pembrolizumab

Therapeutic Classification: antineoplastics

Pharmacologic Classification: monoclonal antibodies, programmed death-1 inhibitors

High Alert

Unresectable or metastatic melanoma.
Adjuvant treatment of Stage IIB, IIC, or III melanoma following complete resection.
First-line treatment of patients with stage III non-small cell lung cancer (NSCLC), who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC and whose tumors express PD-L1 (tumor proportion score [TPS] ≥1%) and have no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations (as monotherapy).
Metastatic NSCLC expressing PD-L1 (TPS ≥1%) that has progressed on or after platinum-containing chemotherapy (as monotherapy). Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
Adjuvant treatment of Stage IB, II, or IIIA NSCLC following resection and platinum-based chemotherapy (as monotherapy).
Resectable (tumors ≥4 cm or node positive) NSCLC (in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery).
First-line treatment of metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations (in combination with pemetrexed and platinum chemotherapy).
First-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma (in combination with pemetrexed and platinum chemotherapy).
First-line treatment of metastatic nonsquamous NSCLC (in combination with carboplatin and either paclitaxel or nab-paclitaxel [albumin-bound]).
Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that has progressed on or after platinum-containing chemotherapy.
First-line treatment of metastatic or unresectable recurrent HNSCC (in combination with platinum and fluorouracil).
First-line treatment of metastatic or unresectable recurrent HNSCC expressing PD-L1 (combined positive score [CPS] ≥1).
Resectable locally advanced HNSCC expressing PD-L1 (CPS ≥1) as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy with or without cisplatin, and then as a single agent.
Adults with relapsed or refractory classical Hodgkin lymphoma (cHL).
Children with refractory cHL or cHL that has relapsed after ≥2 lines of therapy.
Primary mediastinal large B-cell lymphoma that is refractory or that has relapsed after ≥2 prior lines of therapy (should not be used in patients who require urgent cytoreductive therapy).
Locally advanced or metastatic urothelial carcinoma in patients who are not eligible for any platinum-containing chemotherapy.
Locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or within 12 mo of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Locally advanced or metastatic urothelial carcinoma (in combination with enfortumab vedotin).
Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle-invasive bladder cancer with carcinoma in situ with or without papillary tumors in patients who are not eligible for or have elected not to undergo cystectomy.
Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.
First-line treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer.
First-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma (in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy).
First-line treatment of locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 (CPS ≥1) (in combination with fluoropyrimidine- and platinum-containing chemotherapy).
Locally advanced or metastatic esophageal or gastroesophageal junction (tumors with epicenter 1–5 cm above the gastroesophageal junction) carcinoma that is not amenable to surgical resection or definitive chemoradiation either as monotherapy after ≥1 prior line of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) or in combination with platinum- and fluoropyrimidine-based chemotherapy in patients whose tumors that express PD-L1 (CPS ≥1).
Locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/nonfunctioning kidney, or spread to adjacent pelvic organs (FIGO 2014 Stage III–IVA) (in combination with chemoradiotherapy).
Recurrent or metastatic cervical cancer expressing PD-L1 (CPS ≥1) that has progressed on or after chemotherapy.
Persistent, recurrent, or metastatic cervical cancer expressing PD-L1 (CPS ≥1) (in combination with chemotherapy, with or without bevacizumab).
Hepatocellular carcinoma secondary to hepatitis B in patients who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen.
Locally advanced unresectable or metastatic biliary tract cancer (in combination with gemcitabine and cisplatin).
Recurrent locally advanced or metastatic Merkel cell carcinoma.
First-line treatment of advanced renal cell carcinoma (RCC) (in combination with axitinib or lenvatinib).
Adjuvant treatment of RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Primary advanced or recurrent endometrial carcinoma (in combination with carboplatin and paclitaxel, and then continued as a single agent).
Advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not MSI-H in patients who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation (in combination with lenvatinib).
Advanced endometrial carcinoma that is MSI-H or dMMR in patients who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.
Recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation.
Locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) in patients whose tumors express PD-L1 (CPS ≥10) (in combination with chemotherapy).
High-risk early-stage TNBC (in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery).

Programmed death receptor-1 (PD-1) blocking antibody (an IgG4 kappa immunoglobulin) that binds to PD-1 and blocks its interaction with its ligands, PD-L1 and PD-L2, resulting in activation of the immune system and decreased tumor growth.

Therapeutic effects:

Decreased spread of melanoma, NSCLC, malignant pleural mesothelioma, HNSCC, cHL, urothelial carcinoma, MSI-H or dMMR solid tumors, MSI-H or dMMR colorectal cancer, gastric tumors, cervical cancer, endometrial cancer, esophageal cancer, primary mediastinal large B-cell lymphoma, hepatocellular carcinoma, biliary tract cancer, Merkel cell carcinoma, RCC, TMB-H solid tumors, cutaneous squamous cell carcinoma, and TNBC.

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism/Excretion: Unknown.

Half-Life: 26 days.

ROUTE		ONSET		PEAK		DURATION
IV		within 3 mo		unknown		may persist for >8.8 mo

Contraindicated in:

OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Moderate or severe hepatic impairment;
Solid organ transplant recipients (↑ risk of rejection);
Allogeneic hematopoietic stem cell transplant recipients (↑ risk of transplantation complications);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children <2 yr (cHL, MSI-H cancer, primary mediastinal large B-cell lymphoma, and Merkel cell carcinoma) <12 yr (melanoma), or children <18 yr (all other indications).

Drug-drug:

None reported.

Melanoma

IV (Adults ): 200 mg every 3 wk until disease progression or unacceptable toxicity or 400 mg every 6 wk until disease progression or unacceptable toxicity.

Adjuvant Treatment of Melanoma

IV (Adults ): 200 mg every 3 wk until disease recurrence, unacceptable toxicity, or up to 12 mo or 400 mg every 6 wk until disease recurrence, unacceptable toxicity, or up to 12 mo.
IV (Children ≥12 yr): 2 mg/kg (max = 200 mg) every 3 wk until disease recurrence, unacceptable toxicity, or up to 12 mo.

Non-Small Cell Lung Cancer, Malignant Pleural Mesothelioma, Head and Neck Squamous Cell Carcinoma, Esophageal Cancer, Biliary Tract Cancer, or Locally Recurrent Unresectable or Metastatic Triple Negative Breast Cancer

IV (Adults ): 200 mg every 3 wk until disease progression, unacceptable toxicity, or up to 24 mo or 400 mg every 6 wk until disease progression, unacceptable toxicity, or up to 24 mo. If being administered in combination with chemotherapy, should be administered prior to chemotherapy when given on the same day.

Locally Advanced Head and Neck Squamous Cell Carcinoma,

IV (Adults ): 200 mg every 3 wk or 400 mg every 6 wk. As neoadjuvant therapy, administer as monotherapy for 6 wk or until disease progression that precludes definitive surgery or unacceptable toxicity. As adjuvant therapy, administer in combination with radiotherapy with or without cisplatin, and then continue as monotherapy. Continue until disease recurrence or unacceptable toxicity or up to 1 yr.

Adjuvant Treatment of Non-Small Cell Lung Cancer

IV (Adults ): 200 mg every 3 wk until disease recurrence, unacceptable toxicity, or up to 12 mo or 400 mg every 6 wk until disease recurrence, unacceptable toxicity, or up to 12 mo.

Resectable Non-Small Cell Lung Cancer

IV (Adults ): 200 mg every 3 wk. Neoadjuvant treatment in combination with platinum-containing chemotherapy for 12 wk or until disease progression that precludes definitive surgery, or unacceptable toxicity, followed by neoadjuvant treatment as monotherapy after surgery for 39 wk or until disease recurrence or unacceptable toxicity; or 400 mg every 6 wk. Neoadjuvant treatment in combination with platinum-containing chemotherapy for 12 wk or until disease progression that precludes definitive surgery, or unacceptable toxicity, followed by neoadjuvant treatment as monotherapy after surgery for 39 wk or until disease recurrence or unacceptable toxicity

Urothelial Carcinoma, Gastric Cancer, Cervical Cancer, Endometrial Carcinoma, Hepatocellular Carcinoma, Renal Cell Carcinoma, Cutaneous Squamous Cell Carcinoma, or Microsatellite Instability-High/Mismatch Repair Deficient Colorectal Cancer

IV (Adults ): 200 mg every 3 wk until disease progression, unacceptable toxicity, or up to 24 mo or 400 mg every 6 wk until disease progression, unacceptable toxicity, or up to 24 mo. If being administered in combination with chemotherapy, chemoradiotherapy, bevacizumab, trastuzumab, paclitaxel, or carboplatin, should be administered prior to these therapies when given on the same day; if being administered in combination with enfortumab vedotin, should be administered after this medication when given on the same day.

Adjuvant Treatment of Renal Cell Carcinoma

IV (Adults ): 200 mg every 3 wk until disease recurrence, unacceptable toxicity, or up to 12 mo or 400 mg every 6 wk until disease recurrence, unacceptable toxicity, or up to 12 mo.

Bacillus Calmette-Guerin-Unresponsive, High-Risk Non-Muscle-Invasive Bladder Cancer

IV (Adults ): 200 mg every 3 wk until persistent or recurrent high-risk non-muscle invasive bladder cancer, disease progression, unacceptable toxicity, or up to 24 mo or 400 mg every 6 wk until persistent or recurrent high-risk non-muscle invasive bladder cancer, disease progression, unacceptable toxicity, or up to 24 mo.

Classical Hodgkin Lymphoma, Microsatellite Instability-High/Mismatch Repair Deficient Cancer, Primary Mediastinal Large B-Cell Lymphoma, Merkel Cell Carcinoma, or Tumor Mutational Burden-High Cancer

IV (Adults ): 200 mg every 3 wk until disease progression, unacceptable toxicity, or up to 24 mo or 400 mg every 6 wk until disease progression, unacceptable toxicity, or up to 24 mo.
IV (Children ≥2 yr): 2 mg/kg (max = 200 mg) every 3 wk until disease progression, unacceptable toxicity, or up to 24 mo.

High-Risk, Early-Stage Triple Negative Breast Cancer

IV (Adults ): 200 mg every 3 wk for 24 wk (8 doses) (as neoadjuvant treatment in combination with chemotherapy) or until disease progression or unacceptable toxicity followed by 200 mg every 3 wk for up to 27 wk (9 doses) (as monotherapy as adjuvant treatment after surgery) or 400 mg every 6 wk for 24 wk (4 doses) (as neoadjuvant treatment in combination with chemotherapy) or until disease progression or unacceptable toxicity followed by 400 mg every 6 wk for up to 27 wk (5 doses) (as monotherapy as adjuvant treatment after surgery). If being administered in combination with chemotherapy, should be administered prior to chemotherapy when given on the same day.

Solution for injection: 25 mg/mL

Monitor for signs/symptoms of immune-mediated pneumonitis (shortness of breath, chest pain, new or worse cough) periodically during therapy. Evaluate with x-ray. If Grade ≥2 pneumonitis occurs, treat with corticosteroids. If Grade 2 pneumonitis occurs, hold pembrolizumab. Resume therapy in patients with complete or partial resolution (Grade ≤1) after corticosteroid taper. If Grades 3 or 4 or recurrent Grade 2 pneumonitis occurs, permanently discontinue pembrolizumab.
Monitor for immune-mediated nephritis (hematuria, ↑ BP, oliguria, edema, shortness of breath) during therapy. If nephritis occurs with kidney dysfunction and treatment is interrupted or discontinued, administer systemic corticosteroids (1–2 mg/kg/day prednisone or equivalent) until improvement to Grade ≤1; then follow corticosteroid taper.
Monitor for signs/symptoms of immune-mediated colitis (diarrhea, abdominal pain, mucus or blood in stool, with or without fever). If Grades 2 or 3 colitis occurs, hold pembrolizumab. Resume therapy in patients with complete or partial resolution (Grades ≤1) after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 wk of initiating corticosteroids or if unable to ↓ prednisone dose to ≤10 mg/day (or equivalent) within 12 wk of corticosteroid initiation. If Grade 4 colitis occurs, permanently discontinue pembrolizumab.
Assess for signs/symptoms of immune-mediated hepatitis (yellowing of skin or whites of eyes, unusual darkening of urine, unusual tiredness, pain in right upper stomach) before each dose.
Monitor for signs/symptoms of infusion-related reactions (rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, fever). If Grades 1 or 2 infusion-related reactions occur, hold or slow rate of infusion. If Grades 3 or 4 infusion-related reactions occur, stop infusion and permanently discontinue pembrolizumab.
Monitor for clinical signs/symptoms of hypophysitis (persistent or unusual headache, extreme weakness, dizziness or fainting, vision changes) during therapy. Other endocrinopathies to monitor for include Grade ≥2 adrenal insufficiency, type 1 diabetes, hyperthyroidism, thyroiditis, and hypothyroidism. If Grade 3 or 4 endocrinopathies occur, hold pembrolizumab until clinically stable.
Assess for rash periodically during therapy. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. May cause SJS, TEN, and DRESS. If rash, itching, blistering, or ulcers in mouth or other mucous membranes occur and SJS, TEN, or DRESS are suspected, hold pembrolizumab and refer for assessment and treatment. If SJS, TEN, or DRESS are confirmed, permanently discontinue pembrolizumab.
Monitor for signs/symptoms of encephalitis (headache, fever, tiredness or weakness, confusion, memory problems, sleepiness, hallucinations, seizures, stiff neck) periodically during therapy. If Grade 2 neurological toxicities occur, hold pembrolizumab; resume after complete or partial resolution (Grades 0–1) after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response (Grades 0–1) within 12 wk of initiating corticosteroids or if unable to ↓ prednisone dose to ≤10 mg/day (or equivalent) within 12 wk of corticosteroid initiation. If Grade 3 or 4 neurological toxicities occur, permanently discontinue pembrolizumab and administer corticosteroids at dose of 1–2 mg/kg/day prednisone or equivalent for immune-mediated encephalitis, followed by corticosteroid taper.
Monitor for signs/symptoms of myocarditis (chest pain, dyspnea) during therapy. If Grade 2, 3, or 4 myocarditis occurs, permanently discontinue pembrolizumab.

Lab Test Considerations:

Verify negative pregnancy test prior to starting therapy. Patient selection is based on presence of positive PD-L1 expression in stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, metastatic NSCLC, first-line treatment of metastatic or unresectable recurrent HNSCC, metastatic gastric cancer (if PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate feasibility of obtaining a tumor biopsy for PD-L1 testing), previously treated recurrent locally advanced or metastatic esophageal cancer, and recurrent or metastatic cervical cancer. For MSI-H/dMMR indications, select patients for pembrolizumab as a single agent based on MSI-H/dMMR status in tumor specimens. For TMB-H, select patients for pembrolizumab as a single agent based on TMB-H status in tumor specimens. For combination therapy for non-MSI-H/dMMR advanced endometrial carcinoma, select patients for pembrolizumab in combination with lenvatinib based on MSI or MMR status in tumor specimens. For use of pembrolizumab in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression in locally recurrent unresectable or metastatic TNBC. Information on FDA-approved tests used for patient selection is available at http://www.fda.gov/CompanionDiagnostics.
- Monitor for ↑ serum creatinine before and periodically during therapy. If Grade 2 or 3 ↑ in serum creatinine occur, hold pembrolizumab. Resume in patients with complete or partial resolution (Grade ≤1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 wk of last dose or inability to ↓ prednisone dose to ≤10 mg per day (or equivalent) within 12 wk of starting steroids. If Grade 4 ↑ in blood creatinine occur, permanently discontinue pembrolizumab.
- Monitor for liver function before and periodically during therapy. For hepatitis with no tumor involvement: If AST/ALT >3 and ≤8 times upper limit of normal (ULN) or total bilirubin >1.5 and ≤3 times ULN, hold pembrolizumab. Resume with complete or partial resolution (Grade ≤1) after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial resolution within 12 wk of last dose or inability to ↓ prednisone dose to ≤10 mg per day (or equivalent) within 12 wk of starting steroids. If AST or ALT >8 times ULN or total bilirubin >3 times ULN, permanently discontinue pembrolizumab. For hepatitis with tumor involvement of the liver: If baseline AST/ALT >1 and ≤3 times ULN and ↑ to >5 and ≤10 times ULN or baseline AST/ALT >3 and ≤5 times ULN and ↑ to >8 and ≤10 times ULN, hold pembrolizumab. If AST/ALT >10 times ULN or total bilirubin >3 times ULN, permanently discontinue pembrolizumab.
- Monitor for changes in thyroid function at start of and periodically during therapy, and as indicated based on clinical evaluation. Administer corticosteroids for Grade ≥3 hyperthyroidism; hold pembrolizumab for severe (Grade 3) hyperthyroidism and resume therapy when recovery to Grade ≤1. Permanently discontinue pembrolizumab for life-threatening (Grade 4) hyperthyroidism. Manage hypothyroidism with thyroid replacement without interruption of therapy or corticosteroids.
- Monitor serum blood glucose. May cause hyperglycemia or other signs and symptoms of diabetes.

IV Administration:

Intermittent Infusion:
Y-Site Incompatibility: Do not administer other drugs through same IV line.

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Emphasize importance of keeping scheduled appointments for blood work or other laboratory tests.
Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care provider before taking other medications.
Advise patient to notify health care provider immediately if signs and symptoms of pneumonitis; colitis; hepatitis; kidney problems (change in amount or color of urine); hormone gland problems (rapid heartbeat, weight loss, ↑ sweating, weight gain, hair loss, feeling cold, constipation, deepening of voice, dizziness or fainting, persistent or unusual headache); change in taste; trouble sleeping; flu-like symptoms; or back, bone, joint, muscle, or neck pain occur.
Rep: May cause fetal harm. Advise women of reproductive potential to use highly effective contraception and avoid breastfeeding during and for ≥4 mo after last dose.

Decreased spread of melanoma, NSCLC, malignant pleural mesothelioma, HNSCC, cHL, urothelial carcinoma, MSI-H or dMMR solid tumors, MSI-H or dMMR colorectal cancer, gastric tumors, cervical cancer, endometrial cancer, esophageal cancer, primary mediastinal large B-cell lymphoma, hepatocellular carcinoma, biliary tract cancer, Merkel cell carcinoma, RCC, TMB-H solid tumors, cutaneous squamous cell carcinoma, and TNBC.

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