recurrent endometrial carcinoma is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled trial (KEYNOTE-868/NRG-GY018).1, 75 The 810 women enrolled in KEYNOTE-868 had measurable stage 3, measurable stage 4A, stage 4B, or recurrent endometrial cancer and were divided into 2 different cohorts based on MMR status (dMMR, n=222; or pMMR, n=588).1 Patients were eligible for the trial if they had not received prior systemic therapy or had received prior chemotherapy in the adjuvant setting and had been chemotherapy-free for at least 12 months.1 Patients with endometrial sarcoma, including carcinosarcoma, and patients with a history of active autoimmune disease or a medical condition that requires immunosuppression were ineligible for the study.1 Patients in KEYNOTE-868 were randomized (stratified by MMR status, ECOG performance status, and prior adjuvant chemotherapy) in a 1:1 ratio to receive pembrolizumab 200 mg or placebo IV every 3 weeks plus paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL per minute for 6 cycles, followed by monotherapy with pembrolizumab 400 mg or placebo every 6 weeks for up to 14 cycles.1, 75 Treatment was continued until disease progression or unacceptable toxicity occurred, or for a maximum of 20 cycles (approximately 24 months); however, clinically stable patients or patients with a partial response after completion of cycle 6 with disease progression could continue treatment for up to 10 cycles as determined by the investigator.1, 75 The primary endpoint of the trial was progression-free survival (as determined by the investigator according to RECIST); overall survival was also assessed.1, 75
Patient characteristics varied based on MMR status.1 Patients in the dMMR cohort had a median age of 66 years, and 55% of them were ≥65 years of a 79% were white, 9% were Black, 3% were Asian, and 64% had an ECOG performance status of 0.1 The histologic subtypes were endometrioid carcinoma (81%), adenocarcinoma not otherwise specified (11%), serous (2%), and other (6%).1 Sixty-one percent of patients had recurrent disease, 5% had previously received adjuvant chemotherapy, and 43% had received previous radiotherapy.1 Among patients in the pMMR cohort, the median age was 66 years, and 54% of patients were ≥65 years of a 72% were white, 16% were Black, 5% were Asian, and 67% had an ECOG performance status of 0.1 The histologic subtypes were endometrioid carcinoma (52%), serous (26%), adenocarcinoma not otherwise specified (10%), clear cell carcinoma (7%), and other (5%).1 Fifty-six percent of patients had recurrent disease, 26% had previously received adjuvant chemotherapy, and 41% had received previous radiotherapy.1
In the KEYNOTE-868 study, a planned interim analysis indicated prolonged median progression-free survival in patients who received pembrolizumab compared with those receiving placebo.1 In the dMMR population, progression-free survival was not reached in the pembrolizumab group and was 6.5 months in the placebo group.1 In the pMMR population, progression-free survival was 11.1 months in the pembrolizumab group and 8.5 months in the placebo group.1
Combination Therapy with Lenvatinib for Treatment of Advanced Endometrial Carcinoma that is pMMR or Not MSI-H
The current indication for pembrolizumab in combination with lenvatinib for the treatment of advanced endometrial carcinoma that is pMMR or not MSI-H is based principally on the results of a multicenter, open-label, randomized, phase 3 trial (KEYNOTE-775; Study 309).1, 76 Patients with endometrial sarcoma, including carcinosarcoma, and patients with a history of active autoimmune disease or a medical condition that requires immunosuppression were ineligible for the study.1 In this study, 697 patients with cancer that was pMMR or not MSI-H were randomized (stratified by ECOG performance status, geographic region, and history of pelvic radiation) to receive lenvatinib 20 mg orally once daily continuously in combination with pembrolizumab 200 mg IV every 3 weeks or an investigator's choice of chemotherapy (doxorubicin hydrochloride 60 mg/m2 IV every 3 weeks or paclitaxel 80 mg/m2IV on days 1, 8, and 15 of each 28-day cycle).1
Among the cohort of patients with advanced endometrial carcinoma that was pMMR or not MSI-H, the median age of patients was 65 years; 62% were white, 22% were Asian, 3% were Black, and 60% had an ECOG performance status of 0.1 The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear-cell carcinoma (7%), mixed (4%), and other (3%).1 All patients received prior systemic therapy for endometrial carcinoma; 67, 30, or 3% of patients previously received 1, 2, or ≥3 systemic therapies, respectively.1 Approximately one-third (37%) of patients received prior neoadjuvant or adjuvant therapy.1 The primary endpoints were progression-free survival and overall survival; objective response rate was a key secondary efficacy endpoint.1 In the cohort of patients with advanced endometrial carcinoma that was pMMR or not MSI-H, median progression-free survival was 6.6 months in patients receiving pembrolizumab in combination with lenvatinib and 3.8 months in those receiving an investigator's choice of chemotherapy.1 Median overall survival was prolonged (17.4 versus 12.0 months) and objective response rate was higher (30 versus 15%) in patients receiving pembrolizumab in combination with lenvatinib compared with those receiving an investigator's choice of chemotherapy.1 A final overall survival analysis and updated progression-free survival analysis was performed at a median follow-up of 14.7 months.77 Among patients with cancer that was pMMR, the median overall survival in this analysis was 18 months for the combination of pembrolizumab and lenvatinib and 12.2 months for chemotherapy.77 The median progression-free survival was 6.7 months for the combination of pembrolizumab and lenvatinib and 3.8 months for chemotherapy.77
Single Agent Therapy for Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma
The current indication for pembrolizumab as a single agent for the treatment of MSI-H or dMMR endometrial cancer is based principally on the results from a subset of 90 patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma in an open-label, multicenter, nonrandomized, phase 2 study (KEYNOTE-158).1, 78 Patients received pembrolizumab 200 mg administered as an IV infusion every 3 weeks.1, 78 Treatment was continued for up to 24 months or until unacceptable toxicity or disease progression occurred; however, patients with a previous complete response, partial response, or stable disease could receive retreatment with pembrolizumab for up to 17 cycles following disease progression if safety criteria were met.78 The primary measures of efficacy were objective response rate and duration of response; outcomes were evaluated by a blinded independent central review committee according to RECIST (modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1
The median age of the 90 patients in the KEYNOTE-158 study with unresectable or metastatic MSI-H or dMMR endometrial carcinoma was 64 years; 83% were white, 8% were Asian, and 3% were Black.1 Of these 90 patients, 96% had metastatic disease and 48% had received at least 2 prior therapies for recurrent or metastatic disease.1 All of the patients had an ECOG performance status of 0 or 1.1 The study excluded patients with autoimmune disease or conditions requiring therapy with immunosuppressive agents.1
At a median follow-up of 16 months, the objective response rate in the KEYNOTE-158 study for patients with MSI-H or dMMR endometrial carcinoma was 46%; complete response was achieved in 12% of patients.1 At the time of analysis, the median duration of response had not been reached; however, 68% of patients who responded to pembrolizumab had durable responses of 12 months or more.1
Tumor Mutational Burden-high Cancer
Pembrolizumab is used for the treatment of unresectable or metastatic tumor mutational burden-high (TMB-H; defined as ≥10 mutations per megabase) solid tumors, as determined by an FDA-approved test, that have progressed following prior therapy in adult and pediatric patients who are not candidates for other satisfactory treatment options.1 The accelerated approval of pembrolizumab for this indication is based on tumor response rate and durability of response.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of pembrolizumab in confirmatory studies.1 Safety and efficacy of pembrolizumab in pediatric patients with TMB-H CNS cancers have not been established.1
The current indication for pembrolizumab for the treatment of unresectable or metastatic TMB-H solid tumors is based principally on the results of a prospectively-planned retrospective analysis of data from the open-label, multicenter, nonrandomized, phase 2 KEYNOTE-158 study.1, 79 The analysis included a subset of 102 patients from KEYNOTE-158 with various types of solid tumors with TMB-H and ≥10 mutations per megabase.1, 79 Patients in KEYNOTE-158 received pembrolizumab 200 mg administered as an IV infusion every 3 weeks.1, 79 Treatment was continued until unacceptable toxicity or disease progression occurred.1, 79 Tumor status was assessed every 9 weeks for the first year, then every 12 weeks thereafter.1, 79 The primary measures of efficacy were objective response rate and duration of response; outcomes were evaluated by a blinded independent central review committee according to RECIST (modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1, 79
The median age of the 102 patients in the KEYNOTE-158 study with TMB-H (≥10 mutations per megabase) was 61 years; 81% were white, 41% had an ECOG performance status of 0, 58% had an ECOG performance status of 1, and 56% had received treatment with ≥2 prior lines of therapy.1, 79 Solid tumor types included anal (14%), cervical (16%), endometrial (15%), mesothelioma (1%), neuroendocrine (5%), salivary (3%), small-cell lung (33%), thyroid (2%), and vulvar (12%).79 At a median follow-up of 11.1 months, the objective response rate in the KEYNOTE-158 study for patients with TMB-H cancer was 29%; complete response was achieved in 4% of patients.1, 79 Objective response rates varied by tumor type.1, 79 At the time of analysis, the median duration of response had not been reached; however, 57% of patients who responded to pembrolizumab had durable responses of 12 months or more.1
Cutaneous Squamous Cell Carcinoma
Pembrolizumab is used for the treatment of recurrent or metastatic squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma that cannot be cured by surgery or radiation.1
The current indication for pembrolizumab for the treatment of recurrent, metastatic, or locally advanced cutaneous squamous cell carcinoma is based principally on the results of a multicenter, nonrandomized, open-label trial (KEYNOTE-629).1, 80 Patients with a history of active autoimmune disease or a medical condition that requires immunosuppression were ineligible for the study.1, 80 Patients received pembrolizumab 200 mg administered as an IV infusion every 3 weeks.1, 80 Treatment was continued for up to 24 months or until the occurrence of unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, associated with a decline in performance status, or requiring urgent intervention occurred.1 The primary measures of efficacy were objective response rate and duration of response; outcomes were evaluated by a blinded independent central review committee according to RECIST (modified to follow no more than 10 target lesions and no more than 5 target lesions per organ).1, 80
KEYNOTE-629 included 105 patients with recurrent or metastatic cutaneous squamous cell carcinoma and 54 patients with locally advanced squamous cell carcinoma.1 Patients with recurrent or metastatic disease had a median age of 72 years, and 71% of them were ≥65 years of a 70% were white and race was unknown in 25% of patients.1 All patients had an ECOG performance status of 0 or 1, 45% of patients had locally recurrent disease, 24% had metastatic disease, and 31% had disease that was both locally recurrent and metastatic.1 Most patients had received prior treatment with ≥1 line of therapy (87%) and had previously received radiation therapy (73%).1 Among patients with locally advanced disease, the median age was 76 years (with 80% age 65 years or older), 72% were male, 83% were white, and race was unknown in 13%.1 All patients had an ECOG performance status of 0 or 1, 22% received previous treatment with ≥1 line of therapy, and 63% previously received radiation.1
Results were reported at a median follow-up of 23.8 months for patients with recurrent or metastatic disease and 48 months for patients with locally advanced disease.1 At the time of last follow-up, the objective response rate was 35% among patients with recurrent or metastatic disease (12% as complete responses) and 52% (22% as complete responses) among patients with locally advanced disease.1 The median duration of response was not reached in patients with recurrent or metastatic disease, and was 47.2 months in those with locally advanced disease.1
Pembrolizumab is used, first as neoadjuvant treatment in combination with chemotherapy and then as a single agent as adjuvant treatment after surgery, for the treatment of high-risk, early-stage triple-negative breast cancer.1
Pembrolizumab is also used in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (combined positive score ≥10) as determined by an FDA-approved test.1
High-risk, Early-stage Triple-negative Breast Cancer
The current indication for pembrolizumab for the treatment of high-risk, early-stage triple-negative breast cancer is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled trial (KEYNOTE-522).1, 81 KEYNOTE-522 included 1174 patients with high-risk, early-stage, triple-negative breast cancer (tumor size between 1-2 cm in diameter with nodal involvement or tumor size >2 cm regardless of nodal involvement) that was newly diagnosed and had not previously been treated; patients were enrolled regardless of PD-L1 expression.1 Patients with a history of active autoimmune disease requiring treatment within the previous 2 years or a medical condition requiring immunosuppression were ineligible for the study.1 Patients in KEYNOTE-522 were randomized (stratified by nodal status, tumor size, and carboplatin dosing schedule) in a 2:1 ratio to receive preoperative treatment with pembrolizumab 200 mg or placebo IV every 3 weeks on day 1 of cycles 1-4 of the treatment regimen in combination with IV carboplatin and paclitaxel.1, 81 In both groups, carboplatin was dosed either at an AUC of 5 mg/mL per minute every 3 weeks on day 1 of each cycle or at an AUC of 1.5 mg/mL per minute every week (days 1, 8, and 15 of each cycle); paclitaxel was dosed at 80 mg/m2 weekly on days 1, 8, and 15 of each cycle.1, 81 After this initial treatment, patients in both groups received pembrolizumab 200 mg or placebo IV in combination with IV doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 plus IV cyclophosphamide 600 mg/m2; these agents were administered every 3 weeks on day 1 of cycles 5-8.1, 81 After surgery, patients received 9 additional cycles of pembrolizumab 200 mg or placebo IV every 3 weeks.1, 81 The primary endpoints of the trial were pathological complete response (defined as an absence of invasive cancer in the breast and lymph nodes) and event-free survival; overall survival was also assessed.1, 81
In KEYNOTE-522, patients had a median age of 49 years, and 11% of them were ≥65 years of a 64% were white, 20% were Asian, 4.5% were Black, and 1.8% were American Indian or Alaska Native.1 All patients had an ECOG performance status of 0 or 1, 56% of patients were premenopausal, 68% had a primary tumor classification of T2, 49% had no nodal involvement, and 75% had stage 2 disease.1 A planned interim analysis found substantially higher rates of pathological complete response in patients who received pembrolizumab than those who received placebo (63 or 55.6%, respectively).1 Patients treated with pembrolizumab also had substantially lower event rates than those treated with placebo (16 or 24%, respectively).1 At the final analysis of KEYNOTE-522, estimated 5-year event-free survival rates were 81.2 or 72.2% for pembrolizumab or placebo.82 Estimated overall survival at 5 years was 86.6 or 81.7% for pembrolizumab or placebo.82
Locally Recurrent Unresectable or Metastatic Triple-negative Breast Cancer
The current indication for pembrolizumab in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple-negative breast cancer, regardless of PD-L1 expression, is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (KEYNOTE-355).1, 83 KEYNOTE-355 enrolled 847 women with advanced triple-negative breast cancer who had not previously received chemotherapy in the metastatic setting; patients with a history of active autoimmune disease requiring treatment within the previous 2 years or a medical condition requiring immunosuppression were ineligible for the study.1, 83 Patients in the trial were randomized in a 2:1 ratio (stratified by chemotherapy treatment, tumor PD-L1 expression, and prior treatment history) to receive pembrolizumab 200 mg or placebo IV every 3 weeks on day 1 of the treatment cycle.1, 83 Pembrolizumab or placebo was administered in combination with one of the following IV regimens: 1) protein-bound paclitaxel 100 mg/m2 given on days 1, 8, and 15 every 28 days; 2) conventional paclitaxel 90 mg/m2 on days 1, 8 and 15 every 28 days; or 3) gemcitabine 1000 mg/m2 plus carboplatin AUC 2 mg/mL per minute on days 1 and 8 every 21 days.1, 83 The primary measures of efficacy were overall survival and progression-free survival (as evaluated by a blinded independent central review committee according to RECIST modified to follow no more than 10 target lesions and no more than 5 target lesions per organ), which were evaluated in a subgroup of patients with a combined positive score of ≥10.1, 83 Additional outcome measures were objective response rate and duration of response.1, 83
The median age of patients enrolled in the KEYNOTE-355 study was 53 years and 21% of patients were ≥65 years of a 68% were white, 21% were Asian, and 4% were Black.1 All patients enrolled in the study had an ECOG performance status of 0 or 1, and 68% were postmenopausal.1 Most patients (75%) had a PD-L1 combined positive score of ≥1, and 38% of patients had a PD-L1 combined positive score of ≥10.1
In the KEYNOTE-355 study, the final analysis at a median follow-up of 44.1 months indicated prolonged median progression-free survival in patients with combined positive scores ≥10 who received pembrolizumab compared with placebo (9.7 months vs. 5.6 months, respectively).1, 84 Overall survival was also substantially improved with pembrolizumab versus placebo at final analysis (23 vs. 16.1 months, respectively).1, 84 Patients receiving pembrolizumab had a higher objective response rate compared with those receiving placebo (53 or 41%, respectively); complete responses were achieved in 17% of patients treated with pembrolizumab compared with 14% of those treated with placebo.1 At the time of final analysis, the median duration of response was 12.8 months in the pembrolizumab group and 7.3 months in the placebo group.1
Pembrolizumab is commercially available as an injection concentrate, which must be diluted prior to IV administration.1
The commercially available injection concentrate should be inspected visually for particulate matter and discoloration prior to dilution and administration.1 The solution should be clear to slightly opalescent and colorless to slightly yellow, and should not be used if visible particles are present.1
The commercially available pembrolizumab injection concentrate contains no preservatives and is intended for single use only; any unused portions should be discarded.1
Store vials of injection concentrate under refrigeration (2-8°C) in the original carton to protect from light.1 Do not shake or freeze.1
For preparation of diluted pembrolizumab solution for infusion, the required amount of commercially available injection concentrate should be injected into an infusion bag containing a sufficient volume of 0.9% sodium chloride injection or 5% dextrose injection to yield a final solution with a pembrolizumab concentration of 1-10 mg/mL.1 The diluted pembrolizumab solution for infusion should be mixed by gentle inversion and not shaken.1 Diluted solutions of the drug are stable for up to 6 hours (including infusion time) after dilution of the injection concentrate when stored at room temperature or up to 96 hours when stored under refrigeration (2-8°C); diluted solutions of the drug should be brought to room temperature prior to administration.1 Diluted solutions of the drug should not be frozen.1
Pembrolizumab is administered by IV infusion over 30 minutes.1 Pembrolizumab should be administered through a sterile, nonpyrogenic, low-protein-binding 0.2- to 5-µm inline or add-on filter.1
Pembrolizumab should not be administered simultaneously through the same IV infusion line with any other drug.1
For the treatment of refractory classical Hodgkin lymphoma (cHL) or cHL that has relapsed following at least 2 prior therapies, the recommended pediatric dosage of pembrolizumab is 2 mg/kg (up to a maximum of 200 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued for up to 24 months or until disease recurrence or unacceptable toxicity occurs.1
Primary Mediastinal Large B-cell Lymphoma
For the treatment of refractory primary mediastinal large B-cell lymphoma (PMBCL) or PMBCL that has relapsed following at least 2 prior therapies, the recommended pediatric dosage of pembrolizumab is 2 mg/kg (up to a maximum of 200 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued for up to 24 months or until disease recurrence or unacceptable toxicity occurs.1
Pembrolizumab is not recommended for the treatment of PMBCL in patients who require urgent cytoreduction.1
Microsatellite Instability-high or Mismatch Repair Deficient Cancer
For the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior therapy in patients without satisfactory alternative treatment options, the recommended pediatric dosage of pembrolizumab is 2 mg/kg (up to a maximum of 200 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of single-agent pembrolizumab for the treatment of unresectable or metastatic MSI-H or dMMR solid tumors should be based on MSI-H/dMMR status in tumor specimens.1 Since subclonal dMMR mutations and microsatellite instability can arise in high-grade gliomas in patients during temozolomide therapy, the manufacturer recommends testing for tumor mutational burden-high (TMB-H), MSI-H, and dMMR in primary tumor specimens before initiating temozolomide in patients with high-grade gliomas.1
Because of discordance between local and FDA-approved tests for MSI-H or dMMR status, confirmation of status is recommended in patients with MSI-H or dMMR solid tumors, if feasible.1 If confirmatory MSI-H/dMMR testing cannot be performed, the presence of TMB ≥10 mutations/megabase (mut/Mb; as determined by an FDA-approved test) may be used to select patients for treatment.1
For the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma (MCC), the recommended pediatric dosage of pembrolizumab is 2 mg/kg (up to a maximum of 200 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Tumor Mutational Burden-high Cancer
For the treatment of unresectable or metastatic tumor mutational burden-high (TMB-H) (≥10 mutations/megabase) solid tumors, as determined by an FDA-approved test, that have progressed following prior therapy and who have no satisfactory alternative treatment options, the recommended pediatric dosage of pembrolizumab is 2 mg/kg (up to a maximum of 200 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of single-agent pembrolizumab therapy for TMB-H solid tumors should be based on TMB-H status in tumor specimens.1 Since subclonal dMMR mutations and microsatellite instability can arise in high-grade gliomas in patients during temozolomide therapy, the manufacturer recommends testing for TMB-H, MSI-H, and dMMR in primary tumor specimens before initiating temozolomide in patients with high-grade gliomas.1
Safety and efficacy of pembrolizumab in pediatric patients with TMB-H CNS cancers have not been established.1
Adjuvant Therapy for Locally Advanced Melanoma
For the adjuvant treatment of completely resected advanced stage IIB, IIC, or III melanoma in pediatric patients ≥12 years of age, the recommended pediatric dosage of pembrolizumab is 2 mg/kg (up to a maximum of 200 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued for up to 12 months or until disease recurrence or unacceptable toxicity occurs.1
Unresectable or Metastatic Melanoma : For the treatment of unresectable or metastatic melanoma, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Adjuvant Therapy for Locally Advanced Melanoma : For the adjuvant therapy of completely resected advanced stage IIB, IIC, or III melanoma, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 12 months or until disease recurrence or unacceptable toxicity occurs.1
Non-small Cell Lung Cancer (NSCLC)
Adjuvant Therapy for NSCLC : For single-agent adjuvant treatment following platinum-based chemotherapy and complete resection of advanced stage IB (T2a ≥4 cm), II, or IIIA NSCLC, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 12 months or until disease recurrence or unacceptable toxicity occurs.1
Neoadjuvant Therapy for NSCLC : For the neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) NSCLC, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with platinum-containing chemotherapy (carboplatin, cisplatin).1 Pembrolizumab should be administered before the platinum-containing antineoplastic agent when given on the same day.1 Neoadjuvant therapy in combination with a platinum-containing chemotherapy agent should be continued for 12 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity occurs.1 Single-agent adjuvant treatment with pembrolizumab should then be started after surgery and continued for 39 weeks or until there is disease recurrence or unacceptable toxicity.1
Monotherapy for Metastatic NSCLC : For the initial treatment of metastatic or stage III NSCLC in patients who are not candidates for surgical resection or definitive chemoradiation with epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-negative tumors expressing programmed-death ligand-1 (PD-L1) (defined as a tumor proportion score [TPS] of ≥1%) as determined by an FDA-approved test, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
For the treatment of PD-L1-positive (defined as a TPS of ≥1%) metastatic NSCLC that has progressed during or following platinum-based chemotherapy and, if the tumor is EGFR- or ALK-positive, during or following therapy with an FDA-labeled anti-EGFR or anti-ALK agent, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Patient selection of single-agent pembrolizumab for the treatment of metastatic NSCLC should be based on the presence of PD-L1 expression.1
Combination Therapy for Metastatic NSCLC : For the initial treatment of metastatic nonsquamous NSCLC without EGFR or ALK genomic aberrations, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks, in combination with pemetrexed and a platinum-containing chemotherapy agent (carboplatin, cisplatin).1 Pembrolizumab should be administered before pemetrexed and the platinum-containing chemotherapy agent when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
For the initial treatment of metastatic squamous NSCLC, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks, in combination with carboplatin and paclitaxel (conventional or protein-bound).1 Pembrolizumab should be administered before carboplatin and paclitaxel when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Malignant Pleural Mesothelioma
For the initial treatment of unresectable advanced or metastatic malignant pleural mesothelioma (MPM), the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with pemetrexed and a platinum-containing chemotherapy agent (carboplatin, cisplatin).1 Pembrolizumab should be administered before pemetrexed and the platinum-containing chemotherapy agent when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Head and Neck Squamous Cell Cancer
Monotherapy for Head and Neck Cancer : For the initial treatment of PD-L1-positive (defined as combined positive score [CPS] ≥1), as defined by an FDA-approved test, metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC), the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of single-agent pembrolizumab for the initial treatment of metastatic or unresectable, recurrent HNSCC should be based on the presence of positive PD-L1 expression in tumor specimens.1
For the treatment of recurrent or metastatic HNSCC that has progressed during or following platinum-containing chemotherapy, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Combination Therapy for Head and Neck Cancer : For the initial treatment of metastatic or unresectable, recurrent HNSCC, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with a platinum-containing chemotherapy agent (carboplatin, cisplatin), and fluorouracil.1 Pembrolizumab should be administered before the platinum-containing chemotherapy agent and fluorouracil when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
For the treatment of relapsed or refractory cHL, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
The alternate dosage regimen of 400 mg every 6 weeks in adults with cHL received accelerated approval from the FDA based on pharmacokinetic and safety and efficacy exposure-response data.1 Continued approval for this dosage is contingent on verified and described clinical benefit in confirmatory studies.1
Primary Mediastinal Large B-cell Lymphoma
For the treatment of refractory PMBCL or PMBCL that has relapsed following at least 2 prior therapies, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
The alternate dosage regimen of 400 mg every 6 weeks in adults with PMBCL received accelerated approval from the FDA based on pharmacokinetic and safety and efficacy exposure-response data.1 Continued approval for this dosage is contingent on verified and described clinical benefit in confirmatory studies.1
Pembrolizumab is not recommended for the treatment of PMBCL in patients who require urgent cytoreduction.1
Monotherapy for Urothelial Cancer : For the treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing therapy or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting, or locally advanced or metastatic urothelial carcinoma in patients who are not eligible to receive platinum-containing chemotherapy, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
For the treatment of Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors in patients who are ineligible for or have elected to not undergo cystectomy, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until persistent or recurrent high-risk NMIBC, disease progression, or unacceptable toxicity occurs.1
Combination Therapy for Urothelial Cancer : For the treatment of locally advanced or metastatic urothelial cancer, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with enfortumab vedotin.1 Enfortumab vedotin should be administered before pembrolizumab when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Microsatellite Instability-high or Mismatch Repair Deficient Cancer
For the treatment of unresectable or metastatic MSI-H or dMMR solid tumors, as determined by an FDA-approved test, that have progressed following prior therapy in patients without other satisfactory treatment options, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of single-agent pembrolizumab for the treatment of unresectable or metastatic MSI-H or dMMR solid tumors should be based on MSI-H/dMMR status in tumor specimens.1 Since subclonal dMMR mutations and microsatellite instability can arise in high-grade gliomas in patients during temozolomide therapy, the manufacturer recommends testing for TMB-H, MSI-H, and dMMR in primary tumor specimens before initiating temozolomide in patients with high-grade gliomas.1
Because of discordance between local and FDA-approved tests for MSI-H or dMMR status, confirmation of status is recommended in patients with MSI-H or dMMR solid tumors, if feasible.1 If confirmatory MSI-H/dMMR testing cannot be performed, the presence of TMB ≥10 mut/Mb (as determined by an FDA-approved test) may be used to select patients for treatment.1
Microsatellite Instability-high or Mismatch Repair Deficient Colorectal Cancer
For the treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC), as determined by an FDA-approved test, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of single-agent pembrolizumab for the treatment of unresectable or metastatic MSI-H or dMMR CRC should be based on MSI-H/dMMR status in tumor specimens.1
For the initial treatment of locally advanced unresectable or metastatic HER2-positive, PD-L1-positive (defined as a PD-L1 expression CPS ≥1%) gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction (GEJ), the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy.1 Pembrolizumab should be administered before trastuzumab and other chemotherapy agents when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of pembrolizumab in combination with trastuzumab and chemotherapy for the treatment of HER2-positive, PD-L1-positive gastric or GEJ adenocarcinoma should be based on the presence of PD-L1 expression (CPS ≥1%) in tumor specimens.1
For the initial treatment of locally advanced unresectable or metastatic HER2-negative gastric adenocarcinoma, including adenocarcinoma of the GEJ, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy.1 Pembrolizumab should be administered before other chemotherapy agents when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Monotherapy for Esophageal Cancer : For the treatment of locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1—5 cm above the GEJ) tumors of squamous cell histology that express PD-L1 (CPS ≥10%), based on an FDA-approved test, that are not amenable to surgical resection or definitive chemoradiation after at least 1 prior line of systemic chemotherapy, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of single-agent pembrolizumab for the treatment of PD-L1-positive locally advanced or metastatic esophageal or GEJ carcinoma should be based on the presence of PD-L1 expression in tumor specimens.1
Combination Therapy for Esophageal Cancer : For the treatment of locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1—5 cm above the GEJ) carcinoma not amenable to surgical resection or definitive chemoradiation, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with platinum- and fluoropyrimidine-based chemotherapy.1 Pembrolizumab should be administered prior to chemotherapy agents when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Monotherapy for Cervical Cancer : For the treatment of recurrent or metastatic, PD-L1-positive (defined as a PD-L1 expression CPS ≥1%), as determined by an FDA-approved test, cervical cancer that has progressed during or following chemotherapy, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of pembrolizumab therapy should be based on the presence of PD-L1 expression.1
Combination Therapy for Cervical Cancer : For the treatment of International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III-IVA cervical cancer, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks, in combination with chemoradiotherapy (CRT).1 Pembrolizumab should be administered prior to CRT.1 Therapy should be continued for up to 24 months with pembrolizumab or until disease progression or unacceptable toxicity occurs.1
For the treatment of persistent, recurrent, or metastatic PD-L1-positive (defined as a PD-L1 expression CPS ≥1%), as determined by an FDA-approved test, cervical cancer, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with chemotherapy, with or without bevacizumab.1 Pembrolizumab should be administered prior to chemotherapy with or without bevacizumab when given on the same day.1 Therapy should be continued for up to 24 months with pembrolizumab or until disease progression or unacceptable toxicity occurs.1
Selection of pembrolizumab therapy in combination with chemotherapy with or without bevacizumab should be based on the presence of PD-L1 expression.1
For the treatment of hepatocellular carcinoma (HCC) secondary to hepatitis B in patients who have received other prior systemic therapy besides a PD-1/PD-L1-containing regimen, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
For the treatment of locally advanced unresectable or metastatic biliary tract cancer (BTC), the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with gemcitabine and cisplatin.1 Pembrolizumab should be administered prior to gemcitabine and cisplatin therapy when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
For the treatment of recurrent locally advanced or metastatic MCC, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Adjuvant Therapy for Renal Cell Carcinoma : For the adjuvant treatment of renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 12 months or until disease recurrence or unacceptable toxicity occurs.1
Combination Therapy for Renal Cell Carcinoma : For the initial treatment of advanced RCC, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with axitinib 5 mg orally twice daily.1 When used in combination with pembrolizumab, escalation of axitinib to doses above the initial 5 mg dose may be considered at intervals of 6 weeks or longer.1 Therapy should be continued for up to 24 months with pembrolizumab or until disease progression or unacceptable toxicity occurs.1
For the initial treatment of advanced RCC, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with lenvatinib 20 mg orally once daily.1 Therapy should be continued for up to 24 months with pembrolizumab or until disease progression or unacceptable toxicity occurs.1
Monotherapy for Endometrial Carcinoma : For the treatment of advanced endometrial carcinoma that is MSI-H or dMMR (as determined by an FDA-approved test) in patients with disease progression following prior systemic therapy in any setting who are not candidates for curative surgery or radiation, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Selection of single-agent pembrolizumab for the treatment of advanced endometrial carcinoma should be based on MSI-H/dMMR status in tumor specimens.1 Since subclonal dMMR mutations and microsatellite instability can arise in high-grade gliomas in patients during temozolomide therapy, the manufacturer recommends testing for TMB-H, MSI-H, and dMMR in primary tumor specimens before initiating temozolomide in patients with high-grade gliomas.1
Because of discordance between local and FDA-approved tests for MSI-H or dMMR status, confirmation of status is recommended in patients with MSI-H or dMMR solid tumors, if feasible.1 If confirmatory MSI-H/dMMR testing cannot be performed, the presence of TMB ≥10 mut/Mb (as determined by an FDA-approved test) may be used to select patients for treatment.1
Combination Therapy for Endometrial Carcinoma: For the treatment of primary advanced or recurrent endometrial carcinoma, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with carboplatin and paclitaxel, followed by treatment with single-agent pembrolizumab.1 Pembrolizumab should be given prior to carboplatin and paclitaxel when given on the same day.1 Therapy with pembrolizumab should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
For the treatment of advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as indicated by an FDA-approved test, or not MSI-H, in patients with disease progression following prior systemic therapy in any setting who are not candidates for curative surgery or radiation, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with lenvatinib 20 mg orally once daily.1 Therapy with pembrolizumab should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Initiation of pembrolizumab therapy in combination with lenvatinib in pMMR/not MSI-H advanced endometrial carcinoma should be based on MSI or MMR status in tumor specimens.1 An FDA-approved test for the detection of not MSI-H is currently not available to select patients with not MSI-H endometrial carcinoma for treatment with pembrolizumab in combination with lenvatinib.1
Tumor Mutational Burden-high Cancer
For the treatment of unresectable or metastatic TMB-H (defined as ≥10 mut/Mb) solid tumors (as determined by an FDA-approved test) that have progressed following prior therapy and who have no satisfactory alternative treatment options, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Initiation of single-agent pembrolizumab therapy should be based on TMB-H status in tumor specimens.1
Cutaneous Squamous Cell Carcinoma
For the treatment of recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC not curable by surgery or radiation, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Neoadjuvant Therapy for Triple-negative Breast Cancer : For the neoadjuvant treatment of high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy and continued as single-agent adjuvant treatment after surgery, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks.1 Pembrolizumab as neoadjuvant treatment in combination with chemotherapy should be administered for 24 weeks (8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks), or until disease progression or unacceptable toxicity occurs.1 Single-agent adjuvant treatment with pembrolizumab should follow for up to 27 weeks (9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks) or until disease recurrence or unacceptable toxicity occurs.1 When administered in the neoadjuvant setting, pembrolizumab should be administered prior to chemotherapy when given on the same day.1 Patients who experience disease progression or unacceptable toxicity with pembrolizumab as neoadjuvant treatment should not receive pembrolizumab as single-agent adjuvant treatment.1
Combination Therapy for Triple-negative Breast Cancer : For the treatment of patients with locally recurrent unresectable or metastatic TNBC with tumors expressing PD-L1 (CPS ≥10%) as determined by an FDA-approved test, the recommended adult dosage of pembrolizumab is 200 mg administered as a 30-minute IV infusion every 3 weeks, or alternatively, 400 mg administered as a 30-minute IV infusion every 6 weeks in combination with chemotherapy.1 Pembrolizumab should be administered prior to chemotherapy when given on the same day.1 Therapy should be continued for up to 24 months or until disease progression or unacceptable toxicity occurs.1
Initiation of pembrolizumab in combination with chemotherapy should be based on PD-L1 expression in locally recurrent unresectable or metastatic TNBC.1
Dosage Modifications For Toxicity
No dosage reduction for pembrolizumab is recommended; however, if immune-mediated adverse reactions occur, temporary or permanent discontinuance of pembrolizumab may be required based on severity of the reaction.1
In general, pembrolizumab should be temporarily withheld in patients with severe (grade 3) immune-mediated adverse reactions, and should be permanently discontinued in patients experiencing life-threatening (grade 4) immune-mediated adverse reactions that require systemic immunosuppressive therapy.1 Therapy with the drug also should be permanently discontinued in patients unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.1
When adverse effects occur during concomitant use of pembrolizumab with lenvatinib, modification of the dosage of one or both agents is recommended.1 Temporary or permanent discontinuance of pembrolizumab may be required based on the severity of the reaction.1 Refer to the lenvatinib prescribing information for additional dosage modifications.1
Hematologic Toxicity : If grade 4 hematologic toxicity occurs in patients with cHL or PMBCL, pembrolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1.1
Immune-mediated Pneumonitis : If grade 2 immune-mediated pneumonitis occurs, pembrolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.1 Therapy with the drug should be permanently discontinued in patients who do not recover to grade 0 or 1 within 12 weeks of initiating corticosteroids or who are unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.1
If grade 3 or 4 immune-mediated pneumonitis occurs, pembrolizumab therapy should be permanently discontinued.1
Immune-mediated GI Effects : If grade 2 or 3 immune-mediated colitis occurs, pembrolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.1 Therapy with the drug should be permanently discontinued in patients who do not recover to grade 0 or 1 within 12 weeks of initiating corticosteroids or who are unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.1
If grade 4 immune-mediated colitis occurs, pembrolizumab therapy should be permanently discontinued.1
Immune-mediated Hepatotoxicity (Except When Used in Combination with Axitinib) : For serum aminotransferase (ALT or AST) elevations exceeding 3 times and up to 8 times the upper limit of normal (ULN) or total bilirubin concentrations exceeding 1.5 times and up to 3 times the ULN in patients without liver tumor involvement experiencing hepatotoxicity, pembrolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.1 Therapy with the drug should be permanently discontinued in patients who do not recover to grade 0 or 1 within 12 weeks of initiating corticosteroids or who are unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.1
For ALT or AST elevations exceeding 8 times the ULN or total bilirubin concentrations exceeding 3 times the ULN in patients without liver tumor involvement experiencing hepatotoxicity, pembrolizumab therapy should be permanently discontinued.1
When AST and ALT concentrations are ≤ULN at baseline in patients with liver tumor involvement experiencing hepatotoxicity, temporary or permanent discontinuance of pembrolizumab may be based on recommendations for hepatotoxicity in patients without liver tumor involvement.1
In patients with liver tumor involvement and baseline ALT or AST concentrations exceeding 1 time and up to 3 times the ULN who experience increases in ALT or AST concentrations exceeding 5 times and up to 10 times the ULN, pembrolizumab therapy should be interrupted until hepatotoxicity resolves to grade 0 or 1 or the AST and ALT concentrations return to baseline.1 Therapy with the drug should be permanently discontinued in patients who do not recover to grade 0 or 1 within 12 weeks of initiating corticosteroids or who are unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.1
In patients with liver tumor involvement and baseline ALT or AST concentrations exceeding 3 times and up to 5 times the ULN who experience increases in ALT or AST concentrations exceeding 8 times and up to 10 times the ULN, pembrolizumab therapy should be interrupted until hepatotoxicity resolves to grade 0 or 1 or the AST and ALT concentrations return to baseline.1 Therapy with the drug should be permanently discontinued in patients who do not recover to grade 0 or 1 within 12 weeks of initiating corticosteroids or who are unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.1
For ALT or AST concentrations exceeding 10 times the ULN in patients with liver tumor involvement, pembrolizumab therapy should be permanently discontinued.1
For total bilirubin concentrations exceeding 3 times the ULN in patients with liver tumor involvement, pembrolizumab therapy should be permanently discontinued.1
Hepatotoxicity When Used in Combination with Axitinib for RCC : For treatment of liver enzyme elevations in patients experiencing adverse hepatotoxic effects from pembrolizumab therapy in combination with axitinib, consider corticosteroid therapy.1
For ALT or AST concentrations that are ≥3 times but less than 10 times the ULN in patients receiving pembrolizumab with concomitant axitinib and without concurrent total bilirubin concentrations of at least 2 times the ULN, pembrolizumab and axitinib therapy should be interrupted until the toxicity resolves to grade 0 or 1.1 A single-agent rechallenge or sequential rechallenge with both drugs may be considered after resolution of toxicity.1 If therapy with axitinib is rechallenged, consider dosage reduction according to the axitinib prescribing information.1
For ALT or AST concentrations exceeding 3 times the ULN with concurrent total bilirubin concentrations ≥2 times ULN, pembrolizumab and axitinib should both be permanently discontinued.1
For ALT or AST concentrations ≥10 times the ULN, pembrolizumab and axitinib should both be permanently discontinued.1
Immune-mediated Endocrine Effects : If grade 3 or 4 immune-mediated endocrinopathies occur, pembrolizumab therapy should be interrupted until the patient is clinically stable or the drug should be permanently discontinued.1
Immune-mediated Renal Effects : If grade 2 or 3 immune-mediated nephritis occurs with increased serum creatinine concentrations, pembrolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.1 Therapy with the drug should be permanently discontinued in patients who do not recover to grade 0 or 1 within 12 weeks of initiating corticosteroids or who are unable to reduce the corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.1
If grade 4 immune-mediated nephritis occurs with increased serum creatinine concentrations, pembrolizumab therapy should be permanently discontinued.1
Immune-mediated Dermatologic Effects : If Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS) is suspected, pembrolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.1 Therapy with the drug should be permanently discontinued in patients who do not recover to grade 0 or 1 within 12 weeks of initiating corticosteroids or who are unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroid therapy.1
If SJS, TEN, or DRESS is confirmed, pembrolizumab therapy should be permanently discontinued.1
Immune-mediated Cardiac Effects : If grade 2—4 immune-mediated myocarditis occurs, pembrolizumab therapy should be permanently discontinued.1
Immune-mediated Neurologic Effects : If grade 2 immune-mediated neurologic toxicity occurs, pembrolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.1 Therapy with the drug should be permanently discontinued in patients who do not recover to grade 0 or 1 within 12 weeks of initiating corticosteroids or who are unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroid therapy.1
If grade 3 or 4 immune-mediated neurologic toxicity occurs, pembrolizumab therapy should be permanently discontinued.1
Infusion-related Reactions : If grade 1 or 2 infusion-related reactions occur, the infusion should be interrupted or the infusion rate should be slowed.1
If grade 3 or 4 infusion-related reactions occur, pembrolizumab therapy should be permanently discontinued.1
The manufacturer makes no specific dosage recommendations for patients with preexisting hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with preexisting renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Severe and Fatal Immune-mediated Adverse Reactions
Pembrolizumab, a monoclonal antibody, is part of a drug class that binds to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1) to block the PD-1/PD-L1 pathway, which removes inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated severe, potentially fatal adverse reactions.1 Important immune-mediated adverse reactions listed in the prescribing information for pembrolizumab may not include all potential severe and fatal immune-mediated reactions that can occur during therapy.1
Immune-mediated adverse reactions, which may be severe or potentially fatal, can occur in any organ system or tissue at any time after starting a PD-1/PD-L1 blocking antibody such as pembrolizumab.1 These immune-mediated adverse reactions can occur in more than one body system simultaneously, and generally occur during treatment with a PD-1/PD-L1 blocking antibody, but can also manifest after discontinuation of the PD-1/PD-L1 blocking antibody.1
Early identification and management of immune-mediated adverse reactions are essential in ensuring the safe use of PD-1/PD-L1 blocking antibodies such as pembrolizumab.1 Patients should be monitored closely for signs and symptoms of potential clinical manifestations of underlying immune-mediated adverse reactions.1 The manufacturer recommends assessing liver enzymes, serum creatinine, and thyroid function at baseline and periodic monitoring thereafter in patients receiving pembrolizumab therapy.1 In patients with triple-negative breast cancer (TNBC) receiving pembrolizumab in the neoadjuvant setting, monitoring of blood cortisol is recommended at baseline, prior to surgical procedures, and as clinically indicated.1 Appropriate workup should be initiated to exclude alternative etiologies, including infection, in patients with suspected immune-mediated adverse reactions.1 Medical management should be initiated promptly, with specialty consultation as appropriate.1
Temporary interruption or permanent discontinuance of pembrolizumab may be necessary depending on the severity of the immune-mediated adverse reaction.1 Generally, if temporary interruption or discontinuance of pembrolizumab is necessary, systemic corticosteroid therapy (1—2 mg/kg daily of prednisone or equivalent) is recommended until toxicity improves (unless endocrinopathy or dermatologic reaction) to grade 0 or 1.1 Upon improvement to grade 0 or 1, corticosteroid taper should be initiated and tapered over at least 1 month.1 Consideration of other systemic immunosuppressive therapies is recommended in patients whose toxicity is not controlled with systemic corticosteroids.1 Endocrinopathies and dermatologic reactions do not necessarily require systemic corticosteroids for management.1
Immune-mediated pneumonitis has occurred in patients receiving pembrolizumab therapy.1 The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.1 In clinical studies of pembrolizumab, immune-mediated pneumonitis occurred in 3.4% of patients, including fatal cases in 0.1%.1 Pneumonitis resolved in 59% of patients.1 Systemic corticosteroid therapy was required for management in 67% of cases.1 Permanent discontinuance of pembrolizumab occurred in 1.3% of patients and temporary interruption occurred in 0.9%.1 All patients who were withheld from pembrolizumab reinitiated the drug after symptom improvement, and 23% had recurrence of pneumonitis.1
In clinical studies evaluating single-agent pembrolizumab in patients with classical Hodgkin lymphoma (cHL), immune-mediated pneumonitis occurred in 8% of patients and was grade 3 or 4 in 2.3% of patients receiving the drug.1 The median duration of high-dose corticosteroid therapy was 10 days (range: 2 days to 53 months).1 Rates of immune-mediated pneumonitis were similar in patients who had received prior thoracic radiation compared with those who had not received thoracic radiation.1 Pembrolizumab was permanently discontinued because of immune-mediated pneumonitis in 5.4% of patients receiving the drug.1 Immune-mediated pneumonitis resolved in 77% of patients and resulted in temporary interruption or discontinuance of pembrolizumab in 42% and 68% of patients, respectively.1
In a clinical study evaluating single-agent pembrolizumab as adjuvant therapy in patients with resected non-small cell lung cancer (NSCLC), immune-mediated pneumonitis occurred in 7% and was grade 3 in 1%, grade 4 in 0.3%, and fatal in 0.2% of patients.1 The median duration of high-dose corticosteroid therapy was 10 days (range: 1 day to 2.3 months).1 Pembrolizumab was permanently discontinued because of immune-mediated pneumonitis in 4.5% of patients.1 Immune-mediated pneumonitis resolved in 71% of patients and resulted in temporary interruption or discontinuance of pembrolizumab in 54% and 63% of patients, respectively.1
Temporary interruption or discontinuance of pembrolizumab may be necessary if immune-mediated pneumonitis occurs during therapy with the drug.1
Pembrolizumab therapy has caused immune-mediated colitis, which may present with diarrhea.1 Cytomegalovirus (CMV) infection or reactivation has been reported in patients with immune-mediated colitis refractory to systemic corticosteroids.1 If immune-mediated colitis occurs that is refractory to corticosteroids, consider repeating infectious workup to exclude alternate causes.1
In clinical studies evaluating single-agent pembrolizumab, immune-mediated colitis occurred in 1.7% of patients and was grade 3 or 4 in approximately 1.2% of patients receiving the drug.1 Most patients (69%) experiencing immune-mediated colitis required systemic corticosteroid therapy; additional immunosuppression was required in 4.2% of patients.1 Pembrolizumab was permanently discontinued because of immune-mediated colitis in 0.5% and was temporarily withheld in 0.5% of patients receiving the drug.1 Of the patients with temporary interruption who reinitiated pembrolizumab therapy, 23% had recurrent colitis.1 Immune-mediated colitis resolved in 85% of patients.1
Temporary interruption or permanent discontinuance of pembrolizumab may be necessary if immune-mediated colitis occurs during therapy with the drug.1
Hepatotoxicity and Immune-mediated Hepatitis
Immune-mediated hepatitis has occurred in patients receiving pembrolizumab therapy.1
In clinical studies evaluating single-agent pembrolizumab, immune-mediated hepatitis occurred in 0.7% of patients and was grade 3 or 4 in approximately 0.5% of patients receiving the drug.1 Most patients (68%) experiencing immune-mediated hepatitis required systemic corticosteroid therapy; 11% of these patients required additional immunosuppressive therapy.1 Pembrolizumab was permanently discontinued because of immune-mediated hepatitis in 0.2% of patients receiving the drug.1 The drug was temporarily interrupted in 0.3% of patients, and none had recurrence of hepatitis after reinitiation of therapy.1 Immune-mediated hepatitis resolved in 79% of patients.1
In patients who develop elevations of serum aminotransferase or bilirubin concentrations, temporary interruption of therapy or permanent drug discontinuance may be required.1
In clinical studies evaluating combination therapy with pembrolizumab and axitinib, grade 3 and 4 ALT and AST elevations occurred more frequently than with single-agent pembrolizumab.1 Monitor liver enzymes prior to initiating combination therapy with pembrolizumab and axitinib and periodically thereafter.1 Consider more frequent monitoring of liver enzymes when administering combination therapy compared to when the drugs are used as single agents.1 If liver enzyme elevations occur during combination therapy with pembrolizumab and axitinib, temporarily interrupt treatment and consider administering systemic corticosteroids.1
In clinical studies evaluating combination therapy with pembrolizumab and axitinib, grade 3 or 4 increases in ALT occurred in 20% and increases in AST occurred in 13% of patients.1 The majority of patients (59%) with ALT elevations received systemic corticosteroids.1 Of the patients with ALT elevations ≥3 times ULN (grades 2—4), ALT elevations resolved to grade 0 or 1 in 94% of patients.1 Of the 55 patients who reinitiated combination therapy after temporary interruption, recurrence of ALT elevations ≥3 times ULN occurred in 24 patients; all patients subsequently recovered from the event.1
Immune-mediated Endocrine Effects
Immune-mediated endocrinopathies, including primary or secondary adrenal insufficiency, hypophysitis, thyroid dysfunction (i.e., hyperthyroidism, hypothyroidism, thyroiditis), and diabetes mellitus, have occurred in patients receiving pembrolizumab therapy.1
Adrenal Insufficiency : For grade ≥2 adrenal insufficiency, the manufacturer recommends initiating symptomatic treatment, including hormone replacement therapy as clinically indicated.1 Pembrolizumab should be temporarily withheld based on the severity of the reaction.1
In clinical studies evaluating single-agent pembrolizumab, immune-mediated adrenal insufficiency occurred in 0.8% of patients, including grade 4 (<0.1%), grade 3 (0.3%), and grade 2 (0.3%) adverse reactions.1 Systemic corticosteroids were required in 77% of patients who developed adrenal insufficiency, and the majority of these patients required maintenance corticosteroid treatment.1 Permanent discontinuation of pembrolizumab due to adrenal insufficiency occurred in <0.1% of patients, and pembrolizumab was temporarily withheld in 0.3% of patients.1 In patients in whom pembrolizumab was temporarily withheld, pembrolizumab was restarted after symptom improvement.1
Hypophysitis : Pembrolizumab may cause immune-mediated hypophysitis.1 Hypophysitis can present with acute symptoms associated with mass effect, including headache, photophobia, or visual field defects.1 If hypophysitis develops, hypopituitarism can occur.1 In patients who develop hypophysitis, hormone replacement therapy should be initiated as clinically indicated.1 Temporary interruption or discontinuance of pembrolizumab may be required based on the severity of the reaction.1
In clinical studies evaluating single-agent pembrolizumab, immune-mediated hypophysitis occurred in 0.6% of patients and was grade 3 or 4 in approximately 0.4% of patients receiving pembrolizumab.1 Most patients (94%) experiencing immune-mediated hypophysitis required systemic corticosteroid therapy; the majority of these patients remained on systemic corticosteroid therapy.1 Pembrolizumab was permanently discontinued because of immune-mediated hypophysitis in 0.1%, and was temporarily withheld in 0.3% of patients receiving the drug.1 In patients where pembrolizumab was temporarily withheld, pembrolizumab was restarted after symptom improvement.1
Thyroid Disorders : Immune-mediated thyroid disorders (i.e., hyperthyroidism, hypothyroidism, thyroiditis) can occur in patients receiving pembrolizumab therapy.1 Thyroiditis may present with or without endocrinopathy.1 Hypothyroidism can also develop following hyperthyroidism.1 If hypothyroidism occurs, initiate hormone replacement therapy or institute medical management as clinically indicated.1 Temporary interruption or discontinuance of pembrolizumab may be required depending on thyroid disorder severity.1
Immune-mediated thyroiditis occurred in 0.6% of patients receiving single-agent pembrolizumab, including grade 2 in 0.3%.1 No patients discontinued pembrolizumab due to thyroiditis.1 Pembrolizumab was temporarily withheld in <0.1% of patients.1 In patients where pembrolizumab was temporarily withheld, pembrolizumab was restarted after symptom improvement.1
In clinical studies evaluating single-agent pembrolizumab, immune-mediated hyperthyroidism occurred in 3.4% of patients and was grade 2 or 3 in 0.9% of patients receiving pembrolizumab.1 Pembrolizumab was permanently discontinued because of immune-mediated hyperthyroidism in less than 0.1% of patients receiving the drug.1 The drug was temporarily withheld in 0.3% of patients.1
The incidence of new or worsening hyperthyroidism was increased in clinical studies evaluating single-agent pembrolizumab as adjuvant treatment in resected non-small cell lung cancer (NSCLC), occurring in 11% of patients.1 Grade 3 hyperthyroidism occurred in 0.2% of patients receiving the drug.1
In clinical studies evaluating single-agent pembrolizumab, immune-mediated hypothyroidism occurred in 8% of patients and was grade 2 or 3 in 6.3% of patients receiving pembrolizumab.1 Pembrolizumab was permanently discontinued because of immune-mediated hypothyroidism in <0.1% and temporarily withheld in 0.5% of patients receiving the drug.1 In patients where pembrolizumab was temporarily withheld, pembrolizumab was reinitiated after symptom improvement.1 The majority of patients with hypothyroidism required long-term thyroid hormone replacement.1 In clinical studies evaluating single-agent pembrolizumab or in combination with platinum-chemotherapy and fluorouracil in patients with squamous cell carcinoma of the head and neck, new-onset or worsening immune-mediated hypothyroidism occurred in 16% of patients and was grade 3 in 0.3% of patients receiving the drug.1 The incidence of new or worsening hypothyroidism was increased in patients with classical Hodgkin lymphoma (cHL [17%]) receiving single-agent pembrolizumab, with grade 2 hypothyroidism occurring in 10.8% of patients receiving the drug.1
In clinical studies evaluating single-agent pembrolizumab, new or worsening hypothyroidism was increased in patients with resected NSCLC (22%) receiving single-agent adjuvant pembrolizumab, with grade 3 hypothyroidism occurring in 0.3% of patients receiving the drug.1
Diabetes Mellitus and Diabetic Ketoacidosis : In clinical studies evaluating single-agent pembrolizumab, immune-mediated type 1 diabetes mellitus occurred in 0.2% of patients receiving pembrolizumab.1 Pembrolizumab was permanently discontinued in <0.1% of patients and was temporarily withheld in <0.1% of patients receiving the drug.1 All patients who were temporarily withheld pembrolizumab reinitiated the drug after symptom improvement.1 All patients who developed type 1 diabetes mellitus required long-term insulin therapy.1
Patients receiving pembrolizumab should be monitored for hyperglycemia and other signs and symptoms of diabetes mellitus.1 Insulin should be initiated as clinically indicated.1 Pembrolizumab therapy should be temporarily interrupted based on reaction severity.1
Immune-mediated nephritis has occurred in patients receiving pembrolizumab therapy.1
In clinical studies evaluating single-agent pembrolizumab, immune-mediated nephritis occurred in 0.3% of patients and was grade 3 or 4 in approximately 0.2% of patients receiving the drug.1 Most patients (89%) experiencing immune-mediated nephritis required systemic corticosteroid therapy.1 Pembrolizumab was permanently discontinued because of immune-mediated nephritis in 0.1% of patients and was temporarily withheld in 0.1% of patients receiving the drug.1 Of the patients who reinitiated pembrolizumab after symptom improvement, none had recurrence of nephritis.1 Immune-mediated nephritis resolved in 56% of patients.1
Immune-mediated Dermatologic Adverse Reactions
Immune-mediated rash or dermatitis may occur in patients receiving pembrolizumab therapy.1 Exfoliative dermatitis, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), can also occur in patients receiving pembrolizumab therapy.1 Application of topical emollients and/or topical corticosteroids may be sufficient for the treatment of mild to moderate non-exfoliative rashes.1 Temporary interruption or permanent discontinuance of pembrolizumab may be necessary depending on the severity of the dermatologic adverse reaction.1 .1
In clinical studies evaluating single-agent pembrolizumab, immune-mediated dermatologic reactions occurred in 1.4% of patients and was grade 3 in 1% of patients receiving the drug.1 Systemic corticosteroids were required in 40% of patients who developed immune-mediated dermatologic reactions.1 Pembrolizumab was permanently discontinued because of immune-mediated dermatologic reactions in 0.1% of patients and was temporarily withheld in 0.6% of patients receiving the drug.1 Of the patients who reinitiated pembrolizumab after symptom improvement, 6% had recurrence of the immune-mediated dermatologic reaction.1 Immune-mediated dermatologic reactions resolved in 79% of patients.1
If Stevens-Johnson syndrome, DRESS, or TEN is suspected, pembrolizumab therapy should be temporarily interrupted.1 If Stevens-Johnson syndrome, DRESS, or TEN is confirmed, pembrolizumab should be permanently discontinued.1
Other Immune-mediated Reactions
Other clinically significant immune-mediated adverse reactions occurring at an incidence of <1% (except for arthritis), which may be severe or fatal, have occurred in patients receiving pembrolizumab therapy or receiving other PD-1/PD-L1 blocking antibodies.1
In clinical studies of patients receiving pembrolizumab, clinically significant cardiovascular/vascular immune-mediated adverse reactions reported in <1% of patients include myocarditis, pericarditis, and vasculitis.1 Pembrolizumab led to clinically significant nervous system immune-mediated adverse effects, including meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, and autoimmune neuropathy in <1% of patients.1 In addition, ocular immune-mediated adverse effects reported in <1% of patients receiving pembrolizumab include uveitis, iritis, and other ocular inflammatory toxicities, which can be associated with retinal detachment in some cases.1 Various grades of visual impairment, including blindness, have also been reported.1 Diagnosis of a Vogt-Koyanagi-Harada-like syndrome should be considered in cases where uveitis occurs alongside other immune-mediated adverse reactions; this syndrome may require systemic corticosteroid treatment to reduce the risk of permanent vision loss.1 In clinical studies of patients receiving pembrolizumab, clinically significant GI immune-mediated adverse effects reported in <1% of patients include pancreatitis (including increases in serum amylase and lipase), gastritis, and duodenitis.1 Clinically significant musculoskeletal and connective tissue immune-mediated adverse effects reported in <1% of patients receiving pembrolizumab include myositis/polymyositis, rhabdomyolysis and associated sequelae (including renal failure) and polymyalgia rheumatica; however, immune-mediated arthritis occurred in 1.5% of patients receiving the drug.1 Immune-mediated endocrine disorders reported in <1% of patients include hypoparathyroidism.1 Pembrolizumab also led to clinically significant hematologic/immune adverse effects such as hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, and immune thrombocytopenic purpura.1 Solid organ transplant rejection and other transplant rejection, including corneal graft rejection, have also been reported.1
Severe or life-threatening infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred in 0.2% of patients receiving single-agent pembrolizumab.1
Patients receiving pembrolizumab should be monitored for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever.1 For grade 1 or 2 infusion-related reactions, interrupt or slow the rate of the pembrolizumab infusion.1 In patients experiencing grade 3 or 4 infusion-related reactions, the pembrolizumab infusion should be stopped and the drug permanently discontinued.1
Allogeneic Stem Cell Transplantation-related Complications
Transplant-related complications, including hyperacute graft-versus-host disease (GVHD), acute or chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and corticosteroid-requiring febrile syndrome (without an identified infectious cause), have occurred in patients who underwent allogeneic stem cell transplantation prior to or following therapy with a PD-1/PD-L1 blocking antibody.1 Some cases have resulted in serious complications or death.1 Transplant-related complications following allogeneic stem cell transplantation may occur despite other intervening therapy between PD-1/PD-L1 blockade and transplantation.1
In patients prior to or following allogeneic stem cell transplantation, the potential benefit of a PD-1/PD-L1 blocking antibody should be weighed against the risks of developing complications.1 Patients receiving pembrolizumab should be monitored closely for evidence of transplant-related complications and such conditions should be managed promptly if they occur.1
Increased mortality has been reported in clinical trials in patients with multiple myeloma receiving pembrolizumab in combination with an immunomodulatory agent (i.e., lenalidomide, pomalidomide); pembrolizumab is not currently FDA-labeled for use in patients with multiple myeloma.1, 21 In 2 randomized, controlled phase 3 trials (KEYNOTE-183 and KEYNOTE-185) enrolling 550 patients with multiple myeloma, interim analyses indicated that the risk of death was increased by 61 or 106%, respectively, in patients receiving pembrolizumab in combination with an immunomodulatory agent (pomalidomide or lenalidomide, respectively) and low-dose dexamethasone compared with those receiving the immunomodulatory agent and low-dose dexamethasone.21 Because of these findings, these trials were terminated at FDA's request.21
The manufacturer of pembrolizumab states that an anti-PD-1 or anti-PD-L1 antibody should not be used in combination with an immunomodulatory agent (i.e., lenalidomide, pomalidomide) and dexamethasone in patients with multiple myeloma outside of a controlled clinical trial.1 FDA recommends that ongoing clinical trials evaluating an anti-PD-1 or anti-PD-L1 agent in combination with an immunomodulatory agent or in combination with other drugs for use in hematologic malignancies be evaluated for permanent discontinuance or protocol amendments.21
Fetal/Neonatal Morbidity and Mortality
Pembrolizumab may cause fetal harm if administered to pregnant women.1 Blockade of signaling of the PD-1 and PD-L1 pathway in animals has been shown to disrupt maternal immune tolerance to the fetus and has been associated with increased fetal loss and immune-mediated disorders.1 Therefore, inhibition of this pathway by pembrolizumab may increase the risk of fetal loss (e.g., abortion, stillbirth).1 Human immunoglobulin G4 (IgG4) has been shown to cross the placenta; therefore, fetal exposure to pembrolizumab may occur and increase the risk of immune-mediated disorders or alter normal immune response of the developing fetus.1
Pregnancy should be avoided during pembrolizumab therapy.1 The manufacturer states that pregnancy status should be verified prior to initiation of pembrolizumab therapy in women of childbearing potential and such women should be advised to use a highly effective method of contraception while receiving pembrolizumab and for at least 4 months after the last dose.1 If pembrolizumab is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
The ability of the electrochemiluminescence (ECL) assay to detect anti-pembrolizumab antibodies is limited by the presence of circulating drug.1 Development of anti-pembrolizumab antibodies was detected in 2.1% of patients receiving pembrolizumab 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks; neutralizing antibodies to pembrolizumab were detected in 0.5% of patients receiving the drug at these dosages.1 No effects of antibody formation on pharmacokinetics or safety (i.e., infusion-related reactions) of the drug were observed.1 Because of the low occurrence of anti-pembrolizumab antibodies, the impact of these antibodies on pembrolizumab efficacy is not known.1
There are no human data available to inform the risk of embryo-fetal toxicity.1 Pembrolizumab may cause fetal harm if administered to pregnant women based on its mechanism of action.1 Pembrolizumab has the potential to cross the placenta; advise pregnant women of the potential risk to a fetus.1
Pregnancy status should be verified in women of reproductive potential prior to initiation of pembrolizumab therapy.1
It is not known whether pembrolizumab is distributed into human milk.1 The effects of pembrolizumab on nursing infants or on milk production also are unknown.1 Maternal immunoglobulin G (IgG) is present in human milk.1 The impact of local GI exposure and minimal systemic exposure to pembrolizumab on the breast-fed infant is not known.1 Because of the potential for serious adverse reactions to pembrolizumab in nursing infants, women should be advised to discontinue nursing during pembrolizumab therapy and for 4 months after the last dose.1
Females and Males of Reproductive Potential
Verify pregnancy status in women of reproductive potential prior to initiation of pembrolizumab therapy.1
Pembrolizumab may cause fetal harm if administered during pregnancy.1 Advise women of reproductive potential to use effective contraception during treatment with pembrolizumab and for 4 months following the last dose.1
Safety and efficacy of single-agent pembrolizumab have been established in pediatric patients with melanoma, cHL, primary mediastinal large B-cell lymphoma (PMBCL), Merkel cell carcinoma (MCC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, and tumor mutational burden-high (TMB-H) cancer.1
Safety and efficacy of pembrolizumab for the above indications in pediatric patients are supported by extrapolation of data from clinical studies evaluating pembrolizumab in adults, safety data in pediatric patients, and pharmacokinetic data indicating that age (range of 15-94 years) does not have clinically important effects on clearance of the drug.1
Safety and efficacy of pembrolizumab in pediatric patients have not been established in other approved indications to date.1
Pediatric patients (range: 10 months-17 years of age) receiving pembrolizumab (2 mg/kg every 3 weeks) had similar plasma concentrations of pembrolizumab to those observed in adults receiving the same dosage of the drug.1 In KEYNOTE-051, some adverse reactions occurred at a ≥10% higher incidence in pediatric patients compared to adults, including pyrexia (33%), vomiting (29%), headache (25%), abdominal pain (23%), decreased lymphocyte count (13%), and decreased white blood cell count (11%).1 The median duration of exposure to pembrolizumab was 2.1 months (range: 1 day to 25 months).1 Laboratory abnormalities that occurred at a ≥10% higher incidence were leukopenia (30%), neutropenia (28%), thrombocytopenia (22%), and grade 3 anemia (17%).1
In clinical trials evaluating pembrolizumab for melanoma, NSCLC, squamous cell carcinoma of the head and neck, cHL, and urothelial carcinoma, 48% of patients were ≥65 years of age and 17% were ≥75 years of age.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1
In clinical trials evaluating pembrolizumab for cHL, 12% of patients were ≥65 years of age.1 Patients ≥65 years of age had a higher incidence of severe adverse reactions (50%) compared to younger adults (24%).1 A sufficient number of patients ≥65 years of age were not included in cHL studies to assess if there are differences in pembrolizumab efficacy compared to younger adults.1
In clinical trials evaluating pembrolizumab in patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy, 48% of patients were ≥65 years of age.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1
In clinical trials evaluating pembrolizumab in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin in patients with TNBC, 23% of patients were ≥65 years of age.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1
In clinical trials evaluating pembrolizumab in combination with lenvatinib in patients with endometrial carcinoma, 50% of patients were ≥65 years of age.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1
In clinical trials evaluating pembrolizumab in combination with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer, 44% of patients were 65<74 years of age and 26% were ≥75 years of age.1 No overall differences in safety and efficacy were observed between patients ≥65 years of age and younger adults; however, patients ≥75 years of age experienced a higher incidence of fatal adverse effects compared to younger adults.1 The incidence of fatal adverse effects was 4% in patients <75 years of age compared to 7% in patients ≥75 years of age.1
In clinical trials evaluating pembrolizumab in combination with axitinib for RCC, 40% of patients were ≥65 years of age.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1
In clinical trials evaluating pembrolizumab in combination with chemoradiotherapy (CRT) in patients with FIGO 2014 Stage III<IVA cervical cancer, 14% of patients were ≥65 years of age.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1
Analysis of population pharmacokinetic data indicates that clearance of pembrolizumab is not altered in patients with mild to moderate hepatic impairment (total bilirubin concentration ≤3 times ULN with any AST concentration).1 Insufficient data are available for patients with severe hepatic impairment (total bilirubin concentration >3 times ULN with any AST concentration).1
Analysis of population pharmacokinetic data indicates that clearance of pembrolizumab is not altered in patients with renal impairment (estimated glomerular filtration rate [eGFR] ≥15 mL/minute per 1.73 m2).1
Adverse effects reported in ≥20% of patients in clinical studies receiving single-agent pembrolizumab include fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism.1
Adverse effects reported in ≥20% of patients in clinical studies receiving pembrolizumab in combination with chemotherapy or chemoradiotherapy include fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism.1
Adverse effects reported in ≥20% of patients in clinical studies receiving pembrolizumab in combination with chemotherapy plus bevacizumab include peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite.1
Adverse effects reported in ≥20% of patients in clinical studies receiving pembrolizumab in combination with axitinib include diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.1
Adverse effects reported in ≥20% of patients in clinical studies receiving pembrolizumab in combination with lenvatinib include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury.1
Adverse effects reported in ≥20% of patients in clinical studies receiving pembrolizumab in combination with enfortumab vedotin include rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eyes, nausea, constipation, dysgeusia, and urinary tract infection.1
Pembrolizumab, a humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody, is an antineoplastic agent.1, 7, 8 The drug is an IgG4 kappa immunoglobulin.1, 8
Pembrolizumab is highly selective for PD-1, an immune-checkpoint receptor expressed on activated T-cells, monocytes, B-cells, natural killer (NK) T-cells, and dendritic cells.1, 3, 5, 8 Overexpression of PD-1 ligands on the surface of tumor cells results in activation of PD-1 and suppression of cytotoxic T-cell activity.1, 8 Pembrolizumab blocks the interaction between PD-1 and its ligands, resulting in enhanced immune response, including enhanced antitumor immune response.1, 8 In syngeneic mouse tumor models, pembrolizumab also has been shown to reduce tumor growth.1 Combination treatment with an anti-PD-1 antibody and lenvatinib in syngeneic mouse tumor models decreased tumor-associated macrophages, increased activated cytotoxic T cells, and reduced tumor growth compared to either treatment given alone.1
Area under the serum concentration-time curve (AUC), peak plasma concentration, and trough concentration of pembrolizumab are proportional to dose over the dosage range of 2-10 mg/kg every 3 weeks.1 Following repeated doses of pembrolizumab every 3 weeks, steady-state concentrations are reached by 16 weeks; systemic accumulation of the drug is 2.1-fold.1 Based on exposure-response relationships for efficacy and safety, the manufacturer states that there are no clinically important differences in safety and efficacy between pembrolizumab 200 mg every 3 weeks and pembrolizumab 2 mg/kg every 3 weeks regardless of cancer type.1 Based on observed exposure-response relationships for efficacy and safety in adult patients with melanoma, the manufacturer states that there are no clinically important differences between pembrolizumab 200 mg every 3 weeks or pembrolizumab 2 mg/kg every 3 weeks and pembrolizumab 400 mg every 6 weeks in patients with solid tumors.1 The manufacturer states that exposure-response relationships for efficacy and safety have not been fully characterized at pembrolizumab dosages of 400 mg every 6 weeks in patients with classical Hodgkin lymphoma (cHL) or primary mediastinal large B-cell lymphoma (PMBCL).1 Clearance of pembrolizumab is approximately 23% lower at steady state than following the initial dose; however, this difference is not considered clinically important.1 The mean terminal half-life of pembrolizumab is 22 days.1
The pharmacokinetics of pembrolizumab do not appear to be affected by age (range: 15-94 years), sex, race (89% white), renal impairment (eGFR ≥15 mL/minute per 1.73 m2), mild to moderate hepatic impairment (total bilirubin concentration ≤3 times ULN with any AST concentration), or tumor burden.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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43. Long GV, Carlino MS, McNeil C, et al. Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase III KEYNOTE-006 study. Ann Oncol . 2024;35(12):1191-1199.
44. Eggermont AMM, Kicinski M, Blank CU, et al. Five-Year Analysis of Adjuvant Pembrolizumab or Placebo in Stage III Melanoma. NEJM Evid . 2022;1(11):EVIDoa2200214.
45. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet . 2022;399(10336):1718-1729.
46. Long GV, Luke JJ, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol . 2022;23(11):1378-1388.
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