Nivolumab, a fully human anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody, is an antineoplastic agent.1 The drug is an IgG4 kappa immunoglobulin.1
Nivolumab and hyaluronidase-nvhy (nivolumab/hyaluronidase-nvhy) is a fixed combination of nivolumab (an anti-PD-1 monoclonal antibody) and hyaluronidase (an endoglycosidase).42
Nivolumab (Opdivo®) is used as monotherapy or in combination with ipilimumab for the treatment of unresectable or metastatic melanoma in adults and pediatric patients ≥12 years of a 1 nivolumab is designated an orphan drug by FDA for the treatment of this cancer.4
The fixed combination of nivolumab and hyaluronidase-nvhy (nivolumab/hyaluronidase-nvhy; Opdivo Qvantig®) is used as monotherapy for the treatment of unresectable or metastatic melanoma in adults; nivolumab/hyaluronidase-nvhy is not indicated for use in combination with ipilimumab, but may be used following combination treatment with IV nivolumab and ipilimumab.42
Nivolumab is used as adjuvant therapy in adults and pediatric patients ≥12 years of age with stage IIB, IIC, III, or IV melanoma following complete resection; nivolumab/hyaluronidase-nvhy is used for this indication in adults only.1, 42
Unresectable or Metastatic Melanoma
The current indications for nivolumab as monotherapy or in combination with ipilimumab for the treatment of unresectable or metastatic melanoma are based principally on the results of an open-label, multicenter, randomized, phase 3 study (CheckMate-037) and results of 2 multicenter, double-blind, randomized, phase 3 studies (CheckMate-066 and CheckMate-067).1, 2, 14, 15, 41, 43
The CheckMate-037 study included 405 adults with unresectable or metastatic melanoma that had progressed during or following therapy with ipilimumab and, in those with tumors bearing the b-Raf serine-threonine kinase (BRAF) V600 mutation, therapy with a BRAF inhibitor.1, 2 Patients were randomized (stratified by programmed-death ligand-1 [PD-L1] expression status, BRAF mutation status, and response to prior ipilimumab therapy) in a 2:1 ratio to receive either nivolumab (3 mg/kg administered by IV infusion every 2 weeks) or investigator's choice of chemotherapy (either dacarbazine 1 g/m2 every 3 weeks or carboplatin at the dose required to obtain an AUC of 6 mg/mL per minute in combination with paclitaxel 175 mg/m2 every 3 weeks) until disease progression or unacceptable toxicity occurred.1, 2 However, clinically stable patients with disease progression could continue treatment if they were considered to be deriving clinical benefit.2 In a planned noncomparative interim analysis, efficacy in the initial 120 patients randomized to receive nivolumab was evaluated based on overall response rate (as evaluated by a blinded independent central review committee) and duration of response.1, 2 The median age of patients in the initial nivolumab-treated cohort was 58 years; all patients in this cohort had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1 Most patients (76%) in this cohort had TNM metastasis stage M1c disease, 68% had received 2 or more prior systemic therapies for their disease, 56% had elevated LDH concentrations, 22% had tumors bearing the BRAF V600 mutation, and 18% had a history of brain metastasis.1 Demographic characteristics of the entire study population were similar to those of the initial nivolumab-treated cohort.1, 2 This study excluded patients receiving immunosuppressive agents and those with autoimmune disease, ocular melanoma, active brain metastasis, or a history of immune-mediated adverse effects with prior ipilimumab therapy (i.e., any grade 4 immune-mediated adverse effect [except for endocrinopathies] or grade 3 immune-mediated adverse effect that persisted for more than 12 weeks).1, 2
After a minimum follow-up of 6 months in the CheckMate-037 study, the overall response rate in the initial cohort of nivolumab-treated patients was 32%; complete response was achieved in 4 patients.1, 2 At the time of analysis, the median duration of response had not been reached; most (87%) of the patients who responded to nivolumab had ongoing responses.1, 2 Exploratory analysis suggested higher objective response rates for nivolumab compared with investigator's choice of chemotherapy regardless of BRAF mutation status or prior ipilimumab benefit; although a response benefit was observed for nivolumab compared with chemotherapy in patients with negative PD-L1 expression, the benefit of nivolumab relative to that of chemotherapy appeared to be greater in those with positive PD-L1 expression (defined as PD-L1 expression of any intensity on at least 5% of tumor cells as detected by immunohistochemistry assay).2 In the entire study population, median overall survival was 15.7 or 14.4 months in patients receiving nivolumab or investigator's choice of chemotherapy, respectively.1, 43
In the CheckMate-066 study, 418 patients with previously untreated unresectable or metastatic BRAF wild-type melanoma were randomized (stratified by PD-L1 expression status and stage of metastasis) to receive either nivolumab (3 mg/kg administered by IV infusion every 2 weeks) or dacarbazine (1 g/m2 every 3 weeks) until disease progression or unacceptable toxicity occurred.1, 14 However, patients with disease progression could continue receiving treatment if they were considered to be deriving clinical benefit.14 The primary measure of efficacy was overall survival; additional outcome measures were progression-free survival and overall response rate.1, 14 The median age of patients was 65 years; 99.5% were white and 59% were male.1, 14 Most patients (99%) enrolled in the study had an ECOG performance status of 0 or 1; however, a larger proportion of patients receiving nivolumab had an ECOG performance status of 0 compared with those receiving dacarbazine (71 versus 58%).1, 14 Most patients (61%) had TNM metastasis stage M1c disease, 74% had cutaneous melanoma, 11% had mucosal melanoma, 37% had elevated LDH concentrations, 35% had positive PD-L1 expression (defined as PD-L1 expression of any intensity on at least 5% of tumor cells as detected by immunohistochemistry assay), and 4% had a history of brain metastasis.1, 14 Patients with a history of serious autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastasis were excluded from the study.1, 14
In the CheckMate-066 study, median overall survival in patients receiving nivolumab had not been reached at the time of the interim analysis; however, nivolumab reduced the risk of death by 58% compared with dacarbazine.1, 14 At the time of the initial interim analysis, patients receiving nivolumab had a higher overall response rate (34 versus 9%) and longer median progression-free survival (5.1 versus 2.2 months) compared with patients receiving dacarbazine.1, 14 Progression-free survival for nivolumab- and dacarbazine-treated patients at the time of the updated analysis remained similar to the initial interim results.44 At the time of the updated analysis, overall response rates in nivolumab- and dacarbazine-treated patients were 42 and 14%, respectively; complete responses were achieved in 20 and 1% of nivolumab- and dacarbazine-treated patients, respectively.44 Median duration of response had not been reached in those receiving nivolumab and was 6 months in those receiving dacarbazine.44 The median time to complete or partial response was 2.1 months in nivolumab-treated patients and 2.2 months, respectively, in dacarbazine-treated patients.44
In the CheckMate-067 study, 945 patients with previously untreated unresectable or metastatic melanoma were randomized (stratified by PD-L1 expression status, BRAF V600 mutation status, and stage of metastasis) to receive one of 3 regimens: nivolumab (1 mg/kg by IV infusion) in combination with ipilimumab (3 mg/kg by IV infusion) every 3 weeks for 4 doses, followed by nivolumab monotherapy (3 mg/kg by IV infusion every 2 weeks); nivolumab (3 mg/kg by IV infusion every 2 weeks) and placebo; or ipilimumab (3 mg/kg by IV infusion every 3 weeks for 4 doses) and placebo.1, 15 Treatment was continued until disease progression or unacceptable toxicity occurred; however, patients with disease progression could continue receiving treatment if they were considered to be deriving clinical benefit.15 The primary measures of efficacy were progression-free survival and overall survival; additional outcome measures were overall response rate and duration of response.1, 15 In this study, the median age of patients was 61 years; 97% were white, 65% were male, 46% had positive PD-L1 expression (defined as PD-L1 expression of any intensity on at least 5% of tumor cells as detected by immunohistochemistry assay), 36% had elevated LDH concentrations, 32% had BRAF V600 mutation-positive melanoma, 22% had received prior adjuvant therapy, and 4% had a history of brain metastasis.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients (93%) had metastatic disease; 58% of patients had TNM metastasis stage M1c disease.1 Patients with autoimmune disease, conditions requiring therapy with immunosuppressive agents, ocular melanoma, or active brain metastasis were excluded from the study.1, 15
After a minimum follow-up of 28 months in the CheckMate-067 study, overall survival rate was higher in patients receiving nivolumab in combination with ipilimumab and in those receiving nivolumab compared with those receiving ipilimumab (59 and 55%, respectively, versus 37%).1 Progression-free survival also was prolonged in patients receiving nivolumab in combination with ipilimumab and in those receiving nivolumab compared with those receiving ipilimumab (11.7 and 6.9 months, respectively, versus 2.9 months).1, 15 In addition, patients receiving nivolumab in combination with ipilimumab and those receiving nivolumab had higher overall response rates compared with those receiving ipilimumab (50 and 40%, respectively, versus 14%); complete responses were achieved in 8.9, 8.5, or 1.9% of patients receiving combination therapy with nivolumab and ipilimumab, nivolumab, or ipilimumab, respectively.1, 15 After a minimum follow-up of 28 months, 55, 56, or 39% of patients receiving these respective treatments had durable responses of 24 months or more.1 After a minimum follow-up of 48 months, median overall survival was 36.9 or 19.9 months in patients receiving nivolumab or ipilimumab, respectively, but had not been reached in those receiving nivolumab in combination with ipilimumab.1, 41 At the final analysis conducted after a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab alone, and 19.9 months with ipilimumab alone.45 Progression-free survival remained similar to the initial interim results.45 Results of a subgroup analysis (including PD-L1 expression status and BRAF V600 mutation status, among others) suggested that the progression-free survival and overall survival benefit of nivolumab or nivolumab in combination with ipilimumab versus ipilimumab was consistent across all subgroups.45
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously was based on the previously summarized studies conducted with IV nivolumab (Opdivo®), and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between nivolumab/hyaluronidase-nvhy and IV nivolumab.42
Adjuvant Therapy for Locally Advanced or Metastatic Melanoma
The current indication for nivolumab as adjuvant therapy for stage IIB, IIC, III, or IV melanoma is based principally on the results of 2 randomized, double-blind, phase 3 studies (CheckMate-76K and CheckMate-238) in patients with completely resected stage IIIB, IIC, III, or IV melanoma.1, 26, 46
In CheckMate-76K, 790 patients ≥12 years of age with completely resected stage IIB/C melanoma were randomized (stratified by disease stage) to receive either nivolumab 480 mg or placebo by IV infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable toxicity occurred.1, 46 The primary measure of efficacy was investigator-assessed recurrence-free survival.1, 46 The median age of patients enrolled in the study was 62 years; 98% were white, 94% had a baseline ECOG performance status of 0, 61% were male, and 61% had stage IIB disease.1 Patients were eligible for enrollment in the study following complete resection of melanoma within 12 weeks prior to randomization.1, 46 The study excluded patients with a history of autoimmune disease, ocular/uveal or mucosal melanoma, or any condition requiring therapy with systemic corticosteroids or immunosuppressive agents; those who had received prior therapy for melanoma other than surgery were also excluded.1, 46
After a minimum follow-up of 7.8 months, 12.5% of patients treated with nivolumab and 26.1% of patients in the placebo group had recurrence or death.46 The benefits seen with nivolumab were consistent across all stages of melanoma.46
In CheckMate-238, 906 patients were randomized (stratified by disease stage and PD-L1 expression status) to receive either nivolumab (3 mg/kg administered by IV infusion every 2 weeks) or ipilimumab (10 mg/kg by IV infusion every 3 weeks for 4 doses then every 12 weeks beginning at week 24) for up to 1 year or until disease recurrence or unacceptable toxicity occurred.1, 26 The primary measure of efficacy was recurrence-free survival.1, 26 The median age of patients enrolled in the study was 55 years; 95% were white, 90% had a baseline ECOG performance status of 0, 58% were male, 81% had stage IIIB or IIIC disease, 42% had BRAF V600 mutation-positive melanoma, 48% had macroscopic lymph node involvement, 34% had positive PD-L1 expression (defined as PD-L1 expression of any intensity on at least 5% of tumor cells as detected by a clinical trial assay), 32% had tumor ulceration, and 8% had elevated LDH concentrations.1, 26 Patients were eligible for enrollment in the study following complete resection of melanoma within 12 weeks prior to randomization.1, 26 The study excluded patients with a history of autoimmune disease, ocular/uveal melanoma, or any condition requiring therapy with systemic corticosteroids or immunosuppressive agents; those who had received prior therapy for melanoma other than surgery; those who had received adjuvant radiation therapy following neurosurgical resection; and those who had received adjuvant therapy with interferon alfa 6 months or more prior to randomization.1, 26
After a minimum follow-up of 18 months, median recurrence-free survival had not been reached in either group; however, nivolumab reduced the risk of recurrence or death by 35% compared with ipilimumab.1, 26 At 18 months, the recurrence-free survival rate was 66.4 or 52.7% in patients receiving nivolumab or ipilimumab, respectively.26 Results of a subgroup analysis (based on age, gender, disease stage, PD-L1 status, BRAF mutation status, presence of tumor ulceration, lymph node involvement, and disease subtype) suggested that the effect of nivolumab on recurrence-free survival was consistent across most subgroups; however, a recurrence-free survival benefit for nivolumab versus ipilimumab was not apparent in patients with stage IV M1c disease, those with microscopic lymph node involvement and ulceration of the primary tumor, or those with a mucosal subtype.26 After a minimum follow-up of 4 years, median recurrence-free survival was 52.4 months in patients receiving nivolumab and 24.1 months in the ipilimumab group.47
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized studies conducted with IV nivolumab (Opdivo®).42
Nivolumab and nivolumab/hyaluronidase-nvhy are used in combination with platinum doublet chemotherapy for the treatment of adults with resectable (node-positive or tumors ≥4 cm) non-small cell lung cancer (NSCLC) in the neoadjuvant setting.1, 42
Nivolumab and nivolumab/hyaluronidase-nvhy are used for the treatment of adults with resectable NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, for neoadjuvant treatment in combination with platinum doublet chemotherapy followed by single-agent nivolumab or nivolumab/hyaluronidase-nvhy as adjuvant treatment after surgery.1, 42
Nivolumab (Opdivo®) is used in combination with ipilimumab for the first-line treatment of adults with 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 high PD-L1 expression prior to initiation of therapy.1 Nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC.42
Nivolumab (Opdivo®) is used in combination with ipilimumab and 2 cycles of platinum doublet chemotherapy for the first-line treatment of adults with metastatic or recurrent NSCLC with no EGFR or ALK genomic aberrations.1 Nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC.42
Nivolumab and nivolumab/hyaluronidase-nvhy are used for the treatment of adults with metastatic NSCLC that has progressed during or following therapy with platinum-based chemotherapy and, in those with EGFR mutation- or ALK-positive tumors, therapy with an EGFR or ALK inhibitor.1, 42
Neoadjuvant/Adjuvant Treatment of Resectable NSCLC
The current indication for nivolumab as neoadjuvant treatment of resectable NSCLC is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-816).1, 48 In CheckMate-816, 358 patients with resectable stage IB, II, or IIIA NSCLC were randomized (stratified by tumor PD-L1 expression status, disease stage, and sex) to receive either nivolumab 360 mg IV plus platinum doublet chemotherapy or platinum doublet chemotherapy alone; therapy was administered every 3 weeks for up to 3 cycles and patients underwent surgery within 6 weeks following completion of neoadjuvant therapy.1, 48 Choice of agents for platinum doublet chemotherapy was based on histology: paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 5 or 6 mg/mL per minute for any histology; pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 for non-squamous histology; or gemcitabine 1000 mg/m2 or 1250 mg/m2 and cisplatin 75 mg/m2 for squamous histology.1 Patients in the platinum doublet chemotherapy arm (any histology) also had 2 additional treatment regimen options: vinorelbine 25 mg/m2 or 30 mg/m2 and cisplatin 75 mg/m2; or docetaxel 60 mg/m2or 75 mg/m2 and cisplatin 75 mg/m2.1 The primary measures of efficacy were event-free survival (as evaluated by blinded independent central review) and pathological complete response (as evaluated by blinded independent pathological review); overall survival was assessed as an additional outcome measure.1, 48 The median age of patients enrolled in the study was 65 years; 50% were Asian and 47% were white, 71% were male, 89% were former or current smokers, and 50% had tumors with PD-L1 expression ≥1% at baseline.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients had stage IIIA disease (64%), 35% had stage IB/II, and 51% of tumors had squamous histology.1 This study excluded patients with unresectable or metastatic NSCLC, known EGFR mutations or ALK translocations, peripheral neuropathy with grade ≥2, active autoimmune disease, or medical conditions requiring systemic immunosuppression.1, 48
At a minimum follow-up of 21 months, median event-free survival was 31.6 months in the nivolumab plus chemotherapy group and 20.8 months with chemotherapy alone.1, 48 Pathologic complete response occurred in 24% of patients treated with nivolumab plus chemotherapy compared to 2.2% of patients treated with chemotherapy alone.1, 48 At the time of analysis, median overall survival was not reached in either group.48
The current indication for nivolumab in combination with platinum doublet chemotherapy as neoadjuvant treatment of resectable NSCLC, followed by surgery and then adjuvant treatment with nivolumab monotherapy, is based principally on the results of a randomized, double-blind, phase 3 study (CheckMate-77T).1, 49 In CheckMate-77T, 461 patients with resectable stage IIA to IIIB NSCLC were randomized (stratified by disease stage, tumor histology, and PD-L1 expression status) to receive neoadjuvant therapy with nivolumab 360 mg IV plus platinum doublet chemotherapy or placebo plus platinum doublet chemotherapy; therapy was administered every 3 weeks for 4 cycles and patients underwent surgery within 6 weeks following completion of neoadjuvant therapy.1, 49 Choice of agents for platinum doublet chemotherapy was based on histology: paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 5 or 6 mg/mL per minute for any histology; pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5 or 6 mg/mL per minute for non-squamous histology; or cisplatin 75 mg/m2 and docetaxel 75 mg/m2 for squamous histology.1 Within 90 days following surgery, patients in the nivolumab or placebo groups received adjuvant treatment with nivolumab 480 mg IV or placebo every 4 weeks, respectively.1, 49 Treatment was administered for up to 13 cycles (1 year) or until disease progression, recurrence, or unacceptable toxicity occurred.1, 49 The primary measure of efficacy was event-free survival (as evaluated by blinded independent central review); overall survival and pathologic complete response were assessed as an additional outcome measures.1, 49 The median age of patients enrolled in the study was 66 years; 72% were white and 25% were Asian, 71% were male, 90% were former or current smokers, and 56% had tumors with PD-L1 expression ≥1% at baseline.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients had stage III disease (64%), 35% had stage II disease, 23% had N1 disease, 39% had N2 disease, and 51% of tumors had squamous histology.1 This study excluded patients with unresectable or metastatic NSCLC, known EGFR mutations or ALK translocations, brain metastasis, peripheral neuropathy with grade ≥2, interstitial lung disease or active noninfectious pneumonitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression.1
At a median follow-up of 25.4 months, median event-free survival was not reached in the nivolumab plus chemotherapy group and 18.4 months with chemotherapy alone.1, 49 The percentage of patients with 18-month event-free survival was 70.2% in the nivolumab plus chemotherapy group and 50% in the chemotherapy group.49 Pathologic complete response occurred in 25.3% of patients treated with nivolumab plus chemotherapy compared to 4.7% of patients treated with chemotherapy alone.49 At the time of analysis, data on overall survival were immature.1
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for these indications was based on the previously summarized studies conducted with IV nivolumab (Opdivo®), and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
First-line Treatment of Metastatic/Recurrent NSCLC
The current indication for nivolumab used in combination with ipilimumab for the first-line treatment of metastatic or recurrent NSCLC is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-227).1, 50 In part 1 of the CheckMate-227 trial, patients with previously untreated recurrent or stage IV NSCLC were randomized (stratified by tumor histology) to receive either nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks or platinum doublet chemotherapy every 3 weeks for up to 4 cycles.1, 50 Choice of agents for platinum doublet chemotherapy was based on histology: pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC 5 or 6 mg/mL per minute for non-squamous histology; or gemcitabine 1000 mg/m2 or 1250 mg/m2 plus cisplatin 75 mg/m2 or gemcitabine 1000 mg/m2 plus carboplatin (AUC 5 mg/mL per minute) for squamous histology.1 Treatment was continued through 2 years of follow up or until disease progression or unacceptable toxicity occurred.1, 50 The primary measure of efficacy in part 1a of the trial, which evaluated 793 patients with PD-L1 expression >1%, was overall survival.1, 50 Progression-free survival, objective response rate, and duration of response (all evaluated by blinded independent central review) were also assessed.1 The median age of patients enrolled in the study was 64 years; 76% were white, 65% were male, 85% were former or current smokers, and 50% had tumors with PD-L1 expression ≥50% at baseline.1 Almost all patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients (71%) had non-squamous histology, 29% had squamous histology, and 10% had brain metastases.1 This study excluded patients with known EGFR mutations or ALK translocations, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression.
At a minimum follow-up of 29.3 months, median overall survival was 17.1 months in the nivolumab plus ipilimumab group and 14.9 months with chemotherapy.1, 50 Median progression-free survival was 5.1 months with nivolumab plus ipilimumab and 5.6 months with platinum doublet chemotherapy1 ; the objective response rate was 35.9 or 30%, respectively.50 At the time of analysis, the median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy.1, 50 At a minimum follow-up of 61.3 months, 5-year overall survival rates were 24% for nivolumab plus ipilimumab and 14% for chemotherapy; median duration of response was 24.5 or 6.7 months, respectively.51
The current indication for nivolumab used in combination with ipilimumab and platinum doublet chemotherapy for the first-line treatment of metastatic or recurrent NSCLC is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-9LA).1, 52 In CheckMate-9LA, 719 patients with recurrent or stage IV NSCLC not previously treated in the metastatic setting were randomized (stratified by tumor PD-L1 expression level, tumor histology, and sex) to receive either nivolumab 360 mg IV every 3 weeks plus ipilimumab 1 mg/kg IV every 6 weeks and platinum doublet chemotherapy IV every 3 weeks for 2 cycles, or platinum doublet chemotherapy alone every 3 weeks for up to 4 cycles.1, 52 Choice of agents for platinum doublet chemotherapy was based on histology: pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC 5 or 6 mg/mL per minute for non-squamous histology; or paclitaxel 200 mg/m2 plus carboplatin (AUC 6 mg/mL per minute) for squamous histology.1, 52 Patients with non-squamous histology could also receive optional maintenance therapy with pemetrexed.1, 52 Treatment was continued through 2 years of follow up or until disease progression or unacceptable toxicity occurred.1, 52 The primary measure of efficacy was overall survival.1 Progression-free survival, objective response rate, and duration of response (all evaluated by blinded independent central review) were also assessed.1 The median age of patients enrolled in the study was 65 years; 89% were white, 70% were male, 86% were former or current smokers, and 57% had tumors with PD-L1 expression ≥1% at baseline.1 Almost all patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients (68%) had non-squamous histology, 32% had squamous histology, and 17% had metastases to the CNS.1 This study excluded patients with known EGFR mutations or ALK translocations, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression.1
At a prespecified interim analysis conducted after a minimum follow-up of 8.1 months, median overall survival was 14.1 months in the nivolumab/ipilimumab/chemotherapy group and 10.7 months with chemotherapy alone.1, 52 Median progression-free survival was 6.8 months with nivolumab/ipilimumab/chemotherapy and 5 months with chemotherapy alone.1, 52 The objective response rate was 37.7% with nivolumab/ipilimumab/chemotherapy and 25.1% with chemotherapy alone.52 After an additional 4.6 months of follow-up, median overall survival was 15.6 months with nivolumab/ipilimumab/chemotherapy and 10.9 months with chemotherapy alone.1 The median duration of response was 10 or 5.1 months, respectively.1 At a minimum follow-up of 57.3 months, 5-year overall survival rates were 18% for nivolumab/ipilimumab/chemotherapy and 11% for chemotherapy alone; median 5-year duration of response rates were 19% or 8%, respectively.53
Nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC.42
Second-line Treatment of Metastatic NSCLC
The current indication for nivolumab as second-line treatment of metastatic NSCLC is based principally on the results of 2 randomized phase 3 studies in patients with metastatic squamous NSCLC (CheckMate-017) or metastatic nonsquamous NSCLC (CheckMate-057).1, 16 In the CheckMate-017 study, 272 patients with metastatic squamous NSCLC that had progressed during or following therapy with one platinum-containing, 2-drug combination regimen were randomized to receive either nivolumab (3 mg/kg administered by IV infusion every 2 weeks) or docetaxel (75 mg/m2 administered by IV infusion every 3 weeks).1 The primary measure of efficacy was overall survival.1 The median age of patients enrolled in the study was 63 years; all patients enrolled in the study had an ECOG performance status of 0 or 1.1 Patients were eligible for enrollment in the study regardless of tumor expression of PD-L1.1 This study excluded patients with autoimmune disease, any condition requiring therapy with immunosuppressive agents, symptomatic interstitial lung disease, or untreated brain metastasis.1
At the time of data analysis in the CheckMate-017 study, median overall survival (9.2 versus 6 months) and progression-free survival (3.5 versus 2.8 months) were prolonged and overall response rates (20 versus 9%) were higher in patients receiving nivolumab compared with those receiving docetaxel; complete response was achieved in 1 patient receiving nivolumab and none of those receiving docetaxel.1 Median overall survival, median progression-free survival, and overall response rates remained similar at the time of a 24-month analysis.22 Among patients with evaluable PD-L1 expression, there were no clear differences in overall survival based on PD-L1 expression.1
In the CheckMate-057 study, 582 patients with metastatic nonsquamous NSCLC that had progressed during or following therapy with one platinum-containing, 2-drug combination regimen were randomized to receive either nivolumab (3 mg/kg administered by IV infusion every 2 weeks) or docetaxel (75 mg/m2 administered by IV infusion every 3 weeks) until disease progression or unacceptable toxicity occurred.1, 16 The primary measure of efficacy was overall survival; additional outcome measures were overall response rate and progression-free survival.1, 16 The median age of patients enrolled in the study was 62 years; all patients enrolled in the study had an ECOG performance status of 0 or 1, 93% had adenocarcinoma histology, 14% had EGFR mutation-positive disease, 3.6% had ALK-positive disease, and 40% had received maintenance therapy as part of their first-line regimen.1, 16 This study excluded patients with autoimmune disease, symptomatic interstitial lung disease, untreated brain metastasis, or any condition requiring therapy with immunosuppressive agents.1, 16
At the time of the interim analysis in the CheckMate-057 study, patients receiving nivolumab had longer median overall survival compared with those receiving docetaxel (12.2 versus 9.4 months).1, 16 Although not statistically significant, progression-free survival appeared to be shorter in patients receiving nivolumab compared with those receiving docetaxel (2.3 versus 4.2 months).1, 16 Patients receiving nivolumab had a higher overall response rate compared with those receiving docetaxel (19 versus 12%); complete responses were achieved in 1.4 or 0.3% of patients receiving nivolumab or docetaxel, respectively.1, 16 At the time of analysis, the median duration of response was 17 months in patients receiving nivolumab and 6 months in those receiving docetaxel;1, 16 however, responses were ongoing in nivolumab-treated patients.1 Median overall survival, median progression-free survival, and overall response rates remained similar at the time of a 24-month analysis.22 Subgroup analysis based on relevant patient characteristics (prior maintenance therapy, line of therapy, age, gender, ECOG performance status, smoking status, EGFR mutation status, KRAS mutation status) suggested that nivolumab had a greater effect on overall survival relative to docetaxel in most patient subgroups; however, a survival benefit for nivolumab versus docetaxel was not apparent for patients receiving the drug as third-line therapy, those who had never smoked, and those with EGFR mutation-positive disease.16 Subgroup analysis also indicated that increasing levels of PD-L1 expression were associated with overall survival and progression-free survival benefits for nivolumab compared with docetaxel.1
In the CheckMate-063 study, 117 patients with advanced squamous NSCLC that had progressed following therapy with a platinum-based regimen and at least one additional systemic therapy received nivolumab 3 mg/kg administered by IV infusion every 2 weeks.3 The primary measure of efficacy was overall response rate (as evaluated by an independent central review committee); an additional outcome measure was duration of response.3 The median age of patients enrolled in the study was 65 years; all patients enrolled in the study had an ECOG performance status of 0 or 1.3 Patients were eligible for enrollment in the study regardless of their PD-L1 status.1 This study excluded patients with autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis.3 After a minimum follow-up of 10 months, the overall response rate was 15%; there were no complete responses.3 At the time of analysis, 76% of the responders had ongoing responses; 59% of these patients had durable responses of 6 months or more.3 After a minimum follow-up of 64.2 (CheckMate-017) and 64.5 (CheckMate-057) months, 5-year pooled overall survival rates were 13.4% for patients treated with nivolumab and 2.6% for those treated with docetaxel; 5-year progression-free survival rates were 8 and 0%, respectively.54
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized studies conducted with IV nivolumab (Opdivo®), and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Malignant Pleural Mesothelioma
Nivolumab (Opdivo®) is used in combination with ipilimumab for the first-line treatment of unresectable malignant pleural mesothelioma (MPM) in adults;1 nivolumab has been designated an orphan drug by FDA for the treatment of this cancer.4
The current indication for nivolumab in combination with ipilimumab as first-line treatment of unresectable MPM is based principally on the results of an open-label, randomized, phase 3 study (CheckMate-743).1, 55 Adults with unresectable MPM, with no prior treatment and no palliative radiotherapy within the past 14 days, were enrolled.1, 55 In this study, 605 patients were randomized (stratified by tumor histology and sex) in a 1:1 ratio to receive nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks for up to 2 years or chemotherapy with cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 or carboplatin AUC 5 mg/mL per minute plus pemetrexed 500 mg/m2 given every 3 weeks for 6 cycles.1, 55 Treatment was continued for up to 2 years, or until disease progression or unacceptable toxicity occurred.1, 55 The primary measure of efficacy was overall survival; additional efficacy measures included progression-free survival, objective response rate, and duration of response, as assessed by blinded independent central review committee according to Response Evaluation Criteria in Solid Tumors (RECIST).1, 55 The median age of patients enrolled was 69 years; 85% were white, 11% were Asian, and 77% were male.1 Most patients (75%) had epithelioid and 25% had non-epithelioid histology; 75% had PD-L1 expression ≥1%, 35% had stage III disease, and 51% had stage IV disease.1 All patients enrolled had an ECOG performance status of 0 or 1.1 This study excluded patients with active autoimmune disease, conditions requiring therapy with immunosuppressive agents, active brain metastases, or interstitial lung disease.1, 55
At a minimum of 22.1 months of follow-up, median overall survival was 18.1 months with nivolumab plus ipilimumab versus 14.1 months for chemotherapy; median progression-free survival was 6.8 or 7.2 months, respectively.1, 55 Patients treated with nivolumab plus ipilimumab had an objective response rate of 40% versus 43% for patients treated with chemotherapy.1, 55 The duration of response was 11 or 6.7 months for nivolumab plus ipilimumab or chemotherapy, respectively.1, 55 At a median follow-up of 43.1 months, overall survival benefits of nivolumab plus ipilimumab were sustained.56
Nivolumab (Opdivo®) is used in combination with ipilimumab for the treatment of intermediate- or poor-risk, previously untreated, advanced renal cell carcinoma in adults.1 Nivolumab/ hyaluronidase-nvhy (Opdivo Qvantig®) is used for this indication after initial treatment with IV nivolumab (Opdivo®) plus ipilimumab and is not indicated for use in combination with ipilimumab.42
Nivolumab and nivolumab/hyaluronidase-nvhy are used in combination with cabozantinib as first-line treatment for adults with advanced renal cell carcinoma.1, 42
Nivolumab and nivolumab/hyaluronidase-nvhy are used as monotherapy for the treatment of adults with advanced renal cell carcinoma previously treated with antiangiogenic therapy.1, 42
First-line Therapy for Advanced Renal Cell Carcinoma
The current indication for nivolumab in combination with ipilimumab for the treatment of intermediate- or poor-risk, previously untreated, advanced renal cell carcinoma is based principally on the results of a randomized, open-label phase 3 study (CheckMate-214) in adults with previously untreated advanced renal cell carcinoma.1, 37 In this study, 1082 patients were randomized (stratified by geographic region and International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk score) to receive either nivolumab (3 mg/kg by IV infusion) in combination with ipilimumab (1 mg/kg by IV infusion) every 3 weeks for 4 doses, followed by nivolumab monotherapy (3 mg/kg by IV infusion every 2 weeks), or sunitinib (50 mg orally once daily for 4 consecutive weeks of each 6-week cycle).1, 37 Treatment was continued until disease progression or unacceptable toxicity occurred.1 The primary measures of efficacy were overall survival, progression-free survival (as evaluated by an independent review committee according to RECIST), and objective response rate (as evaluated by an independent review committee according to RECIST) in patients with intermediate- or poor-risk disease (defined as patients with at least one prognostic risk factor according to IMDC criteria).1, 37 The median age of patients enrolled in the study was 61 years (8% of patients were 75 years of age or older); 87% were white and 73% were male.1 All patients enrolled in the study had a baseline Karnofsky performance status of 70 or greater.1, 37 Patients were eligible for enrollment in the study regardless of tumor expression of PD-L1.1 This study excluded patients with active autoimmune disease, any history of or active brain metastasis, or any condition requiring therapy with immunosuppressive agents.1, 37
At a median follow-up of 25.2 months, median overall survival for patients with intermediate- or poor-risk disease receiving nivolumab in combination with ipilimumab had not been reached; however, nivolumab in combination with ipilimumab reduced the risk of death by 37% compared with sunitinib.1, 37 Progression-free survival was 11.6 months in patients receiving nivolumab in combination with ipilimumab and 8.4 months in those receiving sunitinib; however, the difference was not statistically significant.1, 37 Patients with intermediate- or poor-risk disease receiving nivolumab in combination with ipilimumab also had higher objective response rates (41.6 versus 26.5%); complete response was achieved in 9.4% of patients receiving nivolumab in combination with ipilimumab and 1.2% of those receiving sunitinib.1, 37 At the time of analysis, the median duration of response had not been reached in patients receiving nivolumab in combination with ipilimumab and was 18.2 months in those receiving sunitinib.1, 37 Results of a subgroup analysis (based on age, gender, geographic region, IMDC risk category, prior nephrectomy, baseline level of PD-L1 expression, and site of metastases) in patients with intermediate- or poor-risk disease suggested a survival benefit for nivolumab in combination with ipilimumab relative to sunitinib across subgroups.37 In an exploratory analysis, an overall survival benefit for the nivolumab-ipilimumab combination regimen compared with sunitinib was not apparent in the subgroup of patients who had favorable-risk disease (hazard ratio: 1.45).1, 37 At 5 years from randomization, mean overall survival was 40.7 months for patients treated with nivolumab plus ipilimumab versus 36.1 months for patients treated with sunitinib.57
The current indication for nivolumab in combination with cabozantinib as first-line treatment for adults with advanced renal cell carcinoma is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-9ER).1, 58 The CheckMate-9ER study compared the combination of cabozantinib tablets and nivolumab with sunitinib in 651 patients with previously untreated advanced renal cell carcinoma.1, 58 Patients were randomized to receive cabozantinib tablets 40 mg orally daily in combination with nivolumab 240 mg IV every 2 weeks, or sunitinib 50 mg orally daily for the first 4 weeks of each 6-week cycle (4 weeks on treatment followed by 2 weeks off).1 The primary efficacy end point was progression-free survival; secondary end points were overall survival and objective response rate.1
The median age of patients in the CheckMate-9ER study was 61 years; 74% were male, 82% were white, and 23% and 77% of patients had a baseline Karnofsky Performance Score of 70-80% and 90-100%, respectively.1 Risk status by IMDC was favorable in 22% of patients, intermediate in 58%, and poor in 20%.1 At a median follow-up duration of 18.1 months, a substantial improvement in progression-free survival (16.6 versus 8.3 months), overall survival (hazard ratio of 0.60), and objective response rate (55.7% versus 27.1%) was observed in patients receiving cabozantinib plus nivolumab compared with those receiving sunitinib.1, 58 Consistent results for progression-free survival were observed across prespecified subgroups of IMDC risk categories and PD-L1 tumor expression status.1
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for these indications was based on the previously summarized studies conducted with IV nivolumab (Opdivo®), and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Previously Treated Advanced Renal Cell Carcinoma
The current indication for nivolumab as monotherapy in the treatment of advanced renal cell carcinoma is based principally on the results of a randomized, open-label phase 3 study (CheckMate-025) in adults with advanced renal cell carcinoma that had progressed during or following treatment with 1 or 2 prior antiangiogenic therapies.1, 17 In this study, 821 patients were randomized (stratified by geographic region, Memorial Sloan-Kettering Cancer Center [MSKCC] risk category, number of prior therapies including an antiangiogenic agent) to receive either nivolumab (3 mg/kg administered by IV infusion every 2 weeks) or everolimus (10 mg orally once daily).1, 17 The primary measure of efficacy was overall survival.1, 17 The median age of patients enrolled in the study was 62 years (9% of patients were 75 years of age or older); 88% were white, 75% were male, 81% had MSKCC favorable- or intermediate-risk disease, and 77% had received one prior antiangiogenic therapy.1, 17 All patients enrolled in the study had a baseline Karnofsky performance status of 70 or greater.1 Patients were eligible for enrollment in the study regardless of tumor expression of PD-L1.1, 17 This study excluded patients with active autoimmune disease, any history of or active brain metastasis, or any condition requiring therapy with immunosuppressive agents, and those previously treated with a mammalian target of rapamycin (mTOR) inhibitor.1, 17
After a minimum follow-up of 14 months, patients receiving nivolumab had longer median overall survival compared with those receiving everolimus (25 versus 19.6 months).1, 17 Results of a subgroup analysis suggested that the effect of nivolumab on overall survival was consistent regardless of MSKCC risk category, number of prior therapies including an antiangiogenic agent, and geographic region; however, an overall survival benefit for nivolumab versus everolimus was not apparent in the small group of patients 75 years of age or older.17 Patients receiving nivolumab also had higher objective response rates (21.5 versus 3.9%), with a median response duration of 23 months for those receiving nivolumab and 13.7 months for those receiving everolimus.1 The median time to response was 3 months (range: 1.4-13 months) for nivolumab-treated patients.1 This study was terminated prematurely at the request of the independent data monitoring committee because of improved overall survival observed during the prespecified interim analysis in patients receiving nivolumab.17 At a minimum follow-up of 64 months, nivolumab maintained an overall survival benefit compared to everolimus (median overall survival of 25.8 versus 19.7 months, respectively).59
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized studies conducted with IV nivolumab (Opdivo®), and additional pharmacokinetic and safety data (including data from the CheckMate-67T trial) demonstrating comparable pharmacokinetics between Opdivo Qvantig™ and IV nivolumab.42, 60 CheckMate-67T compared IV nivolumab with subcutaneous nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) for previously treated advanced renal cell carcinoma and found similar pharmacokinetics and objective response rates (18 versus 24%, respectively) between treatments.42
Nivolumab (Opdivo®) is used for the treatment of classical Hodgkin lymphoma (cHL) that has relapsed or progressed following autologous stem cell transplantation and subsequent therapy with brentuximab vedotin or following failure of at least 3 systemic therapies (including autologous stem cell transplantation);1 nivolumab has been designated an orphan drug by FDA for the treatment of this cancer.4 The accelerated approval of nivolumab for this indication is based on objective response rate.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of nivolumab in confirmatory studies.1
The current indication for nivolumab for the treatment of cHL is based principally on analysis of combined data from a cohort of patients in an open-label, multicenter, noncomparative phase 2 study (CheckMate-205) and an open-label, multicenter phase 1 dose-escalation study (CheckMate-039);1, 19, 20 95 patients with cHL that had relapsed or progressed following autologous stem cell transplantation and subsequent therapy with brentuximab vedotin and 258 patients with cHL that had relapsed or progressed following autologous stem cell transplantation were included in the pooled analysis.1 The primary measure of efficacy was objective response rate as assessed by an independent review committee; an additional outcome measure was duration of response.1 Patients in both studies received nivolumab 3 mg/kg administered by IV infusion every 2 weeks.1, 19, 20 Treatment was continued until disease progression, maximum clinical benefit, or unacceptable toxicity occurred.1, 19, 20 Patients were eligible for enrollment in these studies regardless of tumor expression of PD-L1.1 The studies excluded patients with an ECOG performance status of 2 or greater, autoimmune disease, or symptomatic interstitial lung disease; those who had received an allogeneic stem cell transplant; those who had received radiation therapy to the chest area within 24 weeks prior to enrollment; and those with a history of pulmonary toxicity who had an adjusted diffusion lung capacity for carbon monoxide (DLCO) of 60% or less.1
In the cohort of patients who had relapsed or had experienced disease progression following autologous stem cell transplantation and subsequent therapy with brentuximab vedotin, the median age of patients was 37 years; 87% were white and 64% were male.1 The median number of previous systemic therapies for patients in this cohort was 5 (range: 2-15).1 The overall response rate for patients in this cohort was 66%; complete response was achieved in 6% of patients in this cohort.1 At a median follow-up of 9.9 months, the estimated median duration of response was 13.1 months for patients in this cohort.1 The median time to response was 2 months (range: 0.7-11.1 months).1
In the cohort of patients who had relapsed or had experienced disease progression following autologous stem cell transplantation, the median age of patients was 34 years; 86% were white and 59% were male.1 Most patients (85%) in this cohort had received at least 3 prior therapies; the median number of previous therapies was 4 (range: 2-15).1 Most patients (76%) in this cohort had received prior therapy with brentuximab vedotin; 78% of patients received brentuximab vedotin following stem cell transplantation, 17% received the drug prior to stem cell transplantation, and 5% received the drug prior to and following stem cell transplantation.1 The overall response rate for patients in this cohort was 69%; complete response was achieved in 14% of patients in this cohort.1 At a median follow-up of 6.7 months, the median duration of response had not been reached.1 The median time to response was 2 months (range: 0.7-11.1 months).1
Squamous Cell Carcinoma of the Head and Neck
Nivolumab and nivolumab/hyaluronidase-nvhy are used for the treatment of adults with metastatic or recurrent squamous cell carcinoma of the head and neck that has progressed during or following therapy with platinum-based chemotherapy.1, 42 In patients with metastatic or recurrent squamous cell carcinoma of the head and neck, nivolumab therapy has been shown to prolong overall survival compared with standard chemotherapy.1, 21
The current indication for nivolumab for the treatment of metastatic or recurrent squamous cell carcinoma of the head and neck is based principally on the results of a randomized, open-label phase 3 study (CheckMate-141) in adults with metastatic or recurrent squamous cell carcinoma of the head and neck that had progressed during or within 6 months following platinum-based chemotherapy in the neoadjuvant, adjuvant, primary (unresectable locally advanced), or metastatic setting.1, 21 In this study, 361 patients were randomized (stratified by prior cetuximab use) to receive either nivolumab (3 mg/kg administered by IV infusion every 2 weeks) or investigator's choice of standard chemotherapy (cetuximab 400 mg/m2 by IV infusion followed by cetuximab 250 mg/m2 by IV infusion weekly; methotrexate 40-60 mg/m2 by IV infusion weekly; or docetaxel 30-40 mg/m2 by IV infusion weekly) until disease progression or unacceptable toxicity occurred.1, 21 However, nivolumab therapy could be continued in patients with disease progression if they were considered to be deriving clinical benefit.21 The primary measure of efficacy was overall survival; additional outcome measures were overall response rate and progression-free survival.1, 21 The median age of patients enrolled in the study was 60 years; most patients (98%) had an ECOG performance status of 0 or 1, 90% had metastatic disease, 83% were white, 83% were male, 76% were former or current smokers, 55% had received at least 2 prior therapies, 51% had unknown human papillomavirus (HPV) status, and 25% had HPV-positive disease (as assessed by p16 immunohistochemistry assay).1, 21 This study excluded patients with autoimmune disease, untreated brain metastasis, conditions requiring therapy with immunosuppressive agents, human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, or salivary gland or nonsquamous histology (e.g., mucosal melanoma).1, 21
A planned interim analysis indicated that patients receiving nivolumab had longer overall survival compared with patients receiving standard chemotherapy (7.5 versus 5.1 months).1, 21 The median follow-up at the time of the interim analysis was 5.1 months.21 Results of the interim analysis suggested a numerical, but not statistically significant, increase in overall response rate with nivolumab compared with standard chemotherapy; progression-free survival was similar in both groups.1, 21 Results of a subgroup analysis (based on age, ECOG performance status, prior cetuximab therapy, lines of prior therapy, investigator's choice of standard chemotherapy, site of primary tumor, and platinum-refractory disease in the primary setting) suggested that the effect of nivolumab on overall survival was consistent across all subgroups.21 A planned exploratory analysis indicated a survival benefit for nivolumab compared with standard chemotherapy regardless of PD-L1 expression or p16 tumor status; although the survival benefit appeared to be more pronounced in patients with PD-L1 expression on 1% or more of tumor cells compared with those with PD-L1 expression levels of less than 1% (hazard ratios: 0.55 and 0.89, respectively) and in patients with p16-positive tumors compared with those with p16-negative tumors (hazard ratios: 0.56 and 0.73, respectively),1, 21 these interactions were not statistically significant.21 At a minimum follow-up of 24.2 months, nivolumab continued to improve overall survival compared to standard chemotherapy.61
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized studies conducted with IV nivolumab (Opdivo®), and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Nivolumab and nivolumab/hyaluronidase-nvhy are used for the adjuvant treatment of adults with urothelial carcinoma who are at high risk of recurrence following radical resection.1, 42
Nivolumab and nivolumab/hyaluronidase-nvhy are used in combination with cisplatin and gemcitabine for first-line treatment of adults with unresectable or metastatic urothelial carcinoma.1, 42
Nivolumab and nivolumab/hyaluronidase-nvhy are used for the treatment of adults with 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.1, 42
Adjuvant Treatment of Urothelial Carcinoma at High Risk of Recurrence
The current indication of nivolumab for the adjuvant treatment of urothelial carcinoma at high risk of recurrence is based principally on the results of a multicenter, randomized, double-blind, phase 3 trial (CheckMate-274).1, 62 Adults with urothelial carcinoma of the bladder or upper urinary tract (with or without use of neoadjuvant cisplatin-based chemotherapy) who were within 120 days of radical resection and at high risk of recurrence were enrolled.1, 62 In this study, patients were randomized (stratified by pathological nodal status, tumor PD-L1 expression, and use of neoadjuvant cisplatin) in a 1:1 ratio to receive nivolumab 240 mg or placebo IV every 2 weeks for a maximum duration of 1 year, or until recurrence or unacceptable toxicity occurred.1, 62 The primary measure of efficacy was disease-free survival; this outcome was evaluated in all patients who were randomized and in the subset of patients with tumor PD-L1 expression ≥1%.1, 62 Overall survival was assessed as an additional efficacy measure.1, 62 The median age of patients enrolled was 67 years; 76% were white, 76% were male, and most patients had an ECOG performance status of 0 or 1.1 Previous neoadjuvant cisplatin was administered in 43% of patients; 40% of patients had tumor PD-L1 expression ≥1%, and 21% of patients had urothelial carcinoma of the upper urinary tract.1
At a prespecified interim analysis (median follow-up of 20.9 months for patients in the nivolumab group or 19.5 months for patients in the placebo group), median disease-free survival was 20.8 months with nivolumab versus 10.8 months with placebo.1, 62 In the subpopulation of patients with tumor PD-L1 expression ≥1%, median disease-free survival was not reached for nivolumab and 8.4 months with placebo.1 At a minimum follow-up of 31.6 months, median disease-free survival in the entire population was 22 or 10.9 months for nivolumab versus placebo, respectively, and 52.6 or 8.4 months, respectively, in the subpopulation of patients with PD-L1 expression ≥1%.63 Overall survival was 69.5 months with nivolumab and 50.1 months with placebo in the overall population and was not reached in either arm among patients with PD-L1 expression ≥1%.63
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
First-line Treatment of Unresectable or Metastatic Urothelial Carcinoma
The current indication for nivolumab as first-line treatment of adults with unresectable or metastatic urothelial carcinoma is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-901).1, 64 In CheckMate-901, 608 adults with previously untreated urothelial carcinoma that was unresectable or metastatic were randomized to receive nivolumab plus cisplatin and gemcitabine or cisplatin plus gemcitabine alone; previous neoadjuvant or adjuvant chemotherapy was permitted if administered ≥12 months prior to disease recurrence.1, 64 Patients were stratified by PD-L1 status and liver metastasis and then randomized in a 1:1 ratio to receive IV treatment with: 1) nivolumab 360 mg plus cisplatin 70 mg/m2 on day 1, plus gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle for up to 6 cycles, followed by nivolumab 480 mg IV as monotherapy every 4 weeks for up to 2 years, or 2) cisplatin 70 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle for up to 6 cycles.1, 64 Therapy was continued until disease progression or unacceptable toxicity occurred.1, 64 The primary measures of efficacy were overall survival and progression-free survival as evaluated by a blinded independent central review committee using RECIST version 1.1.1, 64 Objective response rate (as assessed by a blinded independent central review committee) and duration of response were also evaluated.1, 64 The median age of patients enrolled was 65 years; 72% were white, 12% were Hispanic or Latino, 77% were male, and most patients had an ECOG performance status of 0 (53%) or 1 (46%).1 Urothelial carcinoma was metastatic in 87% of patients (20% of whom had liver metastasis) and locally advanced in 11%.1
At final analysis (median follow-up of 33.6 months), median overall survival was 21.7 months with the nivolumab plus cisplatin-gemcitabine group versus 18.9 months with cisplatin-gemcitabine alone; median progression-free survival was 7.9 or 7.6 months, respectively.1, 64 More patients receiving nivolumab plus cisplatin-gemcitabine achieved an objective response (57.6 versus 43.1% with cisplatin-gemcitabine alone); patients who received nivolumab plus cisplatin-gemcitabine also had a longer duration of response compared to those who did not receive nivolumab (9.5 versus 7.3 months, respectively).1, 64
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Previously Treated Advanced or Metastatic Urothelial Carcinoma
The current indication for nivolumab for the treatment of locally advanced or metastatic urothelial carcinoma is based principally on the results of a multicenter, noncomparative phase 2 study (CheckMate-275) in adults with locally advanced or metastatic urothelial carcinoma that had progressed during or following platinum-containing therapy for metastatic disease or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.1, 23 The primary measure of efficacy was objective response rate as assessed by a blinded independent review committee according to RECIST 1.1.1, 23 In this study, the median age of patients was 66 years; 86% were white, 84% had visceral metastases, 78% were male, and 27% had nonbladder urothelial carcinoma.1, 23 All patients enrolled in the study had an ECOG performance status of 0 or 1.1, 23 Approximately one-third (29%) of patients had received at least 2 prior therapies for metastatic disease and 34% had disease progression following platinum-containing therapy in the neoadjuvant or adjuvant setting; 36, 23, or 7% of patients had received prior treatment with cisplatin-, carboplatin-, or both cisplatin- and carboplatin-based regimens, respectively, for metastatic disease.1 Patients received nivolumab 3 mg/kg administered by IV infusion every 2 weeks until disease progression or unacceptable toxicity occurred;1, 23 however, patients with disease progression could continue treatment if they were considered to be deriving clinical benefit.23 Patients with active brain or leptomeningeal metastases, autoimmune disease, or any condition requiring therapy with immunosuppressive agents were excluded from the study.1, 23 Patients were eligible for enrollment in the study regardless of their PD-L1 status.1, 23
At a minimum follow-up of 6 months, the objective response rate was 19.6%; complete responses were achieved in 2.6% of patients.1, 23 Among patients who had received prior therapy only in the neoadjuvant and adjuvant setting, the objective response rate was 23.4%.1 At the time of analysis, the estimated median duration of response was 10.3 months;1 however, 77% of the patients who responded to nivolumab had ongoing responses.23 The median time to response was 1.9 months (range: 1.6-7.2 months).1 In the planned subgroup analysis based on PD-L1 expression (as detected by an immunohistochemistry assay [Dako PD-L1 IHC 28-8 pharmDx]), the objective response rate with nivolumab therapy was 15.1% in patients with PD-L1 expression on less than 1% of tumor cells and 25% in those with PD-L1 expression on 1% or more of tumor cells; complete responses were achieved in 0.7 or 4.8% of patients in these respective subgroups.1, 23 The median progression-free survival as assessed by the blinded independent review committee was 2 months.23 At a median follow-up of 7 months, median overall survival was 8.7 months in the overall population, 11.3 months in those with PD-L1 expression of 1% or more, and 6 months in those with PD-L1 expression of less than 1%.23 Results of a subgroup analysis (based on site of metastasis, ECOG performance status, Bellmunt risk factors, baseline hemoglobin concentration, baseline creatinine clearance, site of primary tumor, and prior therapy for advanced or metastatic disease) suggested that the drug's effect on tumor response was consistent across most subgroups; however, the effect on tumor response appeared to be reduced in patients with increasing number of Bellmunt risk factors.23
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Nivolumab (Opdivo®) is used as monotherapy or in combination with ipilimumab for the treatment of patients ≥12 years of age with metastatic colorectal cancer with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy.1 The accelerated approval of nivolumab as a single agent or in combination with ipilimumab for this indication is based on objective response rate and duration of response.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of nivolumab in confirmatory studies.1
Nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is used as monotherapy, or as monotherapy following treatment with IV nivolumab (Opdivo®) plus ipilimumab, for the treatment of adults with MSI-H or dMMR metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy.42 Nivolumab/hyaluronidase-nvhy is not indicated for use in combination with ipilimumab for this indication.42 The accelerated approval of nivolumab/hyaluronidase-nvhy for this indication is based on objective response rate and duration of response.42 Continued approval for this indication may be contingent on verification and description of clinical benefit of nivolumab in confirmatory studies.42
The current indication for nivolumab as a single agent or in combination with ipilimumab is based principally on the results of an open-label, multicenter, noncomparative phase 2 study (CheckMate-142) in adults with MSI-H or dMMR metastatic colorectal cancer who had experienced disease progression during or following at least one prior therapy, including fluoropyrimidine- and oxaliplatin- or irinotecan-containing therapy, or who had not tolerated such therapies.1, 24, 38 Objective response rate was assessed by a blinded independent review committee according to RECIST 1.1.1 In this study, patients assigned to the monotherapy cohort received nivolumab 3 mg/kg administered as an IV infusion every 2 weeks until disease progression or unacceptable toxicity occurred, and patients assigned to the combination therapy cohort received nivolumab 3 mg/kg administered as an IV infusion and ipilimumab 1 mg/kg administered as an IV infusion on day 1 of each 21-day cycle for 4 doses, followed by single-agent nivolumab therapy (3 mg/kg administered as an IV infusion every 2 weeks) until disease progression or unacceptable toxicity occurred;1, 24, 38 however, patients in both cohorts could continue single-agent nivolumab beyond initial disease progression if they were considered to be deriving clinical benefit.24, 38 Patients with active autoimmune disease, active brain metastasis, any condition requiring therapy with immunosuppressive agents, history of HIV infection, or HBV or HCV infection were excluded from the study.1, 24, 38
In the cohort of 74 patients who received single-agent nivolumab, the median age of patients was 53 years; 98% had an ECOG performance status of 0 or 1, 88% were white, 59% were male, and 36% had a history of Lynch syndrome.1, 24 Most patients (72%) had previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy and 42% of patients had previously received anti-EGFR therapy; 30, 28, 19, or 16% of patients had received 1, 2, 3, or 4 or more prior lines of therapy for metastatic disease, respectively.1 At a minimum follow-up of 33.7 months, the objective response rate was 38%; complete responses were achieved in 11% of patients.1, 24 At the time of analysis, 86 or 82% of patients had durable responses of at least 6 or 12 months, respectively.1 Among patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy, the objective response rate was 32%; complete responses were achieved in 9% of patients who had received such prior therapy; and 94 or 88% of the responders had durable responses of at least 6 or 12 months, respectively.1 Objective responses were observed regardless of PD-L1 expression (on tumor cells or tumor-infiltrating immune cells), presence of mutated or wild-type BRAF or KRAS, or history of Lynch syndrome.24
In the cohort of 119 patients who received nivolumab in combination with ipilimumab, the median age of patients was 58 years; 92% were white, 59% were male, and 29% had a history of Lynch syndrome.1, 38 All patients enrolled in the combination therapy cohort had a baseline ECOG performance status of 0 or 1.1, 38 Most patients (69%) had previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy and 29% of patients had previously received anti-EGFR therapy; 10, 40, 24, or 15% of patients had received 1, 2, 3, or 4 or more prior lines of therapy for metastatic disease, respectively.1, 38 At a minimum follow-up of 27.5 months, the objective response rate was 60%; complete responses were achieved in 14% of patients.1, 38 At the time of analysis, 89 or 77% of patients had durable responses of at least 6 or 12 months, respectively.1 Among patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy, the objective response rate was 56%; complete responses were achieved in 13% of patients who had received such prior therapy; and 87 or 74% of the responders had durable responses of at least 6 or 12 months, respectively.1
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Nivolumab (Opdivo®) is used in combination with ipilimumab for the treatment of adults with hepatocellular carcinoma previously treated with sorafenib;1 nivolumab has been designated an orphan drug by FDA for the treatment of this cancer.4 The accelerated approval of nivolumab for this indication is based on objective response rate and duration of response.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of nivolumab in confirmatory studies.1
Nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is used as monotherapy for the treatment of adults with hepatocellular carcinoma previously treated with sorafenib and following treatment with IV nivolumab (Opdivo®) and ipilimumab.42 Nivolumab/hyaluronidase-nvhy is not indicated for use in combination with ipilimumab for this indication.42 The accelerated approval of nivolumab/hyaluronidase-nvhy for this indication is based on objective response rate and duration of response.42 Continued approval for this indication may be contingent on verification and description of clinical benefit of nivolumab in confirmatory studies.42
The current indication for nivolumab for the treatment of previously treated hepatocellular carcinoma is based principally on the results for a cohort of patients with hepatocellular carcinoma in an open-label, multicenter, noncomparative, phase 1/2 study (CheckMate-040); the cohort included 49 adults with advanced hepatocellular carcinoma who had experienced disease progression during sorafenib therapy or who had not tolerated such therapy and were treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, followed by nivolumab monotherapy (cohort 4).1, 25 The primary measure of efficacy was objective response rate as assessed by a blinded independent review committee according to RECIST 1.1 and modified RECIST for hepatocellular carcinoma.1 The median age of patients in the nivolumab plus ipilimumab cohort was 60 years; 82% had Child-Pugh class A5 hepatic impairment, 88% were male, 80% had extrahepatic spread, 74% were Asian, 57% had active HBV infection, 51% had α-fetoprotein concentrations of 0.4 mg/L or more, 35% had vascular invasion, 8% had active HCV infection, and 29% had received at least 2 prior systemic therapies.1 All patients enrolled in cohort 4 had an ECOG performance status of 0 or 1 and previously had received sorafenib therapy; sorafenib was discontinued because of intolerable toxicity in 10% of patients.1 Alcohol consumption or nonalcoholic liver disease was the cause of hepatocellular carcinoma in 16 or 6% of patients, respectively.1 Prior therapies included surgical resection, locoregional therapy, and radiation therapy in 74, 59, and 29% of patients, respectively.1 Patients in cohort 4 received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by monotherapy with nivolumab 3 mg/kg administered as an IV infusion every 2 weeks until disease progression or unacceptable toxicity occurred.1, 25 The study excluded patients with autoimmune disease, brain metastasis, a history of hepatic encephalopathy, current or prior episodes of clinically important ascites, HIV infection, active HBV and HCV coinfection, or active HBV and hepatitis D virus (HDV) coinfection.1
At a minimum follow-up of 28 months, the objective response rate according to RECIST 1.1 or modified RECIST for patients in cohort 4 of this study was 33 or 35%, respectively; according to these response criteria, complete response was achieved in 8 or 12%, respectively, of patients.1 The duration of response ranged from 4.6 to ≥30.5 months; 88% of patients who responded to the drug had durable responses of 6 months or more, 56% had durable responses of 12 months or more, and 31% had durable responses of 24 months or more.1
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Nivolumab and nivolumab/hyaluronidase-nvhy are used for the treatment of completely resected esophageal or gastroesophageal junction cancer in adults who have received neoadjuvant chemoradiotherapy and have residual pathologic disease;1, 42 nivolumab has been designated an orphan drug by FDA for the treatment of this cancer.4
Nivolumab and nivolumab/hyaluronidase-nvhy are also used in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment of adults with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC);1, 42 nivolumab has been designated an orphan drug by FDA for the treatment of this cancer.4
Nivolumab (Opdivo®) is used in combination with ipilimumab for first-line treatment of adults with unresectable advanced or metastatic ESCC;1 nivolumab has been designated an orphan drug by FDA for the treatment of this cancer.4 Nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC.42
Nivolumab and nivolumab/hyaluronidase-nvhy are also used after prior treatment with fluoropyrimidine- and platinum-containing chemotherapy for the treatment of adults with unresectable advanced, recurrent, or metastatic ESCC;1, 42 nivolumab has been designated an orphan drug by FDA for the treatment of this cancer.4
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
The current indication for nivolumab as adjuvant treatment of resected esophageal or gastroesophageal junction cancer is based principally on the results of a multicenter, randomized, double-blinded, phase 3 trial (CheckMate-577).1, 65 CheckMate-577 enrolled 794 patients with esophageal or gastroesophageal junction cancer that was completely resected (negative margins) within 4-16 weeks before randomization and who had residual pathologic disease following concurrent chemoradiotherapy.1, 65 Patients were randomized 2:1 (stratified by tumor PD-L1 status, pathologic lymph node status, and histology) to receive either nivolumab 240 mg or placebo IV every 2 weeks for 16 weeks, followed by nivolumab 480 mg or placebo IV every 4 weeks beginning at week 17.1 Treatment was continued for up to 1 year, or until disease recurrence or unacceptable toxicity occurred.1, 65
The primary measure of efficacy was disease-free survival.1, 65 The median age of patients enrolled in the study was 62 years; all patients had an ECOG performance status of 0 or 1, 82% were white, 85% were male, 16% had a tumor PD-L1 status ≥1%, and 72% had tumors that were negative for PD-L1.1 At initial diagnosis, most patients had stage III disease (65%); 35% had stage 2 disease, 60% had esophageal carcinoma, and 40% had gastroesophageal junction carcinoma.1 At study entry, 58% had a pathologic positive lymph node status, 71% had histological confirmation of predominant adenocarcinoma, and 29% had predominant squamous cell carcinoma.1 This study excluded patients who did not receive chemoradiotherapy before surgery, those with stage IV resectable disease, those with autoimmune disease, or those with conditions requiring therapy with corticosteroids or other immunosuppressive agents.1 At a median follow-up of 24.4 months, disease-free survival was substantially longer with nivolumab compared to placebo (22.4 versus 11 months, respectively).1, 65
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig®and IV nivolumab.42
First-Line Treatment of Unresectable Advanced or Metastatic ESCC
The current indication for nivolumab as first-line treatment of unresectable advanced or metastatic ESCC is based principally on the results of a randomized, active-controlled, open-label, phase 3 trial (CheckMate-648).1, 66 CheckMate-648 included 970 patients with untreated, unresectable advanced, recurrent, or metastatic ESCC who were not amenable to chemoradiation or surgery with curative intent (although prior treatment with curative intent was allowed if completed >6 months before enrollment); patients were also required to have tumors that were evaluable for PD-L1 expression.1, 66 Patients were randomized (stratified by tumor PD-L1 expression, geographic region, ECOG performance status, and number of organs with metastases) to receive one of the following IV treatment regimens: 1) nivolumab 240 mg on days 1 and 15 plus fluorouracil 800 mg/m2 per day on days 1-5 plus cisplatin 80 mg/m2 on day 1 (of a 4-week cycle); 2) nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; or 3) fluorouracil 800 mg/m2 per day on days 1-5 plus cisplatin 80 mg/m2 on day 1 (of a 4-week cycle).1, 66 Treatment was continued for up to 2 years, or until disease progression or unacceptable toxicity occurred.1, 66 The primary measures of efficacy were overall survival and progression-free survival as assessed by a blinded independent review committee; these outcomes were tested in a hierarchical fashion, first in patients with PD-L1 expression ≥1%, then in the entire population.1, 66 Objective response rate (assessed by blinded independent central review) was also assessed in the entire population.1, 66 The median age of patients enrolled in the study was 64 years; all patients had an ECOG performance status of 0 or 1, 82% were male, 71% were Asian, 98% had histological confirmation of squamous cell carcinoma, and 1.9% had histological confirmation of adenosquamous cell carcinoma.1 This study excluded patients with symptomatic brain metastases, conditions requiring therapy with corticosteroids or immunosuppressive agents, or those at high risk of bleeding or fistula due to apparent invasion of tumor to organs adjacent to the esophageal tumor.1
At a minimum follow-up of 13 months, median overall survival was substantially longer with nivolumab plus chemotherapy compared to chemotherapy alone, both among patients with PD-L1 expression ≥1% (15.4 versus 9.1 months, respectively), and in the entire population (13.2 versus 10.7 months, respectively).1, 66 Median progression-free survival was also substantially longer with nivolumab plus chemotherapy compared to chemotherapy alone among patients with PD-L1 expression ≥1% (6.9 versus 4.4 months, respectively), but was similar between groups in the entire population (5.8 versus 5.6 months, respectively).1, 66 Nivolumab plus chemotherapy was also associated with higher objective response rates, both among patients with PD-L1 expression ≥1% (53 versus 20%, respectively) and the entire population (47 versus 27%, respectively);66 duration of response was also longer with nivolumab plus chemotherapy compared to chemotherapy alone in patients with PD-L1 expression ≥1% (8.4 versus 5.7 months, respectively) and the entire population (8.2 versus 7.1 months, respectively).1, 66
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
When comparing nivolumab plus ipilimumab to chemotherapy alone, median overall survival was substantially longer with nivolumab plus ipilimumab compared to chemotherapy alone, both among patients with PD-L1 expression ≥1% (13.7 versus 9.1 months, respectively) and in the entire population (12.8 versus 10.7 months, respectively).1, 66 Median progression-free survival was similar between patients treated with nivolumab plus ipilimumab and patients treated with chemotherapy alone among the subgroup of patients with PD-L1 expression ≥1% (4 versus 4.4 months, respectively); this outcome was therefore not tested in the overall trial population.1, 66 Nivolumab plus ipilimumab was also associated with higher objective response rates among patients with PD-L1 expression ≥1% (35 versus 20%, respectively), but not the entire population (28 versus 27%, respectively); duration of response was longer with nivolumab plus ipilimumab compared to chemotherapy alone in patients with PD-L1 expression ≥1% (11.8 versus 5.7 months, respectively) and the entire population (11.1 versus 7.1 months, respectively).1, 66
At a minimum follow-up of 29 months, nivolumab plus chemotherapy continued to demonstrate improvements in median overall survival compared to chemotherapy alone (PD-L1 ≥1%, 15 versus 9.1 months, respectively; entire population, 12.8 versus 10.7 months, respectively).67 Similarly, nivolumab plus ipilimumab also demonstrated improvements in median overall survival compared to chemotherapy alone (PD-L1 ≥1%, 13.1 versus 9.1 months, respectively; entire population, 12.7 versus 10.7 months, respectively).67 Nivolumab plus chemotherapy also continued to demonstrate improvements in progression-free survival compared to chemotherapy alone among patients with PD-L1 expression ≥1% (6.8 versus 4.4 months), but not in the entire population (5.8 versus 5.6 months, respectively); progression-free survival was not substantially different between patients treated with nivolumab plus ipilimumab or chemotherapy alone among patients with PD-L1 expression ≥1% (4 versus 4.4 months, respectively).67
Nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) is not indicated for use in combination with ipilimumab for the first-line treatment of patients with unresectable advanced or metastatic ESCC.42
Previously Treated Unresectable Advanced, Recurrent, or Metastatic ESCC
The current indication for nivolumab as treatment for previously treated, unresectable advanced, recurrent, or metastatic ESCC is based principally on the results of a multicenter, randomized, open-label, phase 3 trial (ATTRACTION-3).1, 68 ATTRACTION-3 included 419 patients with unresectable advanced, recurrent, or metastatic ESCC who were refractory or intolerant to ≥1 fluoropyrimidine- and platinum-based regimen.1, 68 Patients were randomized (stratified by region, number of organs with metastases, and PD-L1 status) to receive nivolumab 240 mg IV every 2 weeks or investigator's choice of taxane chemotherapy (either docetaxel 75 mg/m2 IV every 3 weeks or paclitaxel 100 mg/m2 IV once weekly for 6 weeks followed by 1 week off).1, 68 Treatment was continued until disease recurrence or unacceptable toxicity occurred.1, 68 The primary measure of efficacy was overall survival; objective response rate, progression-free survival (as assessed by the investigator using RECIST version 1.1), and duration of response were also assessed.1, 68 The median age of patients enrolled in the study was 65 years; all patients had an ECOG performance status of 0 or 1, 96% were Asian, 87% were male, 67% of patients had received 1 previous systemic therapy regimen, and 26% had received 2 previous systemic regimens.1 Among included patients, 48% had PD-L1 tumor expression ≥1%.1 This study excluded patients who were refractory or intolerant to taxane chemotherapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease or conditions requiring therapy with corticosteroids or other immunosuppressive agents, had tumor invasion of organs adjacent to the esophageal tumor, or had stents in the esophagus or respiratory tract.1
At a minimum follow-up of 17.6 months, median overall survival was 10.9 months with nivolumab compared to 8.4 months with taxane chemotherapy.1, 68 Objective responses were observed in 19% of patients treated with nivolumab versus 22% of patients treated with taxane chemotherapy;68 median progression-free survival was 1.7 or 3.4 months, respectively.1, 68 The median duration of response was 6.9 months with nivolumab and 3.9 months with taxane chemotherapy.68
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
Nivolumab and nivolumab/hyaluronidase-nvhy are used in combination with fluoropyrimidine- and platinum-containing chemotherapy for the treatment of adults with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma;1, 42 nivolumab has been designated an orphan drug by FDA for the treatment of this cancer.4
The current indication for nivolumab as treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma is based principally on the results of a multicenter, randomized, open-label, phase 3 trial (CheckMate-649).1, 69 CheckMate-649 included 1581 adults with previously untreated, unresectable advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.1, 69 Patients were randomized (stratified by tumor PD-L1 status, region, ECOG performance status, and chemotherapy regimen) to receive one of the following treatment regimens: 1) nivolumab 240 mg IV plus mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks alone; 2) nivolumab 360 mg IV plus CapeOX (oral capecitabine and IV oxaliplatin) every 3 weeks or CapeOX every 3 weeks alone.1, 69 Treatment was continued for up to 2 years, or until disease progression or unacceptable toxicity occurred.1, 69
The primary measures of efficacy were overall survival and progression-free survival as assessed by a blinded independent review committee per RECIST version 1.1.1, 69 Overall survival was tested in a hierarchical fashion, first in patients with a PD-L1 combined positive score (CPS) ≥5, then as a secondary outcome in patients with a PD-L1 CPS ≥1 and the entire population.1, 69 Progression-free survival according to blinded independent central review, objective response rate, and duration of response were also assessed across various PD-L1 CPS cutoffs and in the entire population.1, 69 The median age of patients enrolled in the study was 61 years; all patients had an ECOG performance status of 0 or 1, 70% were male, and 69% were white.1 The most common location of adenocarcinoma tumors was the stomach (70%), followed by the gastroesophageal junction (16%) and esophagus (13%).1 Patients who were human epidermal growth factor receptor 2 (HER2)-positive, or who had untreated CNS metastases, were excluded.1
At a minimum follow-up of 12.1 months, median overall survival was substantially longer with nivolumab plus chemotherapy compared to chemotherapy alone in all populations assessed, including patients with a PD-L1 CPS ≥5 (14.4 versus 11.1 months, respectively), PD-L1 CPS ≥1 (14 versus 11.3 months), and the entire population (13.8 versus 11.6 months).1 Median progression-free survival was also substantially longer with nivolumab plus chemotherapy compared to chemotherapy alone in patients with a PD-L1 CPS ≥5 (7.7 versus 6 months, respectively); in the entire population, median progression-free survival was 7.7 months for nivolumab plus chemotherapy and 6.9 months for chemotherapy alone.1 Objective response rates were higher for nivolumab plus chemotherapy compared to chemotherapy alone in all populations assessed, including patients with a PD-L1 CPS ≥5 (50 versus 38%, respectively), PD-L1 CPS ≥1 (49 versus 38%), and the entire population (47 versus 37%).1 Duration of response was also higher for nivolumab plus chemotherapy compared to chemotherapy in these populations: PD-L1 CPS ≥5 (9.5 versus 6.9 months, respectively), PD-L1 CPS ≥1 (8.5 versus 6.9 months), and the entire population (8.5 versus 6.9 months).1 At a minimum of 36.2 months follow-up, consistent benefits were seen for nivolumab plus chemotherapy compared to chemotherapy alone among patients with PD-L1 CPS ≥5; these results were also consistent in the entire population.70
The efficacy of the fixed combination of nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) administered subcutaneously for this indication was based on the previously summarized study conducted with IV nivolumab (Opdivo®) and additional pharmacokinetic and safety data demonstrating comparable pharmacokinetics and safety between Opdivo Qvantig® and IV nivolumab.42
Dispensing and Administration Precautions
Nivolumab (Opdivo®) is administered by IV infusion only.1 The injection is available as a 10 mg/mL single-dose vial.1 Nivolumab single-dose vials require further dilution prior to administration.1
Nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) is administered by subcutaneous injection only.42 The fixed-combination injection is available as a single-dose vial that contains 600 mg of nivolumab and 10,000 units of hyaluronidase per 5 mL (120 mg/2000 units per mL).42
Store product vials under refrigeration (2-8°C) in their original package to protect from light.1, 42 Do not shake or freeze.1, 42
Nivolumab (Opdivo®) is administered as an IV infusion through an IV line containing a sterile, nonpyrogenic, low protein binding in-line filter (pore size of 0.2-1.2 micrometer).1 After administration of the nivolumab infusion, flush the IV administration line.1
When nivolumab is administered in combination with other agents (i.e., ipilimumab, platinum doublet chemotherapy, or fluoropyrimidine- and platinum-containing chemotherapy), administer nivolumab first, followed by the other agents.1 If nivolumab is used in combination with both ipilimumab and platinum doublet chemotherapy, administer ipilimumab after nivolumab, followed by platinum doublet chemotherapy.1 Nivolumab should not be administered simultaneously through the same IV line with any other drug.1 Use separate infusion bags and filters for each infusion and flush the IV line at the end of the infusion.1
For IV infusion over 30 minutes, dilute the appropriate dose of nivolumab injection (containing 10 mg/mL) with an appropriate volume of 0.9% sodium chloride or 5% dextrose injection to a final concentration of 1-10 mg/mL.1 The total volume of the infusion solution must not exceed 160 mL; for adults and pediatric patients weighing less than 40 kg, the total volume of the infusion solution must not exceed 4 mL per kg of body weight.1 Mix the diluted solution by gentle inversion and do not shake.1
Diluted solutions of the drug are stable for up to 8 hours after dilution (up to the end of the infusion) when stored at room temperature and room light or up to 7 days after dilution when stored under refrigeration (2-8°C); diluted solutions of the drug should not be frozen.1
Any unused portion in the vial or infusion bag should be discarded since nivolumab injection contains no preservative.1
After dilution, nivolumab is administered by IV infusion over 30 minutes.1
Nivolumab and hyaluronidase-nvhy (Opdivo Qvantig®) is administered subcutaneously by a healthcare professional using a 23-25G (3/8-5/8”) hypodermic injection needle or subcutaneous administration set (e.g., winged/butterfly).42 Do not administer IV.42 No incompatibilities were observed between nivolumab/hyaluronidase-nvhy and polypropylene and polycarbonate syringes, or polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene propylene subcutaneous administration sets.42 To prepare the solution for subcutaneous administration, remove the appropriate number of vials for the required dose from refrigeration and allow to come to room temperature.42 Do not dilute.42 Use a syringe and a transfer needle to withdraw the solution from the vial(s) into a single syringe.42 Do not shake.42 Select the appropriate syringe label from the product's carton that matches the prescribed dose and apply to the prepared syringe.42 Discard any partially used or empty vials.42
Once withdrawn into the syringe, use the dose of nivolumab/hyaluronidase-nvhy immediately.42 If the dose is not used immediately, attach a tip cap to the syringe before storing it.42 To avoid clogging of the hypodermic injection needle, do not attach the injection needle to the syringe until immediately prior to administration.42 If the dose is not used immediately, the syringe may be stored in the refrigerator at 2-8°C, protected from light, for up to 48 hours, or at room temperature (20-25°C) for up to 8 hours (protection from light is not required); do not freeze.42 Discard the solution if storage time exceeds these limits.42 If stored in the refrigerator, allow the solution to come to room temperature prior to administration.42
Inject nivolumab/hyaluronidase-nvhy into the subcutaneous tissue of 1 of the 4 quadrants of the abdomen, or in the thigh, over 3-5 minutes.42 Do not inject into areas where the skin is red, bruised, tender, or into areas with moles or scars.42 If administration is interrupted, continue administering at the same site or at an alternate site.42 Rotate injection sites for subsequent injections.42 Do not administer other subcutaneous medications at the same site where nivolumab/hyaluronidase-nvhy is administered.42
Monotherapy for Unresectable or Metastatic Melanoma : When used as monotherapy for the treatment of unresectable or metastatic melanoma, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
When used as monotherapy for the treatment of unresectable or metastatic melanoma, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Combination Therapy for Unresectable or Metastatic Melanoma : When used in combination with ipilimumab for the treatment of unresectable or metastatic melanoma, the recommended adult dosage of nivolumab (Opdivo®) is 1 mg/kg administered as a 30-minute IV infusion in combination with ipilimumab 3 mg/kg administered as a 30-minute IV infusion every 3 weeks for up to 4 doses or until unacceptable toxicity, whichever occurs first, followed by single-agent nivolumab therapy at a dosage of 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion until disease progression or unacceptable toxicity occurs.1
When used for the treatment of unresectable or metastatic melanoma following combination treatment with IV nivolumab (Opdivo®) and ipilimumab, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Adjuvant Therapy for Stage IIB, IIC, III, or IV Metastatic Melanoma : For the adjuvant therapy of completely resected stage IIB, IIC, III, or IV melanoma, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued for up to 1 year or until disease recurrence or unacceptable toxicity occurs.1
For the adjuvant therapy of completely resected stage IIB, IIC, III, or IV melanoma, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued for up to 1 year or until disease recurrence or unacceptable toxicity occurs.42
Monotherapy for Metastatic Non-Small Cell Lung Cancer (NSCLC) : For the treatment of metastatic NSCLC that has progressed during or following therapy with platinum-based chemotherapy and, in those with epidermal growth factor receptor (EGFR) mutation- or anaplastic lymphoma kinase (ALK)-positive tumors, therapy with an FDA-labeled EGFR or ALK inhibitor, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of metastatic NSCLC that has progressed during or following therapy with platinum-based chemotherapy and, in those with EGFR mutation- or ALK-positive tumors, therapy with an FDA-labeled EGFR or ALK inhibitor, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Combination Therapy for Neoadjuvant/Adjuvant Treatment of Resectable NSCLC : When used in combination with platinum doublet chemotherapy for the treatment of resectable NSCLC in the neoadjuvant setting, the recommended adult dosage of nivolumab (Opdivo®) is 360 mg administered as a 30-minute IV infusion in combination with platinum doublet chemotherapy on the same day every 3 weeks.1 Neoadjuvant combination therapy should be continued for 3 cycles.1 Nivolumab should be administered before chemotherapy.1
When used in combination with platinum doublet chemotherapy for the treatment of resectable NSCLC in the neoadjuvant setting, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 900 mg nivolumab and 15,000 units hyaluronidase administered as a 3-5 minute subcutaneous injection in combination with platinum doublet chemotherapy on the same day every 3 weeks.42 Neoadjuvant combination therapy should be continued for 3 cycles.42
When used in combination with platinum doublet chemotherapy as neoadjuvant therapy, followed by single-agent treatment with nivolumab after surgery for the treatment of resectable NSCLC in patients without known EGFR mutations or ALK rearrangements, the recommended adult neoadjuvant dosage of nivolumab (Opdivo®) is 360 mg administered as a 30-minute IV infusion in combination with platinum doublet chemotherapy on the same day every 3 weeks.1 Nivolumab should be administered before chemotherapy.1 Neoadjuvant combination therapy should be continued for up to 4 cycles or until disease progression or unacceptable toxicity occurs.1 After surgery, nivolumab should be administered as monotherapy at a dosage of 480 mg every 4 weeks as a 30-minute IV infusion; continue adjuvant nivolumab for up to 13 cycles (approximately 1 year) or until disease recurrence or unacceptable toxicity occurs.1
When used in combination with platinum doublet chemotherapy as neoadjuvant therapy, followed by single-agent treatment with nivolumab after surgery for the treatment of resectable NSCLC in patients without known EGFR mutations or ALK rearrangements, the recommended adult neoadjuvant dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 900 mg nivolumab and 15,000 units hyaluronidase administered as a 3-5 minute subcutaneous injection in combination with platinum doublet chemotherapy on the same day every 3 weeks.42 Neoadjuvant combination therapy should be continued for up to 4 cycles or until disease progression or unacceptable toxicity occurs.42 After surgery, nivolumab/hyaluronidase-nvhy should be administered as monotherapy at a dosage of 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection; continue adjuvant nivolumab for up to 13 cycles (approximately 1 year) or until disease recurrence or unacceptable toxicity occurs.42
Combination Therapy for Metastatic NSCLC : When used in combination with ipilimumab for the treatment of untreated metastatic NSCLC expressing PD-L1 (≥1%, as determined by an FDA-approved test) in patients without EGFR or ALK genomic tumor aberrations, the recommended adult dosage of nivolumab (Opdivo®) is 360 mg administered every 3 weeks as a 30-minute infusion in combination with ipilimumab 1 mg/kg administered every 6 weeks as a 30-minute infusion.1 Continue therapy for up to 2 years in patients without disease progression, or until disease progression or unacceptable toxicity occurs.1
When used in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy for the treatment of untreated metastatic or recurrent NSCLC in patients without EGFR or ALK genomic tumor aberrations, the recommended adult dosage of nivolumab (Opdivo®) is 360 mg administered every 3 weeks as a 30-minute IV infusion in combination with ipilimumab 1 mg/kg administered every 6 weeks as a 30-minute IV infusion along with platinum doublet chemotherapy every 3 weeks for 2 cycles.1 Continue combination therapy with nivolumab and ipilimumab for up to 2 years in patients without disease progression, or until disease progression or unacceptable toxicity occurs.1
Malignant Pleural Mesothelioma
When used in combination with ipilimumab for the treatment of malignant pleural mesothelioma, the recommended adult dosage of nivolumab (Opdivo®) is 360 mg administered as a 30-minute IV infusion every 3 weeks in combination with ipilimumab 1 mg/kg administered every 6 weeks for up to 2 years or until disease progression or unacceptable toxicity occurs.1
Monotherapy for Advanced Renal Cell Carcinoma : When used as monotherapy for the treatment of advanced renal cell carcinoma previously treated with antiangiogenic therapy, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
When used as monotherapy for the treatment of advanced renal cell carcinoma previously treated with antiangiogenic therapy, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Combination Therapy for Advanced Renal Cell Carcinoma : When used in combination with ipilimumab for the treatment of intermediate- or poor-risk, previously untreated, advanced renal cell carcinoma, the recommended adult dosage of nivolumab (Opdivo®) is 3 mg/kg administered as a 30-minute IV infusion in combination with ipilimumab 1 mg/kg administered as a 30-minute IV infusion every 3 weeks for 4 doses, followed by single-agent nivolumab therapy at a dosage of 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion until disease progression or unacceptable toxicity occurs.1
When used for the treatment of intermediate- or poor-risk, previously untreated, advanced renal cell carcinoma following combination treatment with IV nivolumab (Opdivo®) and ipilimumab, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
When used in combination with cabozantinib for the treatment of previously untreated advanced renal cell carcinoma, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg every 2 weeks or 480 mg every 4 weeks administered as a 30-minute IV infusion in combination with oral cabozantinib 40 mg once daily without food.1 Continue nivolumab therapy for up to 2 years or until disease progression or unacceptable toxicity occurs.1
When used in combination with cabozantinib for the treatment of previously untreated advanced renal cell carcinoma, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection in combination with oral cabozantinib 40 mg once daily without food.42 Therapy with nivolumab/hyaluronidase-nvhy should be continued for up to 2 years, or until disease progression or unacceptable toxicity occurs.42
For the treatment of classical Hodgkin lymphoma (cHL) that has relapsed or progressed following autologous stem cell transplantation and subsequent therapy with brentuximab vedotin or following failure of at least 3 systemic therapies (including autologous stem cell transplantation), the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Squamous Cell Carcinoma of the Head and Neck
For the treatment of metastatic or recurrent squamous cell carcinoma of the head and neck that has progressed during or following therapy with platinum-based chemotherapy, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of metastatic or recurrent squamous cell carcinoma of the head and neck that has progressed during or following therapy with platinum-based chemotherapy, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Monotherapy for Locally Advanced or Metastatic Urothelial Carcinoma : 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, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
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, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Adjuvant Treatment of Urothelial Carcinoma : For the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence following radical resection, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued for up to 1 year or until disease recurrence or unacceptable toxicity occurs.1
For the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence following radical resection, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued for up to 1 year or until disease recurrence or unacceptable toxicity occurs.42
Combination Therapy for Unresectable or Metastatic Urothelial Carcinoma : When used in combination with cisplatin and gemcitabine for the treatment of untreated unresectable or metastatic urothelial carcinoma, the recommended adult dosage of nivolumab (Opdivo®) is 360 mg administered as a 30-minute IV infusion in combination with cisplatin and gemcitabine on the same day every 3 weeks.1 Continue combination therapy for up to 6 cycles, then administer nivolumab monotherapy at a dosage of 240 mg every 2 weeks or 480 mg every 4 weeks as a 30-minute IV infusion; continue for up to 2 years from the first dose or until disease progression or unacceptable toxicity occurs.1
When used in combination with cisplatin and gemcitabine for the treatment of untreated unresectable or metastatic urothelial carcinoma, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 900 mg nivolumab and 15,000 units hyaluronidase administered as a 3-5 minute subcutaneous injection in combination with cisplatin and gemcitabine on the same day every 3 weeks.42 Continue combination therapy for up to 6 cycles, then administer nivolumab/hyaluronidase-nvhy at a dosage of 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued for up to 2 years or until disease progression or unacceptable toxicity occurs.42
Monotherapy for Metastatic Colorectal Cancer : When used as monotherapy for the treatment of metastatic colorectal cancer with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy in adults, the recommended dosage of nivolumab (Opdivo®) is 240 mg administered as a 30-minute IV infusion every 2 weeks or 480 mg administered as a 30-minute IV infusion every 4 weeks.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
When used as monotherapy (or as monotherapy following combination treatment with IV nivolumab [Opdivo®] and ipilimumab) for the treatment of metastatic colorectal cancer with MSI-H or dMMR that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy in adults, the recommended dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Combination Therapy for Metastatic Colorectal Cancer : When used in combination with ipilimumab for the treatment of metastatic colorectal cancer with MSI-H or dMMR that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy in adults, the recommended dosage of nivolumab (Opdivo®) is 3 mg/kg administered as a 30-minute IV infusion in combination with ipilimumab 1 mg/kg administered as a 30-minute IV infusion every 3 weeks for 4 doses, followed by single-agent nivolumab therapy at a dosage of 240 mg administered every 2 weeks as a 30-minute IV infusion or 480 mg every 4 weeks as a 30-minute IV infusion until disease progression or unacceptable toxicity occurs.1
When used in combination with ipilimumab for the treatment of hepatocellular carcinoma previously treated with sorafenib, the recommended adult dosage of nivolumab (Opdivo®) is 1 mg/kg administered as a 30-minute IV infusion every 3 weeks in combination with ipilimumab 3 mg/kg administered as a 30-minute IV infusion every 3 weeks for 4 doses, followed by single-agent nivolumab therapy at a dosage of 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion until disease progression or unacceptable toxicity occurs.1
When used for the treatment of hepatocellular carcinoma previously treated with sorafenib following combination treatment with IV nivolumab (Opdivo®) plus ipilimumab, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Monotherapy for Esophageal Squamous Cell Carcinoma (ESCC) : When used as monotherapy for the treatment of unresectable advanced, recurrent, or metastatic ESCC after prior treatment with fluoropyrimidine- and platinum-based chemotherapy, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
When used as monotherapy for the treatment of unresectable advanced, recurrent, or metastatic ESCC after prior treatment with fluoropyrimidine- and platinum-based chemotherapy, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued until disease progression or unacceptable toxicity occurs.42
Monotherapy for Adjuvant Treatment of Resected Esophageal Cancer : When used as monotherapy for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued for a total treatment duration of 1 year or until disease progression or unacceptable toxicity occurs.1
When used as monotherapy for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection.42 Therapy should be continued for up to 1 year or until disease recurrence or unacceptable toxicity occurs.42
Combination Therapy for ESCC : When used in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of unresectable advanced or metastatic ESCC, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion given in combination with fluoropyrimidine- and platinum-containing chemotherapy.1 Nivolumab should be continued for up to 2 years or until disease progression or unacceptable toxicity occurs.1
When used in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of unresectable advanced or metastatic ESCC, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks as a 3-5 minute subcutaneous injection in combination with fluoropyrimidine- and platinum-containing chemotherapy.42 Therapy with nivolumab-hyaluronidase-nvhy should be continued for up to 2 years or until disease progression or unacceptable toxicity occurs.42
When used in combination with ipilimumab for the first-line treatment of unresectable advanced or metastatic ESCC, the recommended adult dosage of nivolumab (Opdivo®) is 3 mg/kg administered every 2 weeks or 360 mg administered every 3 weeks as a 30-minute IV infusion in combination with ipilimumab 1 mg/kg administered every 6 weeks as a 30-minute IV infusion.1 Continue combination therapy for up to 2 years or until disease progression or unacceptable toxicity occurs.1
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
When used in combination with fluoropyrimidine- and platinum-containing chemotherapy for the treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma, the recommended adult dosage of nivolumab (Opdivo®) is 240 mg administered as a 30-minute IV infusion in combination with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks or 360 mg of nivolumab administered as a 30-minute IV infusion in combination with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks.1 Continue therapy for up to 2 years or until disease progression or unacceptable toxicity occurs.1
When used in combination with fluoropyrimidine- and platinum-containing chemotherapy for the treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma, the recommended adult dosage of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is 600 mg nivolumab and 10,000 units hyaluronidase as a 3-5 minute subcutaneous injection in combination with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks or 900 mg nivolumab and 15,000 units hyaluronidase as a 3-5 minute subcutaneous injection in combination with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks.42 Therapy with nivolumab-hyaluronidase-nvhy should be continued for up to 2 years or until disease progression or unacceptable toxicity occurs.42
Pediatric dosing information applies to nivolumab (Opdivo®) only;1 nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) is not currently approved for use in pediatric patients.42
Monotherapy for Unresectable or Metastatic Melanoma : When used as monotherapy for the treatment of unresectable or metastatic melanoma, the recommended dosage of nivolumab in pediatric patients who are ≥12 years of age and weigh ≥40 kg is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 In pediatric patients who are ≥12 years of age and weigh <40 kg, the recommended dosage of nivolumab is 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Combination Therapy for Unresectable or Metastatic Melanoma : When used in combination with ipilimumab for the treatment of unresectable or metastatic melanoma in pediatric patients ≥12 years of age, the recommended pediatric dosage of nivolumab is 1 mg/kg administered as a 30-minute IV infusion in combination with ipilimumab 3 mg/kg administered every 3 weeks for up to 4 doses or until unacceptable toxicity occurs.1
In pediatric patients weighing ≥40 kg, combination therapy is followed by single-agent nivolumab therapy at a dosage of 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion until disease progression or unacceptable toxicity occurs.1 In pediatric patients weighing <40 kg, combination therapy is followed by single-agent nivolumab therapy at a dosage of 3 mg/kg administered every 2 weeks or 6 mg/kg administered every 4 weeks as a 30-minute IV infusion until disease progression or unacceptable toxicity occurs.1
Adjuvant Therapy for Stage IIB, IIC, III, or IV Metastatic Melanoma : For the adjuvant therapy of completely resected stage IIB, IIC, III, or IV metastatic melanoma, the recommended dosage of nivolumab in pediatric patients who are ≥12 years of age and weigh ≥40 kg is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 In pediatric patients who are ≥12 years of age and weigh <40 kg, the recommended dosage of nivolumab is 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks as a 30-minute IV infusion.1 Therapy should be continued for up to 1 year or until disease recurrence or unacceptable toxicity occurs.1
Monotherapy for Metastatic Colorectal Cancer : When used as monotherapy for the treatment of metastatic colorectal cancer with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy in pediatric patients ≥12 years of age and weighing ≥40 kg, the recommended dosage of nivolumab is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion.1 In pediatric patients who are ≥12 years of age and weigh <40 kg, the recommended dosage of nivolumab is 3 mg/kg every 2 weeks as a 30-minute IV infusion.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Combination Therapy for Metastatic Colorectal Cancer : When used in combination with ipilimumab for the treatment of metastatic colorectal cancer with MSI-H or dMMR that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy in pediatric patients ≥12 years of age, the recommended dosage of nivolumab is 3 mg/kg administered as a 30-minute IV infusion in combination with ipilimumab 1 mg/kg administered every 3 weeks for 4 doses.1
In pediatric patients weighing ≥40 kg, combination therapy is followed by single-agent nivolumab therapy at a dosage of 240 mg administered every 2 weeks or 480 mg administered every 4 weeks as a 30-minute IV infusion until disease progression or unacceptable toxicity occurs.1 In pediatric patients weighing <40 kg, combination therapy is followed by single-agent nivolumab therapy at a dosage of 3 mg/kg administered every 2 weeks as a 30-minute IV infusion until disease progression or unacceptable toxicity occurs.1
Therapy Interruption for Toxicity
If immune-mediated adverse effects occur, no dosage reduction is recommended; instead, temporary or permanent discontinuance of nivolumab or nivolumab/hyaluronidase-nvhy may be required based on severity of the reaction.1, 42
Nivolumab and nivolumab/hyaluronidase-nvhy should be withheld in patients experiencing severe (grade 3) immune-mediated adverse effects.1, 42 If nivolumab or nivolumab/hyaluronidase-nvhy therapy is withheld due to toxicity (with the exception of endocrinopathy), resume therapy once the toxicity resolves to grade 0 or 1 after corticosteroid taper.1, 42 If resolution of toxicity to grade 0 or 1 does not occur within 12 weeks of the last dose of therapy, or if there is an inability to reduce the dose of prednisone to ≤10 mg per day (or equivalent) within 12 weeks of initiating steroid treatment, permanently discontinue nivolumab or nivolumab/hyaluronidase-nvhy.1, 42
Nivolumab and nivolumab/hyaluronidase-nvhy should be permanently discontinued in patients experiencing any life-threatening or grade 4 immune-mediated adverse effect.1, 42 Therapy with the drug also should be permanently discontinued if grade 3 immune-mediated adverse effects requiring systemic immunosuppressive therapy recur.1, 42
When nivolumab is administered in combination with ipilimumab, withhold or permanently discontinue both agents for an adverse reaction meeting the dosage modification guidance below.1
If grade 2 immune-mediated pneumonitis occurs, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the toxicity resolves to grade 0 or 1.1, 42
If grade 3 or 4 immune-mediated pneumonitis occurs, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be permanently discontinued.1, 42
Immune-mediated Colitis - Monotherapy
If grade 2 or 3 immune-mediated colitis occurs in patients receiving monotherapy, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the toxicity resolves to grade 0 or 1.1, 42
If grade 4 immune-mediated colitis occurs, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be permanently discontinued.1, 42
Immune-mediated Colitis - Combination Therapy
If grade 2 immune-mediated colitis occurs in patients receiving nivolumab (Opdivo®) in combination with ipilimumab, therapy should be interrupted until the toxicity resolves to grade 0 or 1.1
If grade 3 or 4 immune-mediated colitis occurs in patients receiving nivolumab (Opdivo®) in combination with ipilimumab, therapy should be permanently discontinued.1
Immune-mediated Hepatic Effects - Monotherapy
For serum aminotransferase (ALT or AST) elevations exceeding the upper limit of normal (ULN) at baseline, or for those with ALT or AST elevations exceeding 3 times but not more than 8 times the ULN or total bilirubin concentrations exceeding 1.5 times but not more than 3 times the ULN in patients without tumor involvement of the liver, monotherapy with nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the toxicity resolves to grade 0 or 1.1, 42
For ALT or AST elevations exceeding 8 times the ULN or total bilirubin concentrations exceeding 3 times the ULN in patients without tumor involvement of the liver, monotherapy with nivolumab or nivolumab/hyaluronidase-nvhy therapy should be permanently discontinued.1, 42
For ALT or AST elevations exceeding 5 times but not more than 10 times the ULN in patients with tumor involvement of the liver and baseline ALT or AST concentrations exceeding 1 time but not more than 3 times the ULN, monotherapy with nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the toxicity resolves to grade 0 or 1.1, 42
For ALT or AST elevations exceeding 8 times but not more than 10 times the ULN in patients with tumor involvement of the liver and baseline ALT or AST concentrations exceeding 3 times but not more than 5 times the ULN, monotherapy with nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the toxicity resolves to grade 0 or 1.1, 42
For ALT or AST elevations exceeding 10 times the ULN or total bilirubin concentrations exceeding 3 times the ULN in patients with tumor involvement of the liver, monotherapy with nivolumab or nivolumab/hyaluronidase-nvhy therapy should be permanently discontinued.1, 42
Immune-mediated Hepatic Effects - Combination Therapy
For patients receiving combination therapy with nivolumab (Opdivo®) plus ipilimumab 1) without tumor involvement of the liver; 2) with tumor involvement of the liver that is not hepatocellular carcinoma; or 3) with tumor involvement of the liver or hepatocellular carcinoma and baseline ALT or AST at or below the ULN who have ALT or AST elevations exceeding 3 times but not more than 5 times the ULN or total bilirubin concentrations exceeding 1.5 times but not more than 3 times the ULN and baseline ALT and AST concentrations within normal limits, therapy should be interrupted until the toxicity resolves to grade 0 or 1.1 For ALT or AST elevations exceeding 5 times the ULN or total bilirubin concentrations exceeding 3 times the ULN in such patients, permanently discontinue combination therapy with nivolumab (Opdivo®) plus ipilimumab.1
For patients receiving combination therapy with nivolumab (Opdivo®) plus ipilimumab with tumor involvement of the liver or hepatocellular carcinoma who have ALT or AST elevations exceeding 5 times but not more than 10 times the ULN and baseline ALT or AST concentrations exceeding 1 time but not more than 3 times the ULN, interrupt combination therapy until the toxicity resolves to grade 0 or 1.1 For such patients with ALT or AST elevations exceeding 8 times the ULN but not more than 10 times the ULN and baseline ALT or AST concentrations exceeding 3 times but not more than 5 times the ULN, combination therapy should also be interrupted until the toxicity resolves to grade 0 or 1.1 If the ALT or AST increases above 10 times the ULN or the total bilirubin increases above 3 times the ULN in such patients, permanently discontinue combination therapy.1
For patients receiving combination therapy with nivolumab or nivolumab/hyaluronidase-nvhy plus cabozantinib who have ALT or AST elevations exceeding 3 times but not more than 10 times the ULN and concurrent total bilirubin below 2 times the ULN, withhold both agents until the toxicity resolves to grade 0 or 1.1, 42 Consider corticosteroid therapy for hepatic adverse reactions if nivolumab is withheld when administered in combination with cabozantinib.1, 42 After recovery, rechallenge with one or both agents may be considered; if rechallenging with cabozantinib with or without nivolumab, refer to the cabozantinib prescribing information.1, 42
For patients receiving combination therapy with nivolumab or nivolumab/hyaluronidase-nvhy plus cabozantinib who have ALT or AST elevations exceeding 10 times the ULN or >3 times the ULN with concurrent total bilirubin at or above 2 times the ULN, permanently discontinue both agents.1, 42 Consider corticosteroid therapy for hepatic adverse reactions if nivolumab is discontinued when administered in combination with cabozantinib.1
Immune-mediated Endocrinopathies
If grade 3 or 4 immune-mediated endocrinopathies occur, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the patient is clinically stable; consider discontinuation of therapy depending on the severity of the adverse effect.1, 42 Consider withholding therapy for grade 2 endocrinopathies until symptom improvement occurs with hormone replacement.1, 42 Resume therapy with nivolumab or nivolumab/hyaluronidase-nvhy once acute symptoms have resolved.1, 42
Immune-mediated Nephritis with Renal Dysfunction
For grade 2 or 3 serum creatinine elevations, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the toxicity resolves to grade 0 or 1.1, 42
For grade 4 serum creatinine concentrations, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be permanently discontinued.1, 42
Immune-mediated Exfoliative Dermatologic Conditions
If Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug rash with eosinophilia and systemic symptoms (DRESS) is suspected, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the toxicity resolves to grade 0 or 1.1, 42
If Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS is confirmed, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be permanently discontinued.1, 42
If grade 2, 3, or 4 myocarditis occurs, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be permanently discontinued.1, 42
Immune-mediated Neurological Toxicities
If grade 2 neurological toxicities occur, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be interrupted until the toxicity resolves to grade 0 or 1.1, 42
If grade 3 or 4 neurological toxicity occurs, nivolumab or nivolumab/hyaluronidase-nvhy therapy should be permanently discontinued.1, 42
If grade 1 or 2 infusion-related reactions occur with nivolumab (Opdivo®), the infusion should be interrupted or the infusion rate should be reduced.1
If grade 3 or 4 infusion-related reactions occur, nivolumab therapy should be permanently discontinued.1
For IV nivolumab, no dosage adjustment is necessary in patients with mild or moderate preexisting hepatic impairment.1 Nivolumab has not been studied in patients with severe preexisting hepatic impairment, and the manufacturer provides no specific dosage recommendations for such patients.1
The manufacturer of nivolumab/hyaluronidase-nvhy makes no specific dosage recommendations for patients with hepatic impairment.42
No dosage adjustment of IV nivolumab is necessary in patients with mild, moderate, or severe preexisting renal impairment.1
The manufacturer of nivolumab/hyaluronidase-nvhy makes no specific dosage recommendations for patients with renal impairment.42
The manufacturer makes no specific dosage recommendations for geriatric patients.1, 42
Severe and Fatal Immune-mediated Adverse Reactions
Nivolumab is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed-death receptor-1 (PD-1) or the programmed-death ligand-1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions.1
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue.1, 42 Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody.1, 42 While immune-mediated adverse reactions usually manifest during treatment with PD‑1/PD-L1 blocking antibodies, these reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.1, 42
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies.1, 42 Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions.1, 42 Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.1, 42 In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection.1, 42 Institute medical management promptly, including specialty consultation as appropriate.1, 42
Withhold or permanently discontinue nivolumab or nivolumab/hyaluronidase-nvhy depending on severity.1, 42 In general, if therapy requires interruption or discontinuation, administer systemic corticosteroid therapy (1-2 mg/kg/day prednisone or equivalent) until improvement to grade 1 or less.1, 42 Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.1, 42 Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.1, 42 Certain reactions, such as endocrinopathies and dermatologic reactions, do not necessarily require systemic steroids.1, 42
Nivolumab or nivolumab/hyaluronidase-nvhy can cause immune-related pneumonitis (defined as requiring use of steroids and no clear alternate etiology).1, 42 The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.1 Withhold or permanently discontinue depending on severity.1 Institute appropriate treatment and resume therapy if appropriate.1
Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving nivolumab as a single agent, including grade 4 (<0.1%), grade 3 (0.9%), and grade 2 (2.1%) adverse reactions.1 Pneumonitis led to permanent discontinuation of nivolumab in 1.1% and withholding of nivolumab in 0.8% of patients.1 Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis.1 Pneumonitis resolved in 84% of the 61 patients. 1 Of the 15 patients in whom nivolumab was withheld for pneumonitis, 14 reinitiated nivolumab after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis.1
In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving nivolumab 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including grade 4 (0.5%), grade 3 (3.5%), and grade 2 (4%) immune-mediated pneumonitis.1 Four patients (0.7%) died due to pneumonitis.1 Immune-mediated pneumonitis led to permanent discontinuation of nivolumab with ipilimumab in 5% of patients and withholding of nivolumab with ipilimumab in 3.6% of patients.1 Systemic corticosteroids were required in 100% of patients with pneumonitis.1 Pneumonitis resolved in 72% of the patients.1 Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of nivolumab with ipilimumab.1
Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving nivolumab/hyaluronidase-nvhy, including grade 3 (0.8%) and grade 2 (2%) adverse reactions.42 Pneumonitis led to permanent discontinuation of nivolumab/hyaluronidase-nvhy in 1.6% and withholding of nivolumab/hyaluronidase-nvhy in 1.6% of patients.42 Systemic corticosteroids were required in 100% (7/7) of patients with pneumonitis.42 Pneumonitis resolved in 27% of the 7 patients.42 Of the 4 patients in whom nivolumab/hyaluronidase-nvhy was withheld for pneumonitis, 2 reinitiated nivolumab/hyaluronidase-nvhy after symptom improvement; of these, 1 (50%) had recurrence of pneumonitis.42
Nivolumab or nivolumab/hyaluronidase-nvhy can cause immune-mediated colitis (defined as requiring use of corticosteroids and no clear alternate etiology).1, 42 Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis.1, 42 In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.1, 42 Withhold or permanently discontinue depending on severity.1, 42 Institute appropriate treatment and resume therapy if appropriate.1, 42
Immune-mediated colitis occurred in 2.9% (58/1994) of patients receiving nivolumab as a single agent, including grade 3 (1.7%) and grade 2 (1%) adverse reactions.1 Colitis led to permanent discontinuation of nivolumab in 0.7% and withholding of nivolumab in 0.9% of patients.1 Systemic corticosteroids were required in 100% (58/58) of patients with colitis.1 Four patients required addition of infliximab to high-dose corticosteroids.1 Colitis resolved in 86% of the 58 patients.1 Of the 18 patients in whom nivolumab was withheld for colitis, 16 reinitiated nivolumab after symptom improvement; of these, 12 (75%) had recurrence of colitis.1
In patients who received nivolumab 1 mg/kg with ipilimumab 3 mg/kg, immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or hepatocellular carcinoma, including grade 4 (0.4%), grade 3 (14%), and grade 2 (8%) adverse reactions.1 Colitis led to permanent discontinuation of nivolumab with ipilimumab in 14% and withholding of nivolumab with ipilimumab in 4.4% of patients.1 Systemic corticosteroids were required in 100% (115/115) of patients with colitis.1 Approximately 23% of patients required addition of infliximab to high-dose corticosteroids.1 Colitis resolved in 93% of the 115 patients.1 Of the 20 patients in whom nivolumab with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 9 (56%) had recurrence of colitis.1
In patients who received nivolumab 3 mg/kg with ipilimumab 1 mg/kg, immune-mediated colitis occurred in 9% (60/666) of patients with renal cell carcinoma or colorectal cancer, including grade 3 (4.4%) and grade 2 (3.7%) adverse reactions.1 Colitis led to permanent discontinuation of nivolumab with ipilimumab in 3.2% and withholding of nivolumab with ipilimumab in 2.7% of patients with renal cell carcinoma or colorectal cancer.1 Systemic corticosteroids were required in 100% (60/60) of patients with colitis.1 Approximately 23% of patients with immune-mediated colitis required addition of infliximab to high-dose corticosteroids.1 Colitis resolved in 95% of the 60 patients.1 Of the 18 patients in whom nivolumab with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 10 (63%) had recurrence of colitis.1
Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving nivolumab/hyaluronidase-nvhy, including grade 3 (0.4%) and grade 2 (2.4%) adverse reactions.42 Colitis led to withholding of nivolumab/hyaluronidase-nvhy in 2% of patients.42 Systemic corticosteroids were required in 100% (7/7) of patients with colitis.42 Colitis resolved in 71% of the 7 patients.42 Of the 5 patients in whom nivolumab/hyaluronidase-nvhy was withheld for colitis, 3 reinitiated nivolumab/hyaluronidase-nvhy after symptom improvement; of these, 2 (67%) had recurrence of colitis.42
Immune-mediated Hepatitis and Hepatotoxicity
Nivolumab and nivolumab/hyaluronidase-nvhy can cause immune-mediated hepatitis (defined as requiring the use of corticosteroids and no clear alternate etiology).1, 42 Withhold or permanently discontinue therapy depending on severity.1, 42 Institute appropriate treatment and resume therapy if appropriate.1, 42 Monitor liver function tests prior to initiation of nivolumab therapy and periodically during therapy.1
Immune-mediated hepatitis occurred in 1.8% (35/1994) of patients receiving nivolumab as a single agent, including grade 4 (0.2%), grade 3 (1.3%), and grade 2 (0.4%) adverse reactions.1 Hepatitis led to permanent discontinuation of nivolumab in 0.7% and withholding of nivolumab in 0.6% of patients.1 Systemic corticosteroids were required in 100% (35/35) of patients with hepatitis.1 Two patients required the addition of mycophenolic acid to high-dose corticosteroids.1 Hepatitis resolved in 91% of the 35 patients.1 Of the 12 patients in whom nivolumab was withheld for hepatitis, 11 reinitiated nivolumab after symptom improvement; of these, 9 (82%) had recurrence of hepatitis.1
In patients who received nivolumab 1 mg/kg with ipilimumab 3 mg/kg, immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or hepatocellular carcinoma, including grade 4 (2.4%), grade 3 (11%), and grade 2 (1.8%) adverse reactions.1 Immune-mediated hepatitis led to permanent discontinuation of nivolumab with ipilimumab in 8% or withholding of nivolumab with ipilimumab in 3.5% of patients.1 Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis.1 Approximately 9% of patients with immune-mediated hepatitis required the addition mycophenolic acid to high-dose corticosteroids.1 Hepatitis resolved in 91% of the 70 patients.1 Of the 16 patients in whom nivolumab with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 8 (57%) had recurrence of hepatitis.1
In patients who received nivolumab 3 mg/kg with ipilimumab 1 mg/kg, immune-mediated hepatitis occurred in 7% (48/666) of patients with renal cell carcinoma or colorectal cancer receiving nivolumab 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including grade 4 (1.2%), grade 3 (4.9%), and grade 2 (0.4%) adverse reactions.1 Immune-mediated hepatitis led to permanent discontinuation of nivolumab with ipilimumab in 3.6% and withholding of nivolumab with ipilimumab in 2.6% of patients with renal cell carcinoma or colorectal cancer.1 Systemic corticosteroids were required in 100% (48/48) of patients with hepatitis.1 Approximately 19% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids.1 Hepatitis resolved in 88% of the 48 patients.1 Of the 17 patients in whom nivolumab with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 10 (71%) had recurrence of hepatitis.1
Nivolumab in combination with cabozantinib can cause hepatic toxicity with higher frequencies of grade 3 and 4 ALT and AST elevations compared to nivolumab alone.1 With the combination of nivolumab and cabozantinib, grade 3-4 increased ALT or AST occurred in 11% of patients.1 ALT or AST >3 times the upper limit of normal (ULN) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST elevations resolved to grades 0-1 in 74 patients (89%).1 Among the 44 patients with grade 2 increased ALT or AST who were rechallenged with either nivolumab monotherapy (11 patients), cabozantinib monotherapy (9 patients), or combination therapy (24 patients), recurrence of grade 2 or greater increased ALT or AST was observed in 2 patients receiving nivolumab, 2 patients receiving cabozantinib, and 7 patients receiving both nivolumab and cabozantinib.1
Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving nivolumab/hyaluronidase-nvhy, including grade 3 (1.6%) and grade 2 (0.8%) adverse reactions.42 Hepatitis led to permanent discontinuation of nivolumab/hyaluronidase-nvhy in 0.8% of patients and withholding of nivolumab/hyaluronidase-nvhy in 1.6% of patients.42 Systemic corticosteroids were required in 100% (6/6) of patients with hepatitis.42 Hepatitis resolved in 67% of the 6 patients.42 Of the 2 patients in whom nivolumab/hyaluronidase-nvhy was withheld for hepatitis, 2 reinitiated nivolumab/hyaluronidase-nvhy after symptom improvement; of these, 1 (50%) had recurrence of hepatitis.42
Immune-mediated Endocrinopathies
Immune-mediated endocrinopathies, such as hypophysitis, thyroid dysfunction (i.e., hypothyroidism, hyperthyroidism), adrenal insufficiency, and diabetes mellitus (including diabetic ketoacidosis), have occurred in patients receiving nivolumab therapy.1
Nivolumab or nivolumab/hyaluronidase-nvhy can cause primary or secondary adrenal insufficiency.1, 42 Withhold or permanently discontinue depending on severity.1 Institute appropriate treatment and resume therapy if appropriate.1
Adrenal insufficiency occurred in 1% (20/1994) of patients receiving nivolumab as a single agent, including grade 3 (0.4%) and grade 2 (0.6%) adverse reactions.1 Adrenal insufficiency led to permanent discontinuation of nivolumab in 0.1% and withholding of nivolumab in 0.4% of patients.1 Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy.1 Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency.1 Adrenal insufficiency resolved in 35% of the 20 patients.1 Of the 8 patients in whom nivolumab was withheld for adrenal insufficiency, 4 reinitiated nivolumab after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.1
In patients who received nivolumab 1 mg/kg with ipilimumab 3 mg/kg, adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or hepatocellular carcinoma, including grade 4 (0.2%), grade 3 (2.4%), and grade 2 (4.2%) adverse reactions.1 Adrenal insufficiency led to permanent discontinuation of nivolumab with ipilimumab in 0.4% and withholding of nivolumab with ipilimumab in 2% of patients.1 Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids.1 Adrenal insufficiency resolved in 37% of the 35 patients.1 Of the 9 patients in whom nivolumab with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.1
In patients who received nivolumab 3 mg/kg with ipilimumab 1 mg/kg, adrenal insufficiency occurred in 7% (48/666) of patients with renal cell carcinoma or colorectal cancer, including grade 4 (0.3%), grade 3 (2.5%), and grade 2 (4.1%) adverse reactions.1 Adrenal insufficiency led to permanent discontinuation of nivolumab with ipilimumab in 1.2% and withholding of nivolumab with ipilimumab in 2.1% of patients with renal cell carcinoma or colorectal cancer.1 Approximately 94% (45/48) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids.1 Adrenal insufficiency resolved in 29% of the 48 patients.1 Of the 14 patients in whom nivolumab with ipilimumab was withheld for adrenal insufficiency, 11 reinitiated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 (18%) had recurrence of adrenal insufficiency.1
Adrenal insufficiency occurred in 4.7% (15/320) of patients with renal cell carcinoma who received nivolumab with cabozantinib, including grade 3 (2.2%) and grade 2 (1.9%) adverse reactions.1 Adrenal insufficiency led to permanent discontinuation of nivolumab and cabozantinib in 0.9% and withholding of nivolumab and cabozantinib in 2.8% of patients with renal cell carcinoma.1 Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids.1 Adrenal insufficiency resolved in 4 of the 15 patients.1 Of the 9 patients in whom nivolumab with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.1
Adrenal insufficiency occurred in 2% (5/247) of patients receiving nivolumab/hyaluronidase-nvhy, including grade 3 (0.8%) and grade 2 (1.2%) adverse reactions.42 Adrenal insufficiency led to permanent discontinuation of nivolumab/hyaluronidase-nvhy in 0.4% of patients and withholding of nivolumab/hyaluronidase-nvhy in 0.4% of patients.42 Systemic corticosteroids were required in 100% (5/5) of patients with adrenal insufficiency.42 Adrenal insufficiency resolved in 20% of the 5 patients.42
Nivolumab or nivolumab/hyaluronidase-nvhy can cause immune-mediated hypophysitis that can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects.1, 42 Hypophysitis can cause hypopituitarism.1, 42 Withhold or permanently discontinue depending on severity.1, 42 Institute appropriate treatment and resume nivolumab if appropriate.1, 42
Hypophysitis occurred in 0.6% (12/1994) of patients receiving nivolumab as a single agent, including grade 3 (0.2%) and grade 2 (0.3%) adverse reactions.1 Hypophysitis led to permanent discontinuation of nivolumab in <0.1% and withholding of nivolumab in 0.2% of patients.1 Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids.1 Hypophysitis resolved in 42% of the 12 patients.1 Of the 3 patients in whom nivolumab was withheld for hypophysitis, 2 reinitiated nivolumab after symptom improvement; of these, none had recurrence of hypophysitis.1
In patients who received nivolumab 1 mg/kg with ipilimumab 3 mg/kg, hypophysitis occurred in 9% (42/456) of patients with melanoma or hepatocellular carcinoma, including grade 3 (2.4%) and grade 2 (6%) adverse reactions.1 Hypophysitis led to permanent discontinuation of nivolumab with ipilimumab in 0.9% and withholding of nivolumab with ipilimumab in 4.2% of patients.1 Approximately 86% of patients with hypophysitis received hormone replacement therapy.1 Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis.1 Hypophysitis resolved in 38% of the 42 patients.1 Of the 19 patients in whom nivolumab with ipilimumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement; of these, 1 (11%) had recurrence of hypophysitis.1
In patients who received nivolumab 3 mg/kg with ipilimumab 1 mg/kg, hypophysitis occurred in 4.4% (29/666) of patients with renal cell carcinoma or colorectal cancer, including grade 4 (0.3%), grade 3 (2.4%), and grade 2 (0.9%) adverse reactions.1 Hypophysitis led to permanent discontinuation of nivolumab with ipilimumab in 1.2% and withholding of nivolumab with ipilimumab in 2.1% of patients with renal cell carcinoma or colorectal cancer.1 Approximately 72% (21/29) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids.1 Hypophysitis resolved in 59% of the 29 patients.1 Of the 14 patients in whom nivolumab with ipilimumab was withheld for hypophysitis, 11 reinitiated treatment after symptom improvement; of these, 2 (18%) had recurrence of hypophysitis.1
Nivolumab or nivolumab/hyaluronidase-nvhy can cause immune-mediated thyroid disorders.1, 42 Thyroiditis can present with or without endocrinopathy.1, 42 Hypothyroidism can follow hyperthyroidism.1, 42 Withhold or permanently discontinue depending on severity.1, 42 Institute appropriate treatment and resume therapy if appropriate.1, 42
Thyroiditis occurred in 0.6% (12/1994) of patients receiving nivolumab as a single agent, including grade 2 (0.2%) adverse reactions.1 Thyroiditis led to permanent discontinuation of nivolumab in no patients and withholding of nivolumab in 0.2% of patients.1 Systemic corticosteroids were required in 17% (2/12) of patients with thyroiditis.1 Thyroiditis resolved in 58% of the 12 patients.1 Of the 3 patients in whom nivolumab was withheld for thyroiditis, 1 reinitiated nivolumab after symptom improvement without recurrence of thyroiditis.1
Thyroiditis occurred in 0.4% (1/247) of patients receiving nivolumab/hyaluronidase-nvhy, including a grade 1 (0.4%) adverse reaction.42 Systemic corticosteroids were not required in the patient with thyroiditis.42 Thyroiditis did not resolve in this patient.42
Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving nivolumab as a single agent, including grade 3 (<0.1%) and grade 2 (1.2%) adverse reactions.1 Hyperthyroidism led to the permanent discontinuation of nivolumab in no patients and withholding of nivolumab in 0.4% of patients.1 Approximately 19% of patients with hyperthyroidism received methimazole, 7% received carbimazole, and 4% received propylthiouracil.1 Systemic corticosteroids were required in 9% (5/54) of patients.1 Hyperthyroidism resolved in 76% of the 54 patients.1 Of the 7 patients in whom nivolumab was withheld for hyperthyroidism, 4 reinitiated nivolumab after symptom improvement; of these, none had recurrence of hyperthyroidism.1
In patients who received nivolumab 1 mg/kg with ipilimumab 3 mg/kg, hyperthyroidism occurred in 9% (42/456) of patients with melanoma or hepatocellular carcinoma, including grade 3 (0.9%) and grade 2 (4.2%) adverse reactions.1 Hyperthyroidism led to the permanent discontinuation of nivolumab with ipilimumab in no patients and withholding of nivolumab with ipilimumab in 2.4% of patients.1 Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole.1 Systemic corticosteroids were required in 17% (7/42) of patients.1 Hyperthyroidism resolved in 91% of the 42 patients.1 Of the 11 patients in whom nivolumab with ipilimumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement; of these, 1 (13%) had recurrence of hyperthyroidism.1
In patients who received nivolumab 3 mg/kg with ipilimumab 1 mg/kg, hyperthyroidism occurred in 12% (80/666) of patients with renal cell carcinoma or colorectal cancer, including grade 3 (0.6%) and grade 2 (4.5%) adverse reactions.1 Hyperthyroidism led to permanent discontinuation of nivolumab with ipilimumab in no patients and withholding of nivolumab with ipilimumab in 2.3% of patients with renal cell carcinoma or colorectal cancer.1 Of the 80 patients with renal cell carcinoma or colorectal cancer who developed hyperthyroidism, approximately 16% received methimazole and 3% received carbimazole.1 Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism.1 Hyperthyroidism resolved in 85% of the 80 patients.1 Of the 15 patients in whom nivolumab with ipilimumab was withheld for hyperthyroidism, 11 reinitiated treatment after symptom improvement; of these, 3 (27%) had recurrence of hyperthyroidism.1
Hyperthyroidism occurred in 0.8% (2/247) of patients receiving nivolumab/hyaluronidase-nvhy, including grade 2 (0.4%) adverse reactions.42 Systemic corticosteroids were not required in patients with hyperthyroidism.42 Hyperthyroidism resolved in 1 of the 2 patients.42
Hypothyroidism occurred in 8% (163/1994) of patients receiving nivolumab as a single agent, including grade 3 (0.2%) and grade 2 (4.8%) adverse reactions.1 Hypothyroidism led to the permanent discontinuation of nivolumab in no patients and withholding of nivolumab in 0.5% of patients.1 Approximately 79% of patients with hypothyroidism received levothyroxine.1 Systemic corticosteroids were required in 3.1% (5/163) of patients with hypothyroidism.1 Hypothyroidism resolved in 35% of the 163 patients.1 Of the 9 patients in whom nivolumab was withheld for hypothyroidism, 3 reinitiated nivolumab after symptom improvement; of these, 1 (33%) had recurrence of hypothyroidism.1
In patients who received nivolumab 1 mg/kg with ipilimumab 3 mg/kg, hypothyroidism occurred in 20% (91/456) of patients with melanoma or hepatocellular carcinoma, including grade 3 (0.4%) and grade 2 (11%) adverse reactions.1 Hypothyroidism led to the permanent discontinuation of nivolumab with ipilimumab in 0.9% and withholding of nivolumab with ipilimumab in 0.9% of patients.1 Approximately 89% of patients with hypothyroidism received levothyroxine.1 Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism.1 Hypothyroidism resolved in 41% of the 91 patients.1 Of the 4 patients in whom nivolumab with ipilimumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hypothyroidism.1
In patients who received nivolumab 3 mg/kg with ipilimumab 1 mg/kg, hypothyroidism occurred in 18% (122/666) of patients with renal cell carcinoma or colorectal cancer, including grade 3 (0.6%) and grade 2 (11%) adverse reactions.1 Hypothyroidism led to permanent discontinuation of nivolumab with ipilimumab in 0.2% and withholding of nivolumab with ipilimumab in 1.4% of patients with renal cell carcinoma or colorectal cancer. 1 Of the 122 patients with renal cell carcinoma or colorectal cancer who developed hypothyroidism, approximately 82% received levothyroxine.1 Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism.1 Hypothyroidism resolved in 27% of the 122 patients.1 Of the 9 patients in whom nivolumab with ipilimumab was withheld for hypothyroidism, 5 reinitiated treatment after symptom improvement; of these, 1 (20%) had recurrence of hypothyroidism.1
Hypothyroidism occurred in 9% (23/247) of patients receiving nivolumab/hyaluronidase-nvhy, including grade 2 (5.7%) adverse reactions.42 Hypothyroidism led to withholding of nivolumab/hyaluronidase-nvhy in 0.8% of patients.42 Systemic corticosteroids were not required in patients with hypothyroidism.42 Hypothyroidism resolved in 4.3% of the 23 patients.42 The 1 patient in whom nivolumab/hyaluronidase-nvhy was withheld for hypothyroidism did not reinitiate nivolumab/hyaluronidase-nvhy after symptom improvement.42
Monitor patients for hyperglycemia or other signs and symptoms of diabetes.1, 42 Initiate treatment with insulin as clinically indicated.1, 42 Withhold nivolumab or nivolumab/hyaluronidase-nvhy depending on severity.1, 42
Diabetes occurred in 0.9% (17/1994) of patients receiving nivolumab as a single agent, including grade 3 (0.4%) and grade 2 (0.3%) adverse reactions; 2 cases of diabetic ketoacidosis were also reported.1 Diabetes led to the permanent discontinuation of nivolumab in no patients and withholding of nivolumab in 0.1% of patients.1 No patients (0/17) with diabetes required systemic corticosteroids.1 Diabetes resolved in 29% of the 17 patients.1 Of the 2 patients in whom nivolumab was withheld for diabetes, both reinitiated nivolumab after symptom improvement; of these, neither had recurrence of diabetes.1
Grade 3 diabetes occurred in 0.4% (1/247) of patients receiving nivolumab/hyaluronidase-nvhy.42 No patients with diabetes required systemic corticosteroids.42 Diabetes did not resolve in the patient who developed diabetes.42
Immune-mediated Nephritis with Renal Dysfunction
Nivolumab or nivolumab/hyaluronidase-nvhy can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.1, 42 Withhold or permanently discontinue depending on severity.1, 42 Institute appropriate treatment and resume therapy if appropriate.1, 42 Evaluate renal function prior to initiation of nivolumab therapy and periodically during therapy.1
Immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients receiving nivolumab as a single agent, including grade 4 (<0.1%), grade 3 (0.5%), and grade 2 (0.6%) adverse reactions.1 Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of nivolumab in 0.3% and withholding of nivolumab in 0.4% of patients.1 Systemic corticosteroids were required in 100% (23/23) of patients with nephritis and renal dysfunction.1 Nephritis and renal dysfunction resolved in 78% of the 23 patients.1 Of the 7 patients in whom nivolumab was withheld for nephritis or renal dysfunction, 7 reinitiated nivolumab after symptom improvement; of these, 1 (14%) had recurrence of nephritis or renal dysfunction.1
Grade 2 immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients receiving nivolumab/hyaluronidase-nvhy.42 Immune-mediated nephritis and renal dysfunction led to withholding of nivolumab/hyaluronidase-nvhy in 1.2% of patients.42 Systemic corticosteroids were required in 100% (3/3) of patients with nephritis and renal dysfunction.42 Nephritis and renal dysfunction resolved in 100% of the 3 patients.42 Of the 3 patients in whom nivolumab/hyaluronidase-nvhy was withheld for nephritis or renal dysfunction, 1 reinitiated nivolumab/hyaluronidase-nvhy after symptom improvement without recurrence of nephritis or renal dysfunction.42
Immune-mediated Dermatologic Adverse Reactions
Nivolumab or nivolumab/hyaluronidase-nvhy can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology.1, 42 Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies.1, 42 Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.1, 42 Withhold or permanently discontinue depending on severity.1, 42 Institute appropriate treatment and resume therapy if appropriate.1, 42
Immune-mediated rash occurred in 9% (171/1994) of patients, including grade 3 (1.1%) and grade 2 (2.2%) adverse reactions.1 Immune-mediated rash led to permanent discontinuation of nivolumab in 0.3% and withholding of nivolumab in 0.5% of patients.1 Systemic corticosteroids were required in 100% (171/171) of patients with immune-mediated rash.1 Rash resolved in 72% of the 171 patients.1 Of the 10 patients in whom nivolumab was withheld for immune-mediated rash, 9 reinitiated nivolumab after symptom improvement; of these, 3 (33%) had recurrence of immune-mediated rash.1, 42
In patients who received nivolumab 1 mg/kg with ipilimumab 3 mg/kg, immune-mediated rash occurred in 28% (127/456) of patients with melanoma or hepatocellular carcinoma, including grade 3 (4.8%) and grade 2 (10%) adverse reactions.1 Immune-mediated rash led to permanent discontinuation of nivolumab with ipilimumab in 0.4% and withholding of nivolumab with ipilimumab in 3.9% of patients.1 Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash.1 Rash resolved in 84% of the 127 patients.1 Of the 18 patients in whom nivolumab with ipilimumab was withheld for immune-mediated rash, 15 reinitiated treatment after symptom improvement; of these, 8 (53%) had recurrence of immune-mediated rash.1
In patients who received nivolumab 3 mg/kg with ipilimumab 1 mg/kg, immune-mediated rash occurred in 16% (108/666) of patients with renal cell carcinoma or colorectal cancer, including grade 3 (3.5%) and grade 2 (4.2%) adverse reactions.1 Immune-mediated rash led to permanent discontinuation of nivolumab with ipilimumab in 0.5% of patients and withholding of nivolumab with ipilimumab in 2% of patients with renal cell carcinoma or colorectal cancer.1 Systemic corticosteroids were required in 100% (108/108) of patients with immune-mediated rash.1 Rash resolved in 75% of the 108 patients.1 Of the 13 patients in whom nivolumab with ipilimumab was withheld for immune-mediated rash, 11 reinitiated treatment after symptom improvement; of these, 5 (46%) had recurrence of immune-mediated rash.1
Immune-mediated rash occurred in 7% (17/247) of patients, including grade 3 (0.8%) and grade 2 (2.8%) adverse reactions.42 Immune-mediated rash led to withholding of nivolumab/hyaluronidase-nvhy in 1.2% of patients.42 Systemic corticosteroids were required in 47% (8/17) of patients with immune-mediated rash.42 Rash resolved in 77% of the 17 patients.42 Of the 3 patients in whom nivolumab/hyaluronidase-nvhy was withheld for immune-mediated rash, all reinitiated nivolumab/hyaluronidase-nvhy after symptom improvement; of these, all (100%) had recurrence of immune-mediated rash.42
Other Immune-mediated Adverse Reactions
Clinically significant, immune-mediated adverse reactions in the cardiac/vascular, nervous system, ocular, GI, musculoskeletal, connective tissue, endocrine, hematologic, and immune systems occurred at an incidence of <1% each in patients who received nivolumab, nivolumab/hyaluronidase-nvhy, nivolumab in combination with ipilimumab, or other PD-1/PD-L1 blocking antibodies.1, 42 Severe or fatal cases were reported for some of these adverse reactions.1, 42
If uveitis occurs in conjunction with other immune-mediated adverse effects, a Vogt-Koyanagi-Harada-like syndrome (which has been observed in patients receiving nivolumab as a single agent or in combination with ipilimumab) should be considered.1, 42 Systemic corticosteroid therapy may be required to reduce the risk of permanent vision loss.1, 42
Nivolumab can cause severe infusion-related reactions, which have been reported in <1% of patients in clinical trials.1 Discontinue nivolumab in patients with severe or life-threatening infusion-related reactions.1 Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions.1
In patients who received nivolumab as a 60-minute IV infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.1
In a trial assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received nivolumab as a 60-minute IV infusion or a 30-minute IV infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively.1 Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation, or withholding of nivolumab.1
In patients who received nivolumab 1 mg/kg with ipilimumab 3 mg/kg, infusion-related reactions occurred in 2.5% (10/407) of patients with melanoma and in 8% (4/49) of patients with hepatocellular carcinoma.1
In patients who received nivolumab 3 mg/kg with ipilimumab 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients with renal cell carcinoma and 4.2% (5/119) of patients with colorectal cancer and in 12% (37/300) of patients with malignant pleural mesothelioma.1
Complications of Allogeneic Stem Cell Transplantation
Serious or fatal complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody.1 Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause).1 These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.1
Follow patients closely for evidence of transplant-related complications and intervene promptly.1 Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.1
Fetal/Neonatal Morbidity and Mortality
Nivolumab and nivolumab/hyaluronidase-nvhy can cause fetal harm when administered to a pregnant woman.1, 42 In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death.1, 42
Advise pregnant women of the potential risk to a fetus.1, 42 Advise females of reproductive potential to use effective contraception during treatment with nivolumab and for 5 months after the last dose.1, 42
Increased Mortality in Patients with Multiple Myeloma when Nivolumab is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including nivolumab, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality.1, 42 Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.1, 42
There is a potential for immunogenicity with nivolumab therapy.1 The incidence of anti-nivolumab antibodies ranged from 11% with nivolumab monotherapy to up to 56% with combination regimens.1 Neutralizing antibodies to nivolumab were detected in 7% of patients receiving monotherapy and 3-41% of patients received combination therapy.1 The presence of treatment-emergent anti-nivolumab antibodies increased nivolumab clearance by up to 20% after administration of nivolumab as monotherapy or in combination with ipilimumab.1 These anti-drug antibody-associated pharmacokinetic changes were not considered to be clinically significant.1 There was no identified clinically significant effect of anti-drug antibodies on incidence of infusion-related reactions.1 The effects of anti-drug antibodies on effectiveness have not been fully characterized.1
There is a potential for immunogenicity with nivolumab/hyaluronidase-nvhy.42 During the 2-year treatment period in a clinical trial, 23% (46/202) of patients who received nivolumab/hyaluronidase-nvhy developed anti-nivolumab antibodies and 4.3% (2/46) had neutralizing antibodies against nivolumab.42 The corresponding incidence of anti-nivolumab antibodies was 7% (15/215) and neutralizing antibodies was 0% (0/15) for IV nivolumab in the same study.42 The incidence of anti-hyaluronidase antibodies in the trial was 8.8% (19/215); 5 (26%) of these 19 patients developed neutralizing antibodies.42
Nivolumab clearance increased by approximately 26% in patients who received nivolumab/hyaluronidase-nvhy and tested positive for anti-nivolumab antibodies compared to patients who tested negative for anti-nivolumab antibodies; this change in clearance is not considered clinically significant.42 Local injection-site reactions were reported in 15% (7/46) of patients who developed anti-nivolumab antibodies and 7% (10/155) of patients who did not develop anti-nivolumab antibodies; however, all events were grade 1 or 2 and resolved.42 Because of low occurrence of anti-nivolumab or anti-hyaluronidase antibodies, the effect of these antibodies on the effectiveness of nivolumab/hyaluronidase-nvhy is unknown.42
Nivolumab and nivolumab/hyaluronidase-nvhy can cause fetal harm if administered to pregnant women based on nivolumab's mechanism of action and animal findings.1, 42 The effects of nivolumab and nivolumab/hyaluronidase-nvhy may be greater during the second and third trimesters of pregnancy.1, 42 Verify pregnancy status in females of reproductive potential prior to initiating treatment with nivolumab or nivolumab/hyaluronidase-nvhy.1, 42
It is not known whether nivolumab or hyaluronidase is distributed into human milk; the effects on the breast-fed child and on milk production are also not known.1, 42 Because of the potential for serious adverse reactions in the breast-fed child, women should be advised not to breast-feed during treatment with nivolumab or nivolumab/hyaluronidase-nvhy and for 5 months after the last dose.1, 42
Females and Males of Reproductive Potential
Nivolumab and nivolumab/hyaluronidase-nvhy can cause fetal harm if administered to a pregnant woman.1, 42 Verify pregnancy status in females of reproductive potential prior to initiation of treatment with nivolumab or nivolumab/hyaluronidase-nvhy.1, 42 Advise such females to use effective contraception during treatment and for 5 months after the last dose.1, 42
The safety and efficacy of nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) have not been established in pediatric patients.42
Safety and efficacy of nivolumab (Opdivo®) for the treatment of non-small cell lung cancer (NSCLC), malignant pleural mesothelioma, advanced renal cell carcinoma, classical Hodgkin lymphoma (cHL), squamous cell carcinoma of the head and neck, urothelial carcinoma, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal cancer, and esophageal adenocarcinoma have not been established in pediatric patients younger than 18 years of age.1
Safety and efficacy of nivolumab (Opdivo®) have been established in pediatric patients 12 years of age and older for the following indications: as monotherapy or in combination with ipilimumab for the treatment of unresectable or metastatic melanoma; as a single agent for the adjuvant treatment of completely resected stage IIB, IIC, III, or IV melanoma; and as monotherapy or in combination with ipilimumab for the management of metastatic colorectal cancer with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.1 Use of nivolumab for these indications is supported by evidence from adequate and well-controlled studies in adults and additional pharmacokinetic data in pediatric patients.1 Exposure to nivolumab is similar in pediatric patients ≥12 years of age and adults and the courses of melanoma and MSI-H or dMMR colorectal cancer are similar enough in pediatric patients ≥12 years of age and adults to allow extrapolation of safety and efficacy.1 Safety and efficacy of nivolumab for these indications have not been established in pediatric patients younger than 12 years of age.1
Some clinical studies of nivolumab (Opdivo®) monotherapy in patients with cHL, squamous cell carcinoma of the head and neck, and MSI-H or dMMR metastatic colorectal cancer did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; however, no clinically important differences in safety or efficacy were observed between patients ≥65 years of age and younger adults in other clinical studies in patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, esophageal squamous cell carcinoma, and esophageal or gastroesophageal junction cancer.1 In clinical trials evaluating monotherapy with nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®), 48% of patients were ≥65 years of age and 14% were ≥75 years of a no overall differences in safety or efficacy were observed between geriatric patients and younger adults.42
Trials of IV nivolumab (Opdivo®) in combination with ipilimumab for the following indications included geriatric patients: melanoma (≥65 years, 41%; ≥75 years, 11%), NSCLC (≥65 years, 48%; ≥75 years, 10%), malignant pleural mesothelioma (≥65 years, 77%; ≥75 years, 26%), advanced renal cell carcinoma (≥65 years, 38%; ≥75 years, 8%), and esophageal squamous cell carcinoma (ESCC; ≥65 years, 43%; ≥75 years, 7%).1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1 However, patients ≥75 years of age experienced higher rates of serious adverse reactions and/or discontinuation due to adverse reactions compared to all patients who received combination therapy in trials of patients with NSCLC (29 versus 18%, respectively), malignant pleural mesothelioma (54 versus 28%, respectively), and ESCC (38 versus 23%, respectively).1 Clinical studies of patients with hepatocellular carcinoma treated with nivolumab plus ipilimumab did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger adults.1
Trials of IV nivolumab (Opdivo®) in combination with platinum-containing chemotherapy for the following indications included geriatric patients: NSCLC (combination therapy [≥65 years, 48%; ≥75 years, 6%]; combination therapy followed by nivolumab monotherapy [≥65 years, 56%; ≥75 years, 7%]), ESCC, gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (≥65 years, 42%; ≥75 years, 10%), and urothelial carcinoma (≥65 years, 40%; ≥75 years, 11%).1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1
In trials of IV nivolumab (Opdivo®) in combination with ipilimumab and platinum doublet chemotherapy for the treatment of NSCLC, 51% of patients were ≥65 years of age and 10% were ≥75 years of age.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults; however, patients ≥75 years of age experienced higher rates of discontinuation due to adverse reactions compared to all patients who received combination therapy (43 versus 24%, respectively).1
In trials of IV nivolumab (Opdivo®) in combination with cabozantinib for the treatment of renal cell carcinoma, 41% of patients were ≥65 years of age and 9% were ≥75 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 nivolumab clearance in patients with mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration more than 1 times but no more than 1.5 times the ULN with any AST concentration) and those with moderate hepatic impairment (total bilirubin concentration more than 1.5 times but not more than 3 times the ULN with any AST concentration) is similar to that in patients with normal hepatic function.1 Data are not available for patients with severe hepatic impairment (total bilirubin concentration exceeding 3 times the ULN with any AST concentration).1
Analysis of population pharmacokinetic data indicates that nivolumab clearance in patients with mild, moderate, or severe renal impairment (estimated glomerular filtration rate [GFR] ≥15 mL/minute per 1.73 m2) is similar to that in patients with normal renal function.1
Adverse effects reported in 20% or more of patients receiving nivolumab (Opdivo®) as a single agent include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection.1
Adverse effects reported in 10% or more of patients receiving nivolumab/hyaluronidase-nvhy (Opdivo Qvantig®) monotherapy for the treatment of renal cell carcinoma include musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain.42
Adverse effects reported in 20% or more of patients receiving nivolumab in combination with ipilimumab include fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness.1
Adverse effects reported in 20% or more of patients receiving nivolumab in combination with platinum doublet chemotherapy include nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy.1
Adverse effects reported in 20% or more of patients receiving nivolumab in combination with ipilimumab and platinum doublet chemotherapy include fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.1
Adverse effects reported in 20% or more of patients receiving nivolumab in combination with cabozantinib include diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.1
Adverse effects reported in 20% or more of patients receiving nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy include nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain.1
No formal drug interaction studies have been performed to date.1, 42
Concomitant administration of nivolumab 1 mg/kg every 3 weeks and ipilimumab 3 mg/kg every 3 weeks increased nivolumab clearance by 29% but did not alter clearance of ipilimumab; however, concomitant administration of nivolumab 3 mg/kg every 3 weeks and ipilimumab 1 mg/kg every 3 weeks did not alter clearance of either drug.1 Concomitant administration of nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks increased ipilimumab clearance by 30% but did not alter clearance of nivolumab.1 Concomitant administration of nivolumab 360 mg every 3 weeks and ipilimumab 1 mg/kg every 6 weeks plus chemotherapy increased ipilimumab clearance by 22% but did not alter clearance of nivolumab.1
Nivolumab, a fully human anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody, is an antineoplastic agent.1, 7, 11, 42 The drug is an IgG4 kappa immunoglobulin.1, 3, 7, 11, 42 Hyaluronidase is an endoglycosidase, which depolymerizes hyaluronan within the subcutaneous tissue to cause a temporary increase in tissue permeability.42 Hyaluronidase is coadministered with other subcutaneous agents to increase dispersion and absorption of the coadministered drug.42
Nivolumab is selective for PD-1,1, 9, 11 an immune-checkpoint receptor expressed on activated T cells, monocytes, B cells, natural killer (NK) T cells, and dendritic cells.1, 7, 8, 11 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, 6, 7, 10, 12 Nivolumab blocks the interaction between PD-1 and its ligands, resulting in enhanced immune response, including enhanced antitumor immune response.1, 3, 6, 10, 12 The drug also has been shown to reduce tumor growth in syngeneic mouse tumor models.1 The combination of nivolumab and an anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) antibody (i.e., ipilimumab) also has demonstrated enhanced T-cell function, including enhanced antitumor immune response, compared with either drug alone.1 Combined blockade of PD-1 and CTLA-4 also has been shown to enhance antitumor activity in syngeneic mouse tumor models.1
Systemic exposure to nivolumab is proportional to dose over the dosage range of 0.1-10 mg/kg every 2 weeks.1 Following repeated 3-mg/kg doses of nivolumab every 2 weeks, steady-state concentrations are reached by 12 weeks; systemic accumulation of the drug is 3.7-fold.1 When coformulated with hyaluronidase, the geometric mean bioavailability of nivolumab is 74% and peak concentrations occurred around 6 days.42 The predicted exposure to nivolumab administered as a 30-minute IV infusion is comparable to that observed following administration as a 60-minute IV infusion.1 Although nivolumab clearance decreases over time (by about 25% from baseline to steady state) in patients with metastatic tumors, the decrease in clearance is not considered clinically important.1, 42 Nivolumab clearance does not decrease over time in patients with completely resected melanoma; clearance in this patient population is 24% lower than that observed at steady state in patients with metastatic melanoma.1, 42 The mean terminal half-life of nivolumab is approximately 25 days.1, 42
Clearance of nivolumab does not appear to be affected by age (range of 29-87 years), body weight (35-160 kg), gender, race, baseline LDH concentration, programmed death ligand 1 (PD-L1) expression, solid tumor type, tumor burden, renal impairment, or mild to moderate hepatic impairment.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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion only | 40 mg/4 mL (10 mg/mL) | ||
100 mg/10 mL (10 mg/mL) | Opdivo® | Bristol-Myers Squibb | ||
120 mg/12 mL (10 mg/mL) | Opdivo® | Bristol-Myers Squibb | ||
240 mg/24 mL (10 mg/mL) | Opdivo® | Bristol-Myers Squibb |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for subcutaneous use only | Nivolumab 600 mg and hyaluronidase 10,000 units/5 mL (120 mg/2000 units/mL) | Opdivo Qvantig® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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44. Robert C, Long GV, Brady B, et al. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020;38(33):3937-3946.
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