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Pembrolizumab: Drug information

Pembrolizumab: Drug information
2024© UpToDate, Inc. and its affiliates and/or licensors. All Rights Reserved.
For additional information see "Pembrolizumab: Patient drug information" and "Pembrolizumab: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table
Brand Names: US
  • Keytruda
Brand Names: Canada
  • Keytruda
Pharmacologic Category
  • Antineoplastic Agent, Anti-PD-1 Monoclonal Antibody;
  • Antineoplastic Agent, Immune Checkpoint Inhibitor;
  • Antineoplastic Agent, Monoclonal Antibody
Dosing: Adult

Dosage guidance:

Clinical considerations: Some indications are based on PD-L1 expression, or are based on tumor specimen microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR), mismatch repair proficient (pMMR), or tumor mutational burden-high (TMB-H) status.

Biliary tract cancer, locally advanced unresectable or metastatic

Biliary tract cancer, locally advanced unresectable or metastatic: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with cisplatin (maximum 8 cycles) and gemcitabine; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Breast cancer, triple-negative, high-risk, early stage, neoadjuvant and adjuvant therapy

Breast cancer, triple-negative, high-risk, early stage, neoadjuvant and adjuvant therapy:

Neoadjuvant therapy (pembrolizumab in combination with chemotherapy for 24 weeks): IV: 200 mg once every 3 weeks for 8 doses or 400 mg once every 6 weeks for 4 doses, or until disease progression or unacceptable toxicity (do not administer adjuvant therapy if disease progression or unacceptable toxicity occurs with neoadjuvant therapy).

Adjuvant therapy (pembrolizumab as a single agent for up to 27 weeks): IV: 200 mg once every 3 weeks for 9 doses or 400 mg once every 6 weeks for 5 doses, or until disease progression or unacceptable toxicity.

Trial-specific dosing details:

Neoadjuvant therapy: IV: 200 mg once every 3 weeks (in combination with paclitaxel and carboplatin) for 4 cycles (first neoadjuvant treatment), followed by 200 mg once every 3 weeks (in combination with cyclophosphamide and either doxorubicin or epirubicin) for 4 cycles (second neoadjuvant treatment). Patients underwent definitive surgery 3 to 6 weeks after the last cycle of the neoadjuvant phase (Ref).

Adjuvant therapy: IV: 200 mg once every 3 weeks (in combination with radiation therapy) for up to 9 cycles (Ref).

Breast cancer, triple-negative, locally recurrent unresectable or metastatic, with PD-L1 expression

Breast cancer, triple-negative, locally recurrent unresectable or metastatic, with PD-L1 expression (combined positive score ≥10): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months. Administer in combination with chemotherapy; in the clinical trial, chemotherapy consisted of paclitaxel (protein bound), paclitaxel (conventional), or gemcitabine/carboplatin (Ref).

Cervical cancer, stage III to IVA

Cervical cancer, stage III to IVA: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; in combination with 5 to 6 cycles of cisplatin-based chemoradiotherapy, followed by brachytherapy; continue pembrolizumab (as a single agent) until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Cervical cancer, persistent, recurrent, or metastatic, with PD-L1 expression

Cervical cancer, persistent, recurrent, or metastatic, with PD-L1 expression (CPS ≥1):

Single-agent therapy:

IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Combination therapy:

IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months. Administer in combination with chemotherapy, with or without bevacizumab; in the clinical trial, chemotherapy consisted of paclitaxel in combination with either cisplatin or carboplatin (with or without bevacizumab) (Ref).

Colorectal cancer, unresectable or metastatic, microsatellite instability-high or mismatch repair deficient

Colorectal cancer, unresectable or metastatic, microsatellite instability-high or mismatch repair deficient: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Cutaneous squamous cell carcinoma, recurrent, metastatic, or locally advanced

Cutaneous squamous cell carcinoma, recurrent, metastatic, or locally advanced: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Endometrial carcinoma, advanced, mismatch repair proficient or not microsatellite instability-high

Endometrial carcinoma, advanced, mismatch repair proficient or not microsatellite instability-high: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with lenvatinib; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Endometrial carcinoma, advanced microsatellite instability-high or mismatch repair deficient

Endometrial carcinoma, advanced, microsatellite instability-high or mismatch repair deficient: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Esophageal cancer, recurrent locally advanced or metastatic, with PD-L1 expression

Esophageal cancer, recurrent locally advanced or metastatic, with PD-L1 expression (CPS ≥10): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Esophageal cancer, locally advanced or metastatic

Esophageal cancer, locally advanced or metastatic: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with 6 cycles of fluorouracil and cisplatin; continue pembrolizumab and fluorouracil until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Gastric cancer, locally advanced or metastatic, HER2-positive, with PD-L1 expression

Gastric cancer, locally advanced or metastatic, HER2-positive, with PD-L1 expression (CPS ≥1) (first-line therapy): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Gastric cancer, locally advanced or metastatic, HER2-negative

Gastric cancer, locally advanced or metastatic, HER2-negative (first-line therapy): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with fluoropyrimidine- and platinum-containing chemotherapy; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Head and neck cancer, squamous cell carcinoma, unresectable, recurrent, or metastatic, with PD-L1 expression

Head and neck cancer, squamous cell carcinoma, unresectable, recurrent, or metastatic, with PD-L1 expression (CPS ≥1) (first-line therapy): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Head and neck cancer, squamous cell carcinoma, unresectable, recurrent, or metastatic

Head and neck cancer, squamous cell carcinoma, unresectable, recurrent, or metastatic (first-line therapy): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with 6 cycles of fluorouracil and either carboplatin or cisplatin; continue pembrolizumab (as a single agent) until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Hepatocellular carcinoma, advanced

Hepatocellular carcinoma, advanced: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Hodgkin lymphoma, classical, relapsed or refractory

Hodgkin lymphoma, classical, relapsed or refractory: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Malignant pleural mesothelioma, relapsed or refractory, with PD-L1 expression

Malignant pleural mesothelioma, relapsed or refractory, with PD-L1 expression (off-label use): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Melanoma, stage IIB, IIC, or III, resected, adjuvant therapy

Melanoma, stage IIB, IIC, or III, resected, adjuvant therapy: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease recurrence, unacceptable toxicity, or (in patients without disease recurrence) for up to 12 months (Ref).

Melanoma, advanced, high-risk, resectable, neoadjuvant and adjuvant therapy

Melanoma, advanced, high-risk, resectable, neoadjuvant and adjuvant therapy (off-label use): IV: 200 mg once every 3 weeks for a total of 3 neoadjuvant doses prior to surgery (the interval between the last neoadjuvant dose and surgery should be no longer than 5 weeks), followed by 200 mg once every 3 weeks for an additional 15 doses as postsurgery adjuvant therapy (Ref).

Melanoma, unresectable or metastatic

Melanoma, unresectable or metastatic: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression or unacceptable toxicity.

Merkel cell carcinoma, recurrent locally advanced or metastatic

Merkel cell carcinoma, recurrent locally advanced or metastatic: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Microsatellite instability-high or mismatch repair-deficient cancer, unresectable or metastatic

Microsatellite instability-high or mismatch repair-deficient cancer, unresectable or metastatic: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Mycosis fungoides/Sézary syndrome, relapsed/refractory

Mycosis fungoides/Sézary syndrome, relapsed/refractory (off-label use): IV: 2 mg/kg once every 3 weeks until disease progression or unacceptable toxicity, for up to 24 months (Ref).

Non–small cell lung cancer, stage IB, II, or IIIA, resected, adjuvant therapy

Non–small cell lung cancer, stage IB, II, or IIIA, resected, adjuvant therapy: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease recurrence, unacceptable toxicity, or for up to 12 months in patients without disease recurrence (Ref).

Non–small cell lung cancer, resectable, neoadjuvant and adjuvant therapy

Non– small cell lung cancer, resectable, neoadjuvant and adjuvant therapy:

Neoadjuvant therapy (in combination with chemotherapy for 12 weeks): IV: 200 mg once every 3 weeks for 4 doses or 400 mg once every 6 weeks for 2 doses, or until disease progression that precludes definitive surgery or unacceptable toxicity.

Adjuvant therapy (as a single agent for up to 39 weeks): IV: 200 mg once every 3 weeks for 13 doses or 400 mg once every 6 weeks for 7 doses, or until disease recurrence or unacceptable toxicity.

Trial-specific dosing details:

Neoadjuvant therapy: IV: 200 mg once every 3 weeks (in combination with cisplatin and gemcitabine [squamous histology] or cisplatin and pemetrexed [nonsquamous histology]) for 4 cycles. Patients underwent definitive surgery within 20 weeks after the first cycle of the neoadjuvant phase (Ref).

Adjuvant therapy: IV: 200 mg once every 3 weeks (as a single agent) for up to 13 cycles. Patients initiated adjuvant therapy no sooner than 4 weeks and no later than 12 weeks following definitive surgery (Ref).

Non–small cell lung cancer, stage III or metastatic, with PD-L1 expression

Non–small cell lung cancer, stage III or metastatic, with PD-L1 expression ( tumor proportion score ≥1%) (first-line therapy) : IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Non–small cell lung cancer, metastatic, with PD-L1 expression

Non–small cell lung cancer, metastatic, with PD-L1 expression (tumor proportion score ≥1%) (previously treated): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Non–small cell lung cancer, metastatic, nonsquamous

Non–small cell lung cancer, metastatic, nonsquamous (first-line therapy): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with pemetrexed and either cisplatin or carboplatin for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks or 400 mg once every 6 weeks, with or without optional indefinite pemetrexed maintenance therapy; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles or 24 months (Ref).

Non–small cell lung cancer, metastatic, squamous

Non–small cell lung cancer, metastatic, squamous (first-line therapy): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with carboplatin and either paclitaxel or paclitaxel (protein bound) for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks or 400 mg once every 6 weeks until radiographic disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles (Ref).

Primary mediastinal large B-cell lymphoma, relapsed or refractory

Primary mediastinal large B-cell lymphoma, relapsed or refractory: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Renal cell carcinoma, adjuvant therapy

Renal cell carcinoma, adjuvant therapy:

Note: For use (as a single-agent) in patients at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.

IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease recurrence, unacceptable toxicity, or (in patients without disease recurrence) for up to 12 months (Ref).

Renal cell carcinoma, advanced

Renal cell carcinoma, advanced (first-line therapy):

Single-agent therapy (off-label use):

Note: May be used as monotherapy in patients with limited burden, favorable-risk disease when ipilimumab-based regimens or antiangiogenic agents are not appropriate options (Ref).

IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Combination therapy:

Note: For use in combination with either axitinib or lenvatinib regardless of risk stratification (Ref); some experts may prefer pembrolizumab in combination with axitinib for patients with favorable-risk disease who have substantial disease burden, and pembrolizumab in combination with lenvatinib for patients with intermediate- or poor-risk disease who have symptomatic or life-threatening disease burden (Ref).

IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with axitinib or lenvatinib; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Tumor mutational burden-high cancer, unresectable or metastatic

Tumor mutational burden-high cancer, unresectable or metastatic: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Urothelial cancer, non-muscle invasive, high-risk, Bacillus Calmette-Guerin–unresponsive

Urothelial cancer, non-muscle invasive, high-risk, Bacillus Calmette-Guerin–unresponsive: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks until persistent or recurrent non-muscle invasive bladder cancer, disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Urothelial cancer, locally advanced or metastatic

Urothelial cancer, locally advanced or metastatic:

Single-agent therapy:

IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Combination therapy:

IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks, in combination with enfortumab vedotin; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Kidney impairment prior to treatment initiation:

Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (Ref).

Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzed (large molecular weight) (Ref): No dosage adjustment likely to be necessary (Ref). Several cases of successful use in patients with end-stage kidney disease have been reported (Ref).

Peritoneal dialysis: Unlikely to be significantly dialyzed (large molecular weight): No dosage adjustment likely to be necessary (Ref).

CRRT: No dosage adjustment likely to be necessary (Ref).

PIRRT (eg, slow, low efficiency hemodiafiltration): No dosage adjustment likely to be necessary (Ref).

Kidney toxicity during treatment:

Immune-mediated nephritis with kidney dysfunction: Note: If pembrolizumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to grade 1 or lower, then follow with a corticosteroid taper.

Grade 2 or grade 3 serum creatinine elevation: Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 4 serum creatinine elevation: Permanently discontinue pembrolizumab.

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to treatment initiation:

Mild to moderate impairment (total bilirubin ≤3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, there was no clinically important effect on clearance for patients with mild to moderate hepatic impairment.

Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatotoxicity during treatment:

If pembrolizumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to grade 1 or lower, then follow with a corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Indications except when used in combination with axitinib (for renal cell carcinoma):

Immune-mediated hepatitis without tumor involvement of the liver:

AST or ALT >3 up to 8 times ULN or total bilirubin >1.5 up to 3 times ULN: Withhold pembrolizumab treatment. Resume pembrolizumab treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper.

AST or ALT >8 times ULN or total bilirubin >3 times ULN: Discontinue pembrolizumab permanently.

Immune-mediated hepatitis with tumor involvement of the liver: Note: If AST and ALT are ≤ ULN at baseline, follow recommendations for hepatitis without tumor involvement of the liver.

If baseline AST or ALT >1 up to 3 times ULN and increases to >5 up to 10 times ULN or baseline AST or ALT >3 up to 5 times ULN and increases to >8 up to 10 times ULN: Withhold pembrolizumab treatment. Resume pembrolizumab treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper.

AST or ALT increases to >10 times ULN or total bilirubin increases to >3 times ULN: Discontinue pembrolizumab permanently.

When used in combination with axitinib (for renal cell carcinoma):

AST or ALT ≥3 to <10 times ULN without concurrent total bilirubin ≥2 times ULN: Withhold pembrolizumab (and axitinib) treatment until recovery to grade 0 or 1. After recovery, consider rechallenge with a single drug (either pembrolizumab or axitinib) or sequential rechallenge with both pembrolizumab and axitinib; axitinib may require a dose reduction (refer to axitinib monograph).

AST or ALT ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN: Discontinue pembrolizumab (and axitinib) permanently.

Addition al recommendations for hepatotoxicity during treatment:

Grade 2 immune-mediated hepatitis: Withhold immune checkpoint inhibitor (ICI); if no improvement within 3 to 5 days after ICI is withheld, consider initiation of corticosteroids (prednisone 0.5 to 1 mg/kg/day or equivalent) (ASCO [Schneider 2021]).

Grade 3 or 4 immune-mediated hepatitis: Withhold ICI; initiate corticosteroids (methylprednisolone 1 to 2 mg/kg or equivalent) (ASCO [Schneider 2021]). Based on data from a retrospective cohort study in patients with grade 3 or 4 immune-mediated hepatitis, initial treatment with methylprednisolone 1 mg/kg/day demonstrated similar time to ALT normalization (compared with higher methylprednisolone doses), while reducing the potential for corticosteroid-related complications (Li 2022).

Dosing: Obesity: Adult

American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 : The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status (Ref).

Dosing: Adjustment for Toxicity: Adult

Note: No dosage reductions of pembrolizumab are recommended. Other concomitant anticancer therapies may also require treatment interruption, dosage reduction, and/or discontinuation.

Immune-mediated adverse reactions (general information): Withhold pembrolizumab for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue pembrolizumab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating corticosteroids. If pembrolizumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) until improvement to ≤ grade 1; upon improvement to ≤ grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy. Systemic corticosteroids may not be necessary for certain adverse reactions. Hormone replacement therapy may be required for endocrinopathies (if clinically indicated). See table for additional dosage modification guidance.

Additional management recommendations:Consider withholding checkpoint inhibitor therapy for most grade 2 toxicities and resume when symptoms and/or lab values resolve to ≤ grade 1; systemic corticosteroids (initial dose of 0.5 to 1 mg/kg/day prednisone [or equivalent]) may be administered if indicated for grade 2 toxicities (Ref). Refer to guideline for further information regarding management of immune-mediated adverse reactions associated with checkpoint inhibitor therapy.

Pembrolizumab Recommended Dosage Modifications for Adverse Reactions

Adverse reaction

Severity

Pembrolizumab dosage modification

a Refer to prednisone monograph for tapering recommendations when used for immune-mediated adverse reactions associated with checkpoint inhibitor therapy.

Immune-mediated adverse reactions

Cardiovascular toxicity: Myocarditis

Grade 2, 3, or 4

Permanently discontinue pembrolizumab.

Dermatologic toxicity

Mild or moderate nonexfoliative rash

May be managed with topical emollients and/or topical corticosteroids.

Exfoliative dermatologic conditions: Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS)

Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.a Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Confirmed SJS, TEN, or DRESS

Permanently discontinue pembrolizumab.

Endocrinopathies

Grade 3 or 4

Withhold pembrolizumab until clinically stable or permanently discontinue depending on severity.

Adrenal insufficiency, ≥ grade 2

Initiate symptomatic management (including hormone replacement as clinically indicated).

Diabetes, type 1

Initiate insulin as clinically indicated. Long-term insulin therapy may be required.

Hypophysitis

Withhold or discontinue pembrolizumab (depending on the severity). Initiate hormone replacement therapy as clinically indicated.

Hyperthyroidism/Thyroiditis

Withhold or discontinue pembrolizumab (depending on the severity). Initiate medical management as clinically indicated.

Hypothyroidism

Withhold pembrolizumab (depending on the severity). Initiate thyroid hormone replacement therapy as clinically indicated.

GI toxicity: Colitis

Grade 2 or 3

Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.a Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 4

Permanently discontinue pembrolizumab.

Hematologic toxicity (in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma)

Grade 4

Withhold pembrolizumab until resolution to grade 0 or 1.

Neurologic toxicities

Grade 2

Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.a Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue pembrolizumab.

Ocular disorders: Vogt-Koyanagi-Harada-like syndrome

May require systemic corticosteroids to reduce the risk of permanent vision loss.

Pulmonary toxicity: Pneumonitis

Grade 2

Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.a Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue pembrolizumab.

Other adverse reactions

Infusion reactions

Grade 1 or 2

Interrupt or slow the rate of pembrolizumab infusion.

Grade 3 or 4

Stop infusion and permanently discontinue pembrolizumab.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Pembrolizumab: Pediatric drug information")

Dosage guidance:

Clinical considerations: FDA approval for some indications through an accelerated process.

Hodgkin lymphoma, classical

Hodgkin lymphoma, classical (relapsed or refractory):

Infants ≥6 months, Children, and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months.

Melanoma; stage IIB, IIC, or III following complete resection, adjuvant therapy

Melanoma; stage IIB, IIC, or III following complete resection, adjuvant therapy:

Children ≥12 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 12 months.

Merkel cell carcinoma

Merkel cell carcinoma (recurrent locally advanced or metastatic):

Infants ≥6 months, Children, and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months.

Microsatellite instability-high cancer; non-CNS solid tumors that have progressed following prior treatment without satisfactory alternative treatment options

Microsatellite instability-high cancer (MSI-H) (unresectable or metastatic); non-CNS solid tumors that have progressed following prior treatment without satisfactory alternative treatment options:

Infants ≥6 months, Children, and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months.

Primary mediastinal large B-cell lymphoma

Primary mediastinal large B-cell lymphoma (PMBCL) (relapsed or refractory):

Infants ≥6 months, Children, and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months.

Tumor mutational burden-high; non-CNS solid tumors that have progressed following prior treatment without satisfactory alternative treatment options

Tumor mutational burden-high (TMB-H) (unresectable or metastatic); non-CNS solid tumors that have progressed following prior treatment without satisfactory alternative treatment options:

Infants ≥6 months, Children, and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months. Note: TMB-H defined as ≥10 mutations/megabase (Mut/Mb) and determined by an FDA-approved test.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosage adjustment for toxicity: Infants ≥6 months, Children, and Adolescents:

In general, no dosage reductions of pembrolizumab are recommended; pembrolizumab therapy is withheld or discontinued to manage toxicities. Concomitant medications may also require treatment interruption, dosage reduction, and/or discontinuation.

Immune-mediated adverse reactions (general information): Withhold pembrolizumab for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue pembrolizumab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or inability to reduce corticosteroid dose to the equivalent of prednisone ≤10 mg/day in adults within 12 weeks of initiating corticosteroids. If pembrolizumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) until improvement to ≤ grade 1; upon improvement to ≤ grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy. Systemic corticosteroids may not be necessary for certain adverse reactions. Hormone replacement therapy may be required for endocrinopathies (if clinically indicated). See table for additional dosage modification guidance.

Pembrolizumab Recommended Dosage Modifications for Adverse Reactions

Adverse reaction

Severity

Pembrolizumab dosage modification

Immune-mediated adverse reactions

Cardiovascular toxicity: Myocarditis

Grade 2, 3, or 4

Permanently discontinue pembrolizumab.

Dermatologic toxicity

Mild or moderate nonexfoliative rash

May be managed with topical emollients and/or topical corticosteroids.

Exfoliative dermatologic conditions: Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS)

Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to the equivalent of prednisone ≤10 mg/day in adults within 12 weeks of corticosteroid initiation.

Confirmed SJS, TEN, or DRESS

Permanently discontinue pembrolizumab.

Endocrinopathies

Grade 3 or 4

Withhold pembrolizumab until clinically stable or permanently discontinue depending on severity.

Adrenal insufficiency, ≥ grade 2

Withhold pembrolizumab depending on the severity. Initiate symptomatic management (including hormone replacement as clinically indicated).

Diabetes, type 1

Withhold pembrolizumab depending on the severity. Initiate insulin as clinically indicated. Long-term insulin therapy may be required.

Hypophysitis

Withhold or discontinue pembrolizumab (depending on the severity). Initiate hormone replacement therapy as clinically indicated.

Hyperthyroidism

Withhold or discontinue pembrolizumab (depending on the severity). Initiate medical management as clinically indicated.

Hypothyroidism

Withhold or discontinue pembrolizumab (depending on the severity). Initiate thyroid hormone replacement therapy as clinically indicated.

GI toxicity: Colitis

Grade 2 or 3

Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to the equivalent of prednisone ≤10 mg/day in adults within 12 weeks of corticosteroid initiation.

Grade 4

Permanently discontinue pembrolizumab.

Hematologic toxicity (in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma)

Grade 4

Withhold pembrolizumab until resolution to grade 0 or 1.

Neurologic toxicities

Grade 2

Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to the equivalent of prednisone ≤10 mg/day in adults within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue pembrolizumab.

Ocular disorders: Vogt-Koyanagi-Harada-like syndrome

May require systemic corticosteroids to reduce the risk of permanent vision loss.

Pulmonary toxicity: Pneumonitis

Grade 2

Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to the equivalent of prednisone ≤10 mg/day in adults within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue pembrolizumab.

Other adverse reactions

Infusion reactions

Grade 1 or 2

Interrupt or slow the rate of pembrolizumab infusion.

Grade 3 or 4

Stop infusion and permanently discontinue pembrolizumab.

Dosing: Kidney Impairment: Pediatric

Infants ≥6 months, Children, and Adolescents:

Baseline renal impairment: There are no dosage adjustments provided in the manufacturer's labeling. In a pharmacokinetic study including adolescents ≥15 years of age, no difference in clearance was noted for patients with eGFR ≥15 mL/minute/1.73 m2; no dosage adjustment necessary.

Nephrotoxicity during therapy:

Immune-mediated nephritis with kidney dysfunction: If pembrolizumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to grade 1 or lower, then follow with a corticosteroid taper.

Grade 2 or grade 3 serum creatinine elevation: Withhold pembrolizumab; resume pembrolizumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to the equivalent of prednisone ≤10 mg/day in adults within 12 weeks of corticosteroid initiation.

Grade 4 serum creatinine elevation: Permanently discontinue pembrolizumab.

Dosing: Hepatic Impairment: Pediatric

Infants ≥6 months, Children, and Adolescents:

Baseline hepatic impairment:

Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, there was no clinically important effect on clearance for patients with mild hepatic impairment.

Moderate (total bilirubin >1.5 to 3 times ULN and any AST) to severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatotoxicity during treatment:

If pembrolizumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to grade 1 or lower, then follow with a corticosteroid taper. Permanently discontinue pembrolizumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to the equivalent of prednisone ≤10 mg/day in adults within 12 weeks of corticosteroid initiation.

Immune-mediated hepatitis without tumor involvement of the liver:

AST or ALT >3 up to 8 times ULN or total bilirubin >1.5 up to 3 times ULN: Withhold pembrolizumab treatment. Resume pembrolizumab treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper.

AST or ALT >8 times ULN or total bilirubin >3 times ULN: Discontinue pembrolizumab permanently.

Immune-mediated hepatitis with tumor involvement of the liver: Note: If AST and ALT are ≤ ULN at baseline, follow recommendations for hepatitis without tumor involvement of the liver.

Baseline AST or ALT increases >1 up to 3 times ULN and increases to >5 up to 10 times ULN or baseline AST or ALT >3 up to 5 times ULN and increases to >8 up to 10 times ULN: Withhold pembrolizumab treatment. Resume pembrolizumab treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper.

AST or ALT increases to >10 times ULN or total bilirubin increases to >3 times ULN: Discontinue pembrolizumab permanently.

Adverse Reactions (Significant): Considerations
Cardiovascular toxicity

Acute myocardial infarction and immune mediated myocarditis, pericarditis, and vasculitis have occurred with pembrolizumab. Cardiovascular events are potentially fatal (Ref). Myocarditis may overlap with myositis and myasthenia gravis in patients receiving immune checkpoint inhibitors. Death occurred in 46% of patients with severe myocarditis (Ref). Vasculitis has been reported in large, medium, and small vessels as well as the CNS (Ref).

Mechanism: Non–dose-related; exact mechanism is unknown. Evolving data suggest the presence of common high frequency T‐cell receptors in cardiac muscle (Ref).

Onset: Varied; median reported onset of myocarditis is ~30 to 65 days, with most cases occurring in the first 3 months of treatment (Ref). Late presentations of up to 454 days have also been reported (Ref). Median onset of vasculitis is 3 months (Ref).

Risk factors:

• Autoimmune disease (Ref)

• Diabetes mellitus (Ref)

• Preexisting cardiovascular disease (Ref)

Dermatologic toxicity

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis ([TEN] some fatal), exfoliative dermatitis, and bullous pemphigoid may occur with pembrolizumab (Ref). Among the diverse immune-related adverse events (irAEs), cutaneous toxicities such as skin rash, pruritus, and vitiligo are by far the most common and the earliest to occur (Ref); however, rarer rashes such as lichenoid eruption (eg, lichenoid dermatitis, lichen planus) (Ref), psoriasis flare (eg, plaque) (Ref), and bullous disorders including bullous pemphigoid, SJS, and TEN are of special interest due to their severity and potentially life-threatening consequences (Ref). Additional reported mucosal toxicities include stomatitis, gingivitis, and Sjögren disease-like symptoms (Ref). Although most cutaneous toxicities are transient, they can cause significant morbidity and impairment of patients’ health-related quality of life; some adverse reactions (eg, Sjögren disease) may not fully resolve, necessitating long-term treatment (Ref).

Mechanism: Non–dose-related; exact mechanism unknown. May involve blockade of a common antigen (co-expressed on tumor cells and the dermo-epidermal junction and/or other levels of the skin) (Ref).

Onset: Varied; dermatologic toxicity occurs within the first 3 to 4 weeks of therapy and may occur in patients with any tumor type (Ref) but has also been reported later in therapy (Ref). Median time to onset for Sjögren disease-like symptoms is 70 days (Ref). For most patients, dermatologic toxicity is the earliest irAE experienced (Ref).

Endocrine toxicity

Endocrine toxicities include primary hypothyroidism, hyperthyroidism, adrenocortical insufficiency (primary and secondary), hypophysitis (inflammation of the pituitary gland), and type 1 diabetes mellitus (including diabetic ketoacidosis) (Ref). In rare cases, patients may present with adrenal crisis (Ref). Hypothyroidism and hyperthyroidism are frequently asymptomatic (or present with vague symptoms) (Ref). Immune-mediated endocrinopathies usually require permanent hormone replacement (Ref).

Mechanism: Non–dose-related; mechanisms not fully understood. Thyroid dysfunction may be due to the development of antithyroglobulin or antithyroid peroxidase antibodies. In rare cases, Graves' disease may arise due to the development of anti-thyroid-stimulating hormone receptor antibodies (Ref). Hypophysitis may be due to humoral immunity against the pituitary gland, with involvement of the complement system (Ref).

Onset: Varied; often delayed and can appear at any time throughout treatment with checkpoint inhibitors (Ref). Adrenal insufficiency: Median onset of 10 weeks (Ref). Hypophysitis: Median onset of 76 days (Ref). Hypothyroidism: Median onset of 10 weeks (Ref). Thyrotoxicosis: Median onset of 5 weeks (Ref). Type 1 diabetes mellitus: Up to a year after initiation (Ref).

Risk factors:

• Autoimmune disorders (Ref)

GI toxicity

Immune-mediated colitis has occurred, including cases of grade 2 to 4 colitis. Diarrhea and colitis represent a clinical spectrum where diarrhea is defined as increased stool frequency and colitis involves symptoms of abdominal pain and either clinical or radiologic evidence of colonic inflammation (Ref). Colitis affecting the descending colon is one of the most common complications leading to hospitalization and increased morbidity (Ref). Enteritis with small bowel obstruction has been reported (Ref). Complications, such as small bowel perforation, ischemia, necrosis, bleeding, and toxic megacolon may occur (Ref). Colitis-related mortality is associated with delayed reporting, noncompliance with an antidiarrheal regimen, and delays in drug withholding (Ref). In a retrospective study, when re-challenged up to 34% of patients experienced a recurrence of colitis (Ref).

Mechanism: Non–dose-related; immunologic (Ref).

Onset: Varied. Median onset of 5 to 10 weeks (Ref).

Risk factors:

• Autoimmune disorders of the GI tract (Ref)

• Combination therapy with anti-PD-(L)1 inhibitors and anti-CTLA-4 inhibitors (Ref)

• Gut microbiome (bacteria of the phylum Firmicutes) (Ref)

• Prior treatment with nonsteroidal anti-inflammatory drugs (Ref)

Hematologic toxicity

Hematologic immune-related adverse events occur less frequently. Severity varies from mild, asymptomatic cytopenias to more significant reports of immune thrombocytopenia, autoimmune hemolytic anemia (AIHA), acquired hemophilia, and disseminated intravascular coagulation (Ref). Development of higher grades of anemia have led to treatment discontinuation in a small percentage of patients treated for head and neck cancers, urothelial and cervical cancer, and non-small cell lung cancer (Ref). Although the incidence for AIHA is rare, it can result in fatalities (Ref). AIHA was significantly more common with anti-PD-1/PD-L1 monoclonal antibodies (ie, nivolumab, pembrolizumab, atezolizumab) than with anti-CTLA-4 monoclonal antibodies (ie, ipilimumab) in a review of 68 case reports (Ref). Cases of autoimmune pure red cell aplasia, neutropenia, thrombocytopenia, and pancytopenia have also been reported with anti-PD-1 monoclonal antibodies (Ref). Hemophagocytic lymphohistiocytosis has been reported in patients receiving immunotherapy with pembrolizumab (Ref). This is a rare but potentially fatal syndrome of excessive immune activation resulting in multi-organ failure, including cytopenias and bleeding (Ref).

Mechanism: Non–dose-related; exact mechanism unknown. AIHA may be a result of augmenting or redirecting patients’ immune surveillance. In addition, it is speculated that the random activation of the immune system results in the formation of autoantibodies, activation of T‐cell clones, and the lessening of regulatory T-cell function (Ref). This is different from other drug-induced AIHA where a drug is absorbed to the red blood cell membrane and triggers the development of autoantibodies to the red cell membrane (Ref).

Onset: Varied; AIHA occurred between 2 and 78 weeks with a median of 10 weeks (Ref). Median time to onset has been reported: Neutropenia (10 weeks), autoimmune hemolytic anemia (3.9 weeks), pancytopenia or aplastic anemia (21.7 weeks) (Ref), hemophagocytic lymphohistiocytosis (26 days), immune thrombocytopenia (41 days), pure red cell aplasia (89 days) (Ref).

Risk factors:

Combination immunotherapy and chemotherapy (Ref)

Hepatotoxicity

Immune-mediated hepatitis (grades 2 to 4) may occur with pembrolizumab. Hepatitis is associated with increased serum aspartate transaminase, increased serum alanine transaminase, and occasionally hyperbilirubinemia (Ref). Although clinically significant hepatotoxicity occurs infrequently, fatal immune-related liver injury has been observed (Ref). Hepatoxicity typically involves a hepatocellular or cholestatic pattern of injury and can range from mild laboratory findings to acute liver failure (Ref). Immune-mediated hepatitis ranges in severity from mild to life threatening and has both similarities and differences with idiopathic autoimmune hepatitis (Ref). The incidence of immune mediated hepatotoxic effects is lower in patients treated with anti-PD-1 monoclonal antibodies like pembrolizumab in comparison to those treated with anti-CTLA-4 monoclonal antibodies (Ref).

Mechanism: Possibly dose- and time-related; immunologic (Ref).

Onset: Varied. Hepatotoxicity typically occurs within 1 to 15 weeks but may be delayed by months or years (Ref).

Risk factors:

Cumulative dose (Ref)

Preexisting autoimmune diathesis (Ref)

Chronic infection (Ref)

Tumor infiltration of the liver parenchyma (Ref)

Combinations of pembrolizumab with other antineoplastic agents (Ref)

Autoimmune liver injury (Ref)

Prior exposure to chemotherapy, radiation therapy, transarterial chemoembolization (TACE), or radioembolization (Ref)

In combination with axitinib

Nephrotoxicity

Immune-mediated nephritis has rarely occurred. Although an increased serum creatinine is common, acute kidney injury occurs less frequently (Ref) and may manifest as acute tubular necrosis, autoimmune reactivation of membranous nephropathy, glomerular disease, prerenal disease, or tubulointerstitial nephritis (Ref).

Mechanism: Non–dose-related; immunologic (Ref)

Onset: Varied. Increased serum creatinine: 12 to 48 weeks after initiation (Ref). Acute kidney injury: One study documented a median onset of 13 weeks; case reports of earlier onset of 3 weeks after initiation (Ref). Another study documented a median onset of 9 months (range: 1 to 24 months) (Ref).

Neurologic toxicity

Neurologic toxicity is rare and has been reported with use of pembrolizumab alone or in combination with chemotherapy (Ref). These include cerebral hemorrhage (Ref), confusion, myasthenia gravis, and reversible posterior leukoencephalopathy syndrome (Ref). More common peripheral nervous adverse reactions include peripheral neuropathy and Guillain-Barre syndrome. More common CNS adverse reactions include aseptic meningitis (Ref), encephalitis, and transverse myelitis (Ref). Fatal reversible posterior leukoencephalopathy syndrome with intraventricular hemorrhage occurred in one patient in endometrial cancer clinical trials with pembrolizumab and lenvatinib (Ref). Neurologic toxicity may be fatal or cause permanent impairment (Ref).

Onset: Varied; typically develop within 3 to 4 months of initiation (Ref). Guillain-Barre syndrome: Onset typically within the first 3 cycles (Ref).

Ophthalmic toxicity

Uveitis (anterior, posterior, or panuveitis (Ref)) has been reported in patients receiving both single agent and combination anti-PD-1 and anti-CTLA-4 monoclonal antibodies (Ref). Other ocular reactions reported include blurred vision, dry eye syndrome (Ref), color changes, ocular myasthenia (Ref), photophobia (associated with aseptic meningitis) (Ref), inflammation of the eyelid (Ref), optic neuritis (Ref), optic papillitis (Ref), retinal detachment (Ref), Vogt-Koyanagi-Harada disease (Ref), and vision loss (Ref).

Onset: Varied; median onset of 5 weeks (range: 1 to 72 weeks) (Ref).

Pulmonary toxicity

Immune-mediated pneumonitis has occurred less frequently, including grade 3 and 4 and fatal cases. Pneumonitis was found to be more common with anti-PD-1 monoclonal antibodies compared to anti-PD-L1 monoclonal antibodies (Ref). Recurrent pneumonitis following resolution of symptoms has occurred in patients who were re-challenged with immune checkpoint inhibitor therapy and in patients who were not re-challenged; chronic courses may also occur (Ref).

Mechanism: Non–dose-related; immunologic (Ref).

Onset: Varied; median onset of ~3 months (Ref).

Risk factors:

• Prior thoracic radiation in non-small cell lung cancer patients (Ref)

• Treatment-naive patients (Ref)

• Asthma and/or smoking (higher grade) (Ref)

• Treatment for non-small cell lung cancer or renal cell carcinoma (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence of adverse reactions include unapproved dosing regimens.

>10%:

Cardiovascular: Cardiac arrhythmia (4% to 11%), peripheral edema (11% to 15%)

Dermatologic: Pruritus (11% to 28%), skin rash (13% to 30%) (table 1), vitiligo (13%) (table 2)

Pembrolizumab: Adverse Reaction: Skin Rash

Drug (Pembrolizumab)

Comparator

Placebo

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

24%

8% (Chemotherapy)

N/A

Adolescents and adults

2 mg/kg or 10 mg/kg every 3 weeks

Ipilimumab-refractory melanoma

357

171

N/A

30%

N/A

15%

Adults

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

N/A

496

13%

N/A

9%

Adults

200 mg every 3 weeks

Adjuvant treatment of resected melanoma

509

N/A

502

20%

70% (Cetuximab platinum FU)

N/A

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

24%

23% (Ipilimumab)

N/A

Adults

10 mg/kg every 2 or 3 weeks

Ipilimumab-naive melanoma

555

256

N/A

17%

8% (Docetaxel)

N/A

Adults

2 mg/kg or 10 mg/kg every 3 weeks

Previously treated non–small cell lung cancer

682

309

N/A

20%

13% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

15%

8% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

20%

19% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

21%

N/A

N/A

Adults

200 mg every 3 weeks

Urothelial carcinoma

370

N/A

N/A

Pembrolizumab: Adverse Reaction: Vitiligo

Drug (Pembrolizumab)

Comparator

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

13%

2% (Ipilimumab)

10 mg/kg every 2 or 3 weeks

Ipilimumab-naive melanoma

555

256

Endocrine & metabolic: Decreased serum bicarbonate (22%), hypercalcemia (14% to 22%), hypercholesterolemia (20%), hyperglycemia (38% to 59%), hyperkalemia (13% to 28%), hyperthyroidism (3% to 12%) (table 3), hypertriglyceridemia (33% to 43%), hypoalbuminemia (16% to 44%), hypocalcemia (15% to 27%), hypoglycemia (13% to 19%), hypokalemia (15% to 20%), hypomagnesemia (16% to 25%), hyponatremia (10% to 46%), hypophosphatemia (19% to 31%), hypothyroidism (8% to 22%) (table 4), weight loss (10% to 15%)

Pembrolizumab: Adverse Reaction: Hyperthyroidism

Drug (Pembrolizumab)

Placebo

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Placebo)

12%

0.2%

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

496

10%

1%

200 mg every 3 weeks

Adjuvant treatment of resected melanoma

509

502

3%

N/A

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

11%

N/A

N/A

Resected non-small cell lung cancer

580

581

Pembrolizumab: Adverse Reaction: Hypothyroidism

Drug (Pembrolizumab)

Comparator

Placebo

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

21%

N/A

4%

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

N/A

496

15%

N/A

3%

200 mg every 3 weeks

Adjuvant treatment of resected melanoma

509

N/A

502

11%

N/A

N/A

200 mg every 3 weeks

Cervical cancer

98

N/A

N/A

18%

6% (Cetuximab platinum FU)

N/A

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

12%

2% (Chemotherapy)

N/A

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

8%

N/A

N/A

200 mg every 3 weeks

Primary mediastinal large B-cell lymphoma

53

N/A

N/A

19%

3% (Brentuximab vedotin)

N/A

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

14%

N/A

N/A

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

N/A

22%

N/A

N/A

N/A

Resected non-small cell lung cancer

580

N/A

581

Gastrointestinal: Abdominal pain (11% to 23%) (table 5), constipation (12% to 22%), decreased appetite (15% to 25%), diarrhea (12% to 28%; grades 3/4: ≤3%) (table 6), nausea (11% to 22%; grades 3/4: ≤1%), vomiting (infants, children, adolescents: 29%; adults: 11% to 19%; grades 3/4: ≤1%)

Pembrolizumab: Adverse Reaction: Abdominal Pain

Drug (Pembrolizumab)

Comparator

Placebo

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

23%

N/A

N/A

Infants ≥6 months, children, and adolescents ≤17 years

2 mg/kg every 3 weeks

Advanced melanoma, lymphoma, or PD-L1 positive solid tumors

173

N/A

N/A

13%

8% (Chemotherapy)

N/A

Adolescents and adults

2 mg/kg or 10 mg/kg every 3 weeks

Ipilimumab-refractory melanoma

357

171

N/A

11%

N/A

13%

Adults

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

N/A

496

22%

N/A

N/A

Adults

200 mg every 3 weeks

Cervical cancer

98

N/A

N/A

13%

13% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

11%

13% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

18%

N/A

N/A

Adults

200 mg every 3 weeks

Urothelial carcinoma

370

N/A

N/A

Pembrolizumab: Adverse Reaction: Diarrhea

Drug (Pembrolizumab)

Comparator

Placebo

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

20%

20% (Chemotherapy)

N/A

Adolescents and adults

2 mg/kg or 10 mg/kg every 3 weeks

Ipilimumab-refractory melanoma

357

171

N/A

27%

N/A

23%

Adults

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

N/A

496

28%

N/A

26%

Adults

200 mg every 3 weeks

Adjuvant treatment of resected melanoma

509

N/A

502

16%

35% (Cetuximab platinum FU)

N/A

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

18%

19% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

12%

12% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

22%

17% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

20%

N/A

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

N/A

18%

N/A

N/A

Adults

200 mg every 3 weeks

Urothelial carcinoma

370

N/A

N/A

Genitourinary: Hematuria (12% to 19%), urinary tract infection (2% to 19%)

Hematologic & oncologic: Anemia (17% to 54%; grades 3/4: 0.5% to 24%) (table 7), hemorrhage (19%; grades 3/4: 5%; major hemorrhage: 4%), increased INR (19% to 27%; grades 3/4: ≤2%), leukopenia (31% to 35%; grades 3/4: 9%), lymphocytopenia (infants, children, adolescents: 13%; adults: 24% to 54%; grades 3/4: 1% to 25%) (table 8), neutropenia (7% to 30%; grades 3/4: 1% to 11%) (table 9), prolonged partial thromboplastin time (14%), thrombocytopenia (12% to 34%; grades 3/4: 4% to 10%) (table 10)

Pembrolizumab: Adverse Reaction: Anemia

Drug (Pembrolizumab)

Comparator

Placebo

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

17%

N/A

N/A

Infants ≥6 months, children, and adolescents ≤17 years

2 mg/kg every 3 weeks

Advanced melanoma, lymphoma, or PD-L1 positive solid tumors

173

N/A

N/A

All grades: 28%

N/A

20%

Adults

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

N/A

496

Grades 3/4: 0.5%

N/A

0.4%

Adults

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

N/A

496

All grades: 35%

N/A

N/A

Adults

200 mg every 3 weeks

Bacillus Calmette-Guérin-unresponsive high-risk non-muscle invasive bladder cancer

148

N/A

N/A

Grades 3/4: 1%

N/A

N/A

Adults

200 mg every 3 weeks

Bacillus Calmette-Guérin-unresponsive high-risk non-muscle invasive bladder cancer

148

N/A

N/A

All grades: 54%

N/A

N/A

Adults

200 mg every 3 weeks

Cervical cancer

98

N/A

N/A

Grades 3/4: 24%

N/A

N/A

Adults

200 mg every 3 weeks

Cervical cancer

98

N/A

N/A

All grades: 52%

78% (Cetuximab platinum FU)

N/A

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

Grades 3/4: 7%

19% (Cetuximab platinum FU)

N/A

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

All grades: 35%

33% (Ipilimumab)

N/A

Adults

10 mg/kg every 2 or 3 weeks

Ipilimumab-naive melanoma

555

256

N/A

Grades 3/4: 4%

4% (Ipilimumab)

N/A

Adults

10 mg/kg every 2 or 3 weeks

Ipilimumab-naive melanoma

555

256

N/A

All grades: 52%

68% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

Grades 3/4: 13%

18% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

All grades: 43%

79% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

Grades 3/4: 4%

19% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

All grades: 30%

N/A

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

N/A

Grades 3/4: 6%

N/A

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

N/A

All grades: 24%

33% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

Grades 3/4: 5%

8% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

All grades: 17%

N/A

N/A

Adults

200 mg every 3 weeks

Urothelial carcinoma

370

N/A

N/A

Grades 3/4: 7%

N/A

N/A

Adults

200 mg every 3 weeks

Urothelial carcinoma

370

N/A

N/A

Pembrolizumab: Adverse Reaction: Lymphocytopenia

Drug (Pembrolizumab)

Comparator

Placebo

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

All grades: 13%

N/A

N/A

Infants ≥6 months, children, and adolescents ≤17 years

2 mg/kg every 3 weeks

Advanced melanoma, lymphoma, or PD-L1 positive solid tumors

173

N/A

N/A

All grades: 24%

N/A

16%

Adults

200 mg every 3 weeks

Adjuvant treatment of resected melanoma

509

N/A

502

Grades 3/4: 1%

N/A

1%

Adults

200 mg every 3 weeks

Adjuvant treatment of resected melanoma

509

N/A

502

All grades: 54%

74% (Cetuximab platinum FU)

N/A

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

Grades 3/4: 25%

45% (Cetuximab platinum FU)

N/A

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

All grades: 33%

25% (Ipilimumab)

N/A

Adults

10 mg/kg every 2 or 3 weeks

Ipilimumab-naive melanoma

555

256

N/A

Grades 3/4: 7%

6% (Ipilimumab)

N/A

Adults

10 mg/kg every 2 or 3 weeks

Ipilimumab-naive melanoma

555

256

N/A

All grades: 45%

53% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

Grades 3/4: 15%

25% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

All grades: 30%

41% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

Grades 3/4: 7%

13% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

All grades: 35%

32% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

Grades 3/4: 9%

13% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

Pembrolizumab: Adverse Reaction: Neutropenia

Drug (Pembrolizumab)

Comparator

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

All grades: 28%

N/A

Infants ≥6 months, children, and adolescents ≤17 years

2 mg/kg every 3 weeks

Advanced melanoma, lymphoma, or PD-L1 positive solid tumors

173

N/A

All grades: 7%

71% (Cetuximab platinum FU)

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

Grades 3/4: 1%

42% (Cetuximab platinum FU)

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

All grades: 30%

N/A

Adults

200 mg every 3 weeks

Primary mediastinal large B-cell lymphoma

53

N/A

Grades 3/4: 11%

N/A

Adults

200 mg every 3 weeks

Primary mediastinal large B-cell lymphoma

53

N/A

All grades: 28%

43% (Brentuximab vedotin)

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

Grades 3/4: 8%

17% (Brentuximab vedotin)

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

All grades: 24%

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

Grades 3/4: 7%

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

Pembrolizumab: Adverse Reaction: Thrombocytopenia

Drug (Pembrolizumab)

Comparator

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

All grades: 22%

N/A

Infants ≥6 months, children, and adolescents ≤17 years

2 mg/kg every 3 weeks

Advanced melanoma, lymphoma, or PD-L1 positive solid tumors

173

N/A

All grades: 12%

76% (Cetuximab platinum FU)

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

Grades 3/4: 4%

18% (Cetuximab platinum FU)

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

All grades: 34%

26% (Brentuximab vedotin)

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

Grades 3/4: 10%

5% (Brentuximab vedotin)

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

All grades: 27%

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

Grades 3/4: 4%

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

Hepatic: Hyperbilirubinemia (10% to 16%) (table 11), increased serum alanine aminotransferase (20% to 34%) (table 12), increased serum alkaline phosphatase (17% to 42%), increased serum aspartate aminotransferase (20% to 39%) (table 13)

Pembrolizumab: Adverse Reaction: Hyperbilirubinemia

Drug (Pembrolizumab)

Comparator

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

10%

N/A

200 mg every 3 weeks

Hepatocellular carcinoma

104

N/A

16%

9% (Brentuximab vedotin)

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

10%

N/A

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

Pembrolizumab: Adverse Reaction: Increased Serum Alanine Aminotransferase

Drug (Pembrolizumab)

Comparator

Placebo

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

21%

16% (Chemotherapy)

N/A

Adolescents and adults

2 mg/kg or 10 mg/kg every 3 weeks

Ipilimumab-refractory melanoma

357

171

N/A

20%

N/A

11%

Adults

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

N/A

496

27%

N/A

16%

Adults

200 mg every 3 weeks

Adjuvant treatment of resected melanoma

509

N/A

502

25%

38% (Cetuximab platinum FU)

N/A

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

22%

9% (Docetaxel)

N/A

Adults

2 mg/kg or 10 mg/kg every 3 weeks

Previously treated non-small cell lung cancer

682

309

N/A

33%

34% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

34%

45% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

Pembrolizumab: Adverse Reaction: Increased Serum Aspartate Aminotransferase

Drug (Pembrolizumab)

Comparator

Placebo

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

24%

16% (Chemotherapy)

N/A

Adolescents and adults

2 mg/kg or 10 mg/kg every 3 weeks

Ipilimumab-refractory melanoma

357

171

N/A

24%

N/A

15%

Adults

200 mg every 3 weeks

Adjuvant treatment of resected melanoma

509

N/A

502

20%

N/A

N/A

Adults

200 mg every 3 weeks

Bacillus Calmette-Guérin-unresponsive high-risk non-muscle invasive bladder cancer

148

N/A

N/A

28%

37% (Cetuximab platinum FU)

N/A

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

27%

25% (Ipilimumab)

N/A

Adults

10 mg/kg every 2 or 3 weeks

Ipilimumab-naive melanoma

555

256

N/A

26%

12% (Docetaxel)

N/A

Adults

2 mg/kg or 10 mg/kg every 3 weeks

Previously treated non-small cell lung cancer

682

309

N/A

28%

20% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

31%

32% (Chemotherapy)

N/A

Adults

200 mg every 3 weeks

Previously untreated non-small cell lung cancer

636

615

N/A

39%

41% (Brentuximab vedotin)

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

Infection: Infection (16%; serious infection: 4%)

Nervous system: Asthenia (10% to 11%), fatigue (20% to 43%), headache (infants, children, adolescents: 25%; adults: 11% to 15%), pain (22%), peripheral neuropathy (1% to 11%; grades 3/4: <1%) (table 14)

Pembrolizumab: Adverse Reaction: Peripheral Neuropathy

Drug (Pembrolizumab)

Comparator

Population

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

All grades: 2%

N/A

Adolescents and adults

2 mg/kg or 10 mg/kg every 3 weeks

Ipilimumab-refractory melanoma

357

N/A

All grades: 1%

7% (Cetuximab platinum FU)

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

Grades 3/4: 0%

1% (Cetuximab platinum FU)

Adults

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

All grades: 11%

43% (Brentuximab vedotin)

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

Grades 3/4: 0.7%

7% (Brentuximab vedotin)

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

All grades: 10%

N/A

Adults

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

Neuromuscular & skeletal: Arthralgia (10% to 18%), back pain (11% to 12%), musculoskeletal pain (19% to 41%), myalgia (12%)

Renal: Acute kidney injury (2% to 13%), increased serum creatinine (11% to 40%) (table 15)

Pembrolizumab: Adverse Reaction: Increased Serum Creatinine

Drug (Pembrolizumab)

Comparator

Placebo

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

40%

N/A

28%

200 mg every 3 weeks

Adjuvant treatment of renal cell carcinoma

488

N/A

496

18%

27% (Cetuximab platinum FU)

N/A

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

N/A

35%

28% (Chemotherapy)

N/A

200 mg every 3 weeks

Previously treated urothelial carcinoma

266

255

N/A

28%

14% (Brentuximab vedotin)

N/A

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

148

152

N/A

15%

N/A

N/A

200 mg every 3 weeks

Relapsed or refractory classical Hodgkin lymphoma

210

N/A

N/A

11%

N/A

N/A

200 mg every 3 weeks

Urothelial carcinoma

370

N/A

N/A

Respiratory: Cough (14% to 26%), dyspnea (10% to 23%), flu-like symptoms (11%), pneumonia (3% to 12%), pneumonitis (2% to 11%), upper respiratory tract infection (13% to 41%)

Miscellaneous: Fever (10% to 33%)

1% to 10%:

Cardiovascular: Acute myocardial infarction (2%), cardiac tamponade (2%), ischemic heart disease (2%), myocarditis (≤1%), pericardial effusion (2%), pericarditis (2% to 4%), pulmonary embolism (2%)

Endocrine & metabolic: Adrenocortical insufficiency (1%), diabetic ketoacidosis (1%), thyroiditis (≤2%)

Gastrointestinal: Colitis (2%), dysphagia (8%), stomatitis (3%) (table 16)

Pembrolizumab: Adverse Reaction: Stomatitis

Drug (Pembrolizumab)

Comparator

Dose

Indication

Number of Patients (Pembrolizumab)

Number of Patients (Comparator)

All grades: 3%

28% (Cetuximab platinum FU)

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

Grades 3/4: 0%

4% (Cetuximab platinum FU)

200 mg every 3 weeks

First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer

300

287

Hematologic & oncologic: Febrile neutropenia (1%), tumor flare (1%)

Hepatic: Ascites (grades 3/4: 8%), hepatitis (≤3%)

Hypersensitivity: Facial edema (10%), infusion-related reaction (≤9%; including severe)

Immunologic: Antibody development (2%; neutralizing: <1%)

Infection: Herpes virus infection (9%), herpes zoster infection (≥1%), sepsis (1% to 2%)

Nervous system: Altered mental status (3%), confusion (≥2%), dizziness (5%), insomnia (7%)

Neuromuscular & skeletal: Arthritis (2%), myositis (≤1%), neck pain (6%)

Ophthalmic: Uveitis (≤1%)

Respiratory: Nasopharyngitis (10%), oropharyngeal pain (8%), pleural effusion (2%), respiratory failure (≥2%)

Miscellaneous: Fistula (4%)

<1%:

Cardiovascular: Vasculitis

Endocrine & metabolic: Hypoparathyroidism, hypophysitis, type 1 diabetes mellitus

Gastrointestinal: Duodenitis, gastritis, increased serum amylase, increased serum lipase, pancreatitis

Hematologic & oncologic: Aplastic anemia, hemolytic anemia, hemophagocytic lymphohistiocytosis, immune thrombocytopenia, lymphadenitis (histiocytic necrotizing lymphadenitis [Kikuchi lymphadenitis])

Hypersensitivity: Anaphylaxis

Immunologic: Organ transplant rejection (corneal graft, solid), sarcoidosis

Infection: Systemic inflammatory response syndrome

Nervous system: Demyelinating disease, encephalitis, Guillain-Barre syndrome, meningitis, myasthenia (myasthenic syndrome), myasthenia gravis (including exacerbation of myasthenia gravis), neuropathy (autoimmune), paresis (nerve)

Neuromuscular & skeletal: Myelitis, polymyalgia rheumatica, polymyositis, rhabdomyolysis

Ophthalmic: Iritis

Renal: Nephritis

Frequency not defined:

Cardiovascular: Edema, heart failure

Dermatologic: Cellulitis, dermatitis

Gastrointestinal: Clostridioides difficile-associated diarrhea, rectal hemorrhage

Genitourinary: Urinary tract infection with sepsis, uterine hemorrhage

Immunologic: Graft-versus-host-disease

Infection: Candidiasis, septic shock

Neuromuscular & skeletal: Osteomyelitis

Respiratory: Epistaxis, hemoptysis

Postmarketing:

Cardiovascular: Capillary leak syndrome (Ni 2023)

Dermatologic: Bullous pemphigoid (Hara 2020), lichenoid eruption (including lichenoid dermatitis and lichen planus) (Bansal 2023, Emonet 2023, Park 2023), psoriasis flare (Gargiulo 2023), purpuric dermatitis (Oyeku 2023), pyoderma gangrenosum (Tsibris 2021), Stevens-Johnson syndrome (Haratake 2018), toxic epidermal necrolysis (Ran Cai 2020)

Gastrointestinal: Cholangitis (SITC [Brahmer 2021]), cholecystitis (SITC [Brahmer 2021]), esophagitis (SITC [Brahmer 2021]), gastrointestinal perforation (Beck 2019), hemorrhagic gastritis (Mathialagan 2023), sclerosing cholangitis (Matsumoto 2020, Ooi 2020), xerostomia (SITC [Brahmer 2021])

Genitourinary: Cystitis (non-bacterial) (He 2022)

Hematologic & oncologic: Agranulocytosis (Okuzumi 2023), disseminated intravascular coagulation (Alberti 2020), pancytopenia (Atwal 2017), pure red cell aplasia (SITC [Brahmer 2021]; Meri-Abad 2021), thrombotic thrombocytopenic purpura (Nelson 2022)

Hypersensitivity: Cytokine release syndrome (Sackstein 2021), drug reaction with eosinophilia and systemic symptoms (Lamiaux 2018)

Immunologic: Dermatomyositis (Takatsuki 2021), Sjögren disease (SITC [Brahmer 2021])

Infection: Cytomegalovirus disease (Kim 2020)

Nervous system: Aseptic meningitis (Lima 2019), cerebral hemorrhage (Yamazaki 2017), chronic inflammatory demyelinating polyneuropathy (Maleissye 2016), demyelinating disease of the central nervous system (neuromyelitis optica spectrum disorder) (Hirano 2022), retrobulbar neuritis (optic) (Kawakado 2021), reversible posterior leukoencephalopathy syndrome (LaPorte 2017)

Neuromuscular & skeletal: Lambert-Eaton syndrome (exacerbation) (Takigawa 2023), osteonecrosis of the jaw (Patel 2023), subacute cutaneous lupus erythematosus (Blakeway 2019), systemic sclerosis (Farrugia 2023)

Ophthalmic: Dry eye syndrome (SITC [Brahmer 2021]), maculopathy (acute exudative polymorphous vitelliform maculopathy [AEPVM]) (Lambert 2021), optic neuritis (Makri 2022), optic neuropathy (Daetwyler 2023), optic papillitis (de Vries 2022), retinal detachment (serous) (de Vries 2022), retinopathy (Sakai 2023), vision loss (Telfah 2019)

Renal: Focal segmental glomerulosclerosis (Kim 2021), glomerulonephritis (necrotizing) (Uner 2021), interstitial nephritis (including acute interstitial nephritis) (Fujioka 2024; Peláez Bejarano 2021)

Respiratory: Reactivated tuberculosis (ileitis) (Lau 2021)

Miscellaneous: Vogt-Koyanagi-Harada disease (Tamura 2018)

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to pembrolizumab or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Adverse reactions (immune-mediated): PD-1/PD-L1 blockers (including pembrolizumab) remove immune response inhibition, thus potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Severe and fatal immune-mediated adverse reactions may occur in any organ system or tissue. Reactions generally occur during treatment (may occur at any time after pembrolizumab initiation); reactions may also occur after pembrolizumab discontinuation. Early identification and management of immune-mediated adverse reactions are necessary to ensure safe use of pembrolizumab. If suspected immune-mediated reactions occur, initiate appropriate workup to exclude alternative causes (including infection). Medically manage immune-mediated adverse reactions promptly and refer for specialty consultation as appropriate.

• Infusion-related reactions: Infusion-related reactions (including severe and life-threatening cases) have occurred. Signs/symptoms of a reaction included rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever.

Disease-related concerns:

• Autoimmune disorders: Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. A retrospective study analyzed the safety and efficacy of treatment with anti-PD-1 monoclonal antibodies (eg, pembrolizumab, nivolumab) in melanoma patients with preexisting autoimmune disease or prior significant ipilimumab-mediated adverse immune events. Results showed that while immune toxicities associated with this class of therapy did occur, most reactions were mild and easily manageable and did not require permanent drug therapy discontinuation. A significant percentage of patients achieved clinical response with anti-PD-1 monoclonal antibody therapy, despite baseline autoimmunity or prior ipilimumab-related adverse events (Menzies 2017).

• Hematopoietic cell transplant: Fatal and other serious complications may occur in patients who receive allogeneic hematopoietic cell transplant (HCT) before or after treatment with an anti-PD-L1/PD-1 monoclonal antibody. Transplant-related complications included hyperacute graft-versus-host disease (GVHD), acute or chronic GVHD, hepatic veno-occlusive disease (also known as sinusoidal obstruction syndrome) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (with no identified infectious etiology). These complications may occur despite intervening therapy between PD-L1/PD-1 blockade and HCT. Manage early signs/symptoms of transplant-related complications promptly. Assess the risks/benefits of treatment with an anti-PD-L1/PD-1 monoclonal antibody prior to or after an allogenic HCT.

• Multiple myeloma: An increase in mortality was noted in 2 clinical studies in patients with multiple myeloma who received pembrolizumab in combination with a thalidomide analogue and dexamethasone. Pembrolizumab should not be used to treat multiple myeloma in combination with a thalidomide analogue and dexamethasone unless as part of a clinical trial.

• Myasthenia gravis: Checkpoint inhibitors may worsen or precipitate new myasthenia gravis (MG), especially within the first 16 weeks of treatment; use with caution. Patients with well-controlled MG may be considered for checkpoint inhibitor therapy if MG treatment is maintained (or reinitiated in patients whose MG is in remission), combination therapy (eg, anti-CTLA-4 with anti-PD-a/PD-L1 monoclonal antibodies) is avoided, and respiratory and bulbar function are closely followed. In patients who develop overt MG during checkpoint inhibitor therapy, early aggressive treatment with plasma exchange or IVIG in combination with high-dose corticosteroids may be required (AAN [Narayanaswami 2021]).

Special populations:

• Older adults: Patients ≥75 years of age experienced higher incidences of fatal adverse reactions with pembrolizumab (in combination with enfortumab vedotin for the treatment of locally advanced or metastatic urothelial cancer) compared to patients <75 years of age.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and kidney and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: Some indications are based on PD-L1 expression, or are based on tumor specimen microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR), mismatch repair proficient (pMMR), or tumor mutational burden-high (TMB-H) status. Information on approved tests for patient selection may be found at http://www.fda.gov/companiondiagnostics. Because subclonal dMMR mutations and microsatellite instability may arise in high-grade gliomas during temozolomide therapy, it is recommended to test for TMB-H, MSI-H, or dMMR in the primary tumor specimens obtained prior to temozolomide initiation (in patients with high-grade gliomas). Due to discordance between local tests and approved tests, in patients with MSI-H or dMMR noncolorectal cancer solid tumors, if feasible, confirmation of MSI-H or dMMR status is recommended by an approved test; if unable to perform confirmatory MSI-H/dMMR testing, may select patients for treatment by determining the presence of TMB ≥10 mutations/megabase via an approved test.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Keytruda: 100 mg/4 mL (4 mL) [contains polysorbate 80]

Generic Equivalent Available: US

No

Pricing: US

Solution (Keytruda Intravenous)

100 mg/4 mL (per mL): $1,700.61

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Keytruda: 100 mg/4 mL (4 mL) [contains polysorbate 80]

Administration: Adult

IV: Infuse over 30 minutes through a 0.2 to 5 micron sterile, nonpyrogenic, low-protein binding inline or add-on filter. Do not infuse other medications through the same infusion line.

Interrupt or slow the infusion for grade 1 or 2 infusion-related reactions; permanently discontinue for grade 3 or 4 infusion-related reactions.

Administration sequence (for combination therapy):

Biliary tract cancer (locally advanced unresectable or metastatic), esophageal cancer (locally advanced or metastatic), gastric cancer (locally advanced or metastatic, HER2-negative), head and neck squamous cell carcinoma (unresectable/recurrent, metastatic), non–small cell lung cancer (resectable or metastatic), and triple-negative breast cancer (high-risk, early stage or locally recurrent unresectable or metastatic): When administered in combination with chemotherapy, administer pembrolizumab prior to chemotherapy when administered on the same day.

Cervical cancer (stage III to IVA or persistent, recurrent, or metastatic): When administered in combination with chemoradiotherapy or chemotherapy with or without bevacizumab, administer pembrolizumab prior to chemoradiotherapy or prior to chemotherapy (± bevacizumab) when administered on the same day.

Gastric cancer (locally advanced or metastatic, HER2-positive): When administered in combination with trastuzumab and chemotherapy, administer pembrolizumab prior to trastuzumab and chemotherapy when administered on the same day.

Urothelial cancer (locally advanced or metastatic): When administered in combination with enfortumab vedotin, administer pembrolizumab after enfortumab vedotin (when administered on the same day). In the clinical trial, when both were administered on the same day, pembrolizumab was administered ~30 minutes after enfortumab vedotin (Ref).

Administration: Pediatric

Parenteral: IV: Infuse over 30 minutes through a 0.2 to 5 micron sterile, nonpyrogenic, low-protein binding inline or add-on filter. Do not infuse other medications through the same infusion line.

Infusion-related reaction: Interrupt or slow the infusion for grade 1 or 2 infusion-related reactions; permanently discontinue for grade 3 or 4 infusion-related reactions.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Keytruda: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125514s160lbl.pdf#page=156

Use: Labeled Indications

Biliary tract cancer, locally advanced unresectable or metastatic:

Treatment (in combination with cisplatin and gemcitabine) of locally advanced unresectable or metastatic biliary tract cancer (BTC).

Breast cancer, triple-negative:

Treatment of high-risk early-stage triple-negative breast cancer as neoadjuvant therapy (in combination with chemotherapy), and then continued as adjuvant therapy (as a single agent) following surgery.

Treatment (in combination with chemotherapy) of locally recurrent unresectable or metastatic triple-negative breast cancer in patients whose tumors express PD-L1 (combined positive score [CPS] ≥10) as determined by an approved test.

Cervical cancer:

Treatment (in combination with chemoradiotherapy) of FIGO 2014 stage III to IVA cervical cancer.

Treatment (in combination with chemotherapy, with or without bevacizumab) of persistent, recurrent, or metastatic cervical cancer in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test.

Treatment (as a single agent) of recurrent or metastatic cervical cancer in patients with disease progression on or after chemotherapy and whose tumors express PD-L1 (CPS ≥1), as determined by an approved test.

Cutaneous squamous cell carcinoma, recurrent, metastatic, or locally advanced: Treatment of recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Endometrial carcinoma, advanced:

Treatment (in combination with lenvatinib) of advanced endometrial carcinoma that is mismatch repair proficient (pMMR) (as determined by an approved test), or not microsatellite instability-high (MSI-H), in patients with disease progression following prior systemic therapy (in any setting) and are not candidates for curative surgery or radiation.

Treatment (as a single agent) of advanced endometrial carcinoma that is MSI-H or mismatch repair deficient (dMMR) (as determined by an approved test) in patients with disease progression following prior systemic therapy (in any setting) and are not candidates for curative surgery or radiation.

Esophageal cancer, locally advanced or metastatic:

Treatment (in combination with platinum- and fluoropyrimidine-based chemotherapy) of locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation.

Treatment (as a single agent) of locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation after ≥1 prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an approved test.

Gastric cancer, locally advanced or metastatic:

First-line treatment (in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy) of locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma in adults whose tumors express PD-L1 (CPS ≥1), as determined by an approved test.

First-line treatment (in combination with fluoropyrimidine- and platinum-containing chemotherapy) of locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma in adults.

Head and neck cancer, squamous cell, recurrent or metastatic:

First-line treatment (in combination with platinum and fluorouracil) of metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

First-line treatment (as a single agent) of metastatic or unresectable, recurrent HNSCC in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test.

Treatment (as a single agent) of recurrent or metastatic HNSCC in patients with disease progression on or after platinum-containing chemotherapy.

Hepatocellular carcinoma, advanced: Treatment of hepatocellular carcinoma secondary to hepatitis B in patients who have received prior systemic therapy other than a PD-1/PD-L1–containing regimen.

Hodgkin lymphoma, classical, relapsed or refractory:

Treatment of relapsed or refractory classical Hodgkin lymphoma (cHL) in adults.

Treatment of pediatric patients with refractory cHL or with cHL that has relapsed after 2 or more lines of therapy.

Melanoma:

Adjuvant treatment of stage IIB, IIC, or III melanoma following complete resection in adults and pediatric patients ≥12 years of age.

Treatment of unresectable or metastatic melanoma.

Merkel cell carcinoma, recurrent locally advanced or metastatic: Treatment of recurrent locally advanced or metastatic Merkel cell carcinoma in adult and pediatric patients.

Microsatellite instability-high or mismatch repair-deficient cancer, unresectable or metastatic:

Solid tumors: Treatment of unresectable or metastatic MSI-H or dMMR solid tumors (as determined by an approved test) in adult and pediatric patients with progression following prior treatment and with no satisfactory alternate treatment options.

Colorectal cancer: Treatment of unresectable or metastatic MSI-H or dMMR (as determined by an approved test) colorectal cancer.

Non–small cell lung cancer:

Adjuvant treatment (as a single agent) of stage IB (T2a ≥4 cm), II, or IIIA nonsmall cell lung cancer (NSCLC) following resection and platinum-based chemotherapy in adults.

First-line treatment (as a single agent) of NSCLC in patients with stage III NSCLC (who are not candidates for surgical resection or definitive chemoradiation) or in patients with metastatic NSCLC, and PD-L1 expression (tumor proportion score [TPS] ≥1%), as determined by an approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

First-line treatment (in combination with pemetrexed and platinum chemotherapy) of metastatic nonsquamous NSCLC in patients with no EGFR or ALK genomic tumor aberrations.

First-line treatment (in combination with carboplatin and either paclitaxel or paclitaxel [protein bound]) of metastatic squamous NSCLC.

Treatment of resectable NSCLC (tumors ≥4 cm or node positive) in adults as neoadjuvant treatment (in combination with platinum-containing chemotherapy), and then continued as adjuvant treatment (as a single agent) after surgery.

Treatment (as a single agent) of metastatic NSCLC in patients with PD-L1 expression (TPS ≥1%), as determined by an approved test, and with disease progression on or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving pembrolizumab.

Primary mediastinal large B-cell lymphoma, relapsed or refractory: Treatment of primary mediastinal large B-cell lymphoma (PMBCL) in adult and pediatric patients with refractory disease or who have relapsed after 2 or more prior lines of therapy.

Limitation of use: Pembrolizumab is not recommended for treatment of PMBCL in patients who require urgent cytoreductive therapy.

Renal cell carcinoma:

First-line treatment (in combination with axitinib or in combination with lenvatinib) of advanced renal cell carcinoma.

Adjuvant treatment of renal cell carcinoma in patients at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.

Tumor mutational burden-high cancer, unresectable or metastatic: Treatment of unresectable or metastatic tumor mutational burden-high solid tumors (TMB-H; ≥10 mutations/megabase [mut/Mb]; as determined by an approved test) in adult and pediatric patients who have progressed following prior treatment and have no satisfactory alternative treatment options.

Limitation of use: Safety and efficacy in pediatric patients with TMB-H CNS cancers have not been established.

Urothelial cancer:

Treatment (as a single-agent) of Bacillus Calmette-Guérin-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors in patients who are ineligible for or have elected not to undergo cystectomy.

Treatment (as a single-agent) of locally advanced or metastatic urothelial cancer in patients who are not eligible for any platinum-containing chemotherapy.

Treatment (as a single-agent) of locally advanced or metastatic urothelial cancer in patients with disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Treatment (in combination with enfortumab vedotin) of locally advanced or metastatic urothelial cancer in adults.

Use: Off-Label: Adult

Malignant pleural mesothelioma, relapsed or refractory, with PD-L1 expression; Melanoma, advanced, high-risk, resectable, neoadjuvant regimen; Mycosis fungoides/Sézary syndrome, relapsed or refractory; Renal cell carcinoma, advanced, first-line single-agent therapy

Medication Safety Issues
Sound-alike/look-alike issues:

Pembrolizumab may be confused with atezolizumab, dostarlimab, durvalumab, necitumumab, nivolumab, palivizumab, panitumumab, pemetrexed, pemigatinib, polatuzumab vedotin

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Acetaminophen: May diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy

Antibiotics: May diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy

Axitinib: May enhance the hepatotoxic effect of Pembrolizumab. Risk C: Monitor therapy

Corticosteroids (Systemic): May diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Management: Carefully consider the need for corticosteroids, at doses of a prednisone-equivalent of 10 mg or more per day, during the initiation of immune checkpoint inhibitor therapy. Use of corticosteroids to treat immune related adverse events is still recommended Risk D: Consider therapy modification

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy

Inhibitors of the Proton Pump (PPIs and PCABs): May diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy

Ketoconazole (Systemic): Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies) may enhance the hepatotoxic effect of Ketoconazole (Systemic). Risk C: Monitor therapy

Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy

Thalidomide Analogues: Pembrolizumab may enhance the adverse/toxic effect of Thalidomide Analogues. Specifically, mortality may be increased when this combination is used for treatment of refractory multiple myeloma. Risk X: Avoid combination

Reproductive Considerations

Verify pregnancy status prior to initiation of pembrolizumab treatment in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for 4 months after the last pembrolizumab dose.

Pregnancy Considerations

Pembrolizumab crosses the placenta (Baarslag 2023).

Pembrolizumab is a humanized monoclonal antibody (IgG4). Human IgG crosses the placenta. Fetal exposure is dependent upon the IgG subclass, maternal serum concentrations, placental integrity, newborn birth weight, and GA, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis and the highest during the third trimester (Clements 2020; Palmeira 2012; Pentsuk 2009).

Based on the mechanism of action, in utero exposure to pembrolizumab may disrupt maternal tolerance to the fetus, increasing the risk of abortion or stillbirth. Based on animal data, maternal use of PD-1 inhibitor may also result in immune-mediated disorders in the newborn.

Outcome data following maternal use of pembrolizumab during pregnancy are limited (Anami 2021; Baarslag 2023; Mittra 2021; Polnaszek 2021).

Immune-mediated colitis may occur during treatment with pembrolizumab. Immune-mediated colitis requiring long term treatment (including corticosteroids and infliximab) has been reported in an infant born at 37 weeks' gestation following exposure to pembrolizumab between 16 and 34 weeks' gestation. Symptoms of colitis occurred 4 months after birth. Pembrolizumab was measurable in the infant plasma at 4.5 months of age (Baarslag 2023).

The use of immune checkpoint inhibitors, including pembrolizumab, has been reported for treatment resistant gestational trophoblastic neoplasia (Braga 2023; Ghorani 2017; Niimi 2023; Wang 2023). Although use may be considered, specific recommendations are not available (SOGC [Eiriksson 2021]). Additional research is needed; studies are ongoing (Wang 2023).

The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team) approach (ESMO [Peccatori 2013]).

A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (1-877-635-4499).

Breastfeeding Considerations

It is not known if pembrolizumab is present in breast milk.

Pembrolizumab is a humanized monoclonal antibody (IgG4). Human IgG is present in breast milk; concentrations are dependent upon IgG subclass and postpartum age (Anderson 2021).

Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends that breastfeeding be discontinued during therapy and for 4 months following the last pembrolizumab dose.

Monitoring Parameters

PD-L1 expression; microsatellite instability-high (MSI-H) status, mismatch repair deficient (dMMR) status, mismatch repair proficient (pMMR) status, and/or tumor mutational burden-high (TMB-H) status; see table below.

Pembrolizumab Patient Selection Criteria for Treatment (Where Applicable)a

Indication

PD-L1

dMMR/MSI-H

pMMR/non-MSH-H

TMB-H

Specimen type

a ALK = anaplastic lymphoma kinase; CPS = combined proportion score; dMMR = mismatch repair deficient; EGFR = epidermal growth factor receptor; MSI-H = microsatellite instability-high; mut/Mb = mutations per megabase; pMMR = mismatch repair proficient; TMB-H = tumor mutational burden-high; TPS = tumor proportion score.

b In patients with high grade glioma, test for TMB-H, MSI-H, and dMMR in the primary tumor specimen(s) prior to initiation of temozolomide because subclonal dMMR mutations and microsatellite stability may arise during treatment.

c Confirmation of local testing with an approved test is recommended, if feasible. If confirmatory testing is not possible, the presence of TMB ≥10 mut/Mb may be used to select patients for treatment.

Breast cancer, triple-negative, locally recurrent unresectable or metastatic, with PD-L1 expression

X

(CPS ≥10)

Cervical cancer, persistent, recurrent, or metastatic, with PD-L1 expression (single agent, combination therapy)

X

(CPS ≥1)

Colorectal cancer, unresectable or metastatic, MSI-H or dMMR

X

Tumor

Endometrial carcinoma, advanced, pMMR or non-MSI-H (combination therapy)

X

Tumor

Endometrial carcinoma, advanced, MSI-H or dMMR (single agent)

X

Tumor

Esophageal/gastroesophageal junction cancer, locally advanced or metastatic, with PD-L1 expression (single agent)

X

(CPS ≥10)

Gastric/gastroesophageal junction cancer, locally advanced unresectable or metastatic, HER2-positive, with PD-L1 expression (combination therapy)

X

(CPS ≥1)

Head and neck cancer, squamous cell carcinoma, unresectable, recurrent, or metastatic, with PD-LI expression (first-line therapy, single agent)

X

(CPS ≥1)

MSI-H or dMMR cancer, solid tumors, unresectable or metastatic

X

Tumorb,c

Non-small cell lung cancer (NSCLC), stage III (unresectable) or metastatic, with PD-L1 expression with no EGFR or ALK genomic tumor aberrations (first-line therapy, single agent)

X

(TPS ≥1%)

NSCLC, metastatic, with PD-L1 expression (previously treated, single agent)

X

(TPS ≥1%)

TMB-H cancer, solid tumors, unresectable or metastatic

X

(≥10 mut/Mb)

Tumorb

Monitor LFTs (AST, ALT, and total bilirubin; at baseline and periodically during treatment; consider monitoring more frequently in patients receiving pembrolizumab/axitinib); kidney function (serum creatinine; at baseline and periodically during treatment); thyroid function (at baseline, periodically during treatment and as clinically indicated); monitor blood glucose (for hyperglycemia); CBC with differential (in patients with Hodgkin lymphoma or primary mediastinal large B-cell lymphoma). Monitor blood cortisol at baseline, prior to surgery, and as clinically indicated (in patients with triple-negative breast cancer receiving neoadjuvant pembrolizumab). Evaluate pregnancy status (prior to initiation of pembrolizumab treatment in patients who can become pregnant). Monitor closely for signs/symptoms of immune-mediated adverse reactions, including adrenal insufficiency, diarrhea/colitis (consider initiating or repeating infectious workup in patients with corticosteroid-refractory immune-mediated colitis to exclude alternative causes), dermatologic toxicity, diabetes mellitus, hypophysitis, ocular disorders, thyroid disorders, pneumonitis and other immune-mediated adverse reactions. Monitor for signs/symptoms of infusion-related reactions. If received/receiving hematopoietic cell transplant, monitor closely for early signs/symptoms of transplant-related complications.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Obtain baseline ECG, natriuretic peptides, and troponins in all patients; obtain a baseline echocardiogram in high-risk patients; consider serial ECGs and cardiac troponins prior to doses 2, 3, and 4, and if normal, reduce to every 3 doses until completion of therapy; cardiovascular risk assessment every 6 to 12 months in high-risk patients who require long-term therapy (>12 months therapy, consider cardiovascular risk assessment every 6 to 12 months in all patients requiring long-term therapy) (ESC [Lyon 2022]). Refer to a cardiologist when clinically indicated.

Additional suggested monitoring (ASCO [Schneider 2021):

Prior to therapy: CBC with differential, serum chemistries, creatine kinase, comprehensive clinical assessment including performance status, weight, BMI, heart rate, BP, and oxygen saturation; consider chest x-ray, ECG, and CT scan; assess history of autoimmune conditions, organ-specific disease, endocrinopathies, neuropathy, and infectious disease; assess bowel habits, respiratory symptoms, skin (for rash), arthralgias, and neurologic symptoms.

During therapy: Assess BP, weight, heart rate, and oxygen saturation; assess for infections, screen for hyperglycemia/diabetes (polyuria, polydipsia, weight loss); eye exam (including intraocular pressure after 6 weeks), CBC with differential, serum chemistries, and creatine kinase; monitor bone mineral density (with long-term therapy).

Mechanism of Action

Pembrolizumab is a highly selective anti-PD-1 humanized monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to block PD-1 ligands (PD-L1 and PD-L2) from binding. Blocking the PD-1 pathway inhibits the negative immune regulation caused by PD-1 receptor signaling (Hamid 2013). Anti-PD-1 antibodies (including pembrolizumab) reverse T-cell suppression and induce antitumor responses (Robert 2014).

Pharmacokinetics (Adult Data Unless Noted)

Note: With weight-based dosing (2 mg/kg) every 3 weeks, pembrolizumab concentrations in pediatric patients are comparable to those of adults (at the same dose).

Distribution: Vdss: 6 L.

Half-life elimination: 22 days.

Excretion: Clearance: First dose: 252 mL/day; steady state: 195 mL/day.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Keytruda;
  • (AR) Argentina: Keytruda;
  • (AT) Austria: Keytruda;
  • (AU) Australia: Keytruda;
  • (BE) Belgium: Keytruda;
  • (BG) Bulgaria: Keytruda;
  • (BR) Brazil: Keytruda;
  • (CH) Switzerland: Keytruda;
  • (CL) Chile: Keytruda;
  • (CN) China: Keytruda;
  • (CO) Colombia: Keytruda;
  • (CZ) Czech Republic: Keytruda;
  • (DE) Germany: Keytruda;
  • (DO) Dominican Republic: Keytruda;
  • (EC) Ecuador: Keytruda;
  • (EE) Estonia: Keytruda;
  • (EG) Egypt: Keytruda;
  • (ES) Spain: Keytruda;
  • (FI) Finland: Keytruda;
  • (FR) France: Keytruda;
  • (GB) United Kingdom: Keytruda;
  • (GR) Greece: Keytruda;
  • (HK) Hong Kong: Keytruda;
  • (HR) Croatia: Keytruda;
  • (HU) Hungary: Keytruda;
  • (ID) Indonesia: Keytruda;
  • (IE) Ireland: Keytruda;
  • (IN) India: Keytruda;
  • (IT) Italy: Keytruda;
  • (JO) Jordan: Keytruda;
  • (JP) Japan: Keytruda;
  • (KR) Korea, Republic of: Keytruda;
  • (KW) Kuwait: Keytruda;
  • (LB) Lebanon: Keytruda;
  • (LT) Lithuania: Keytruda;
  • (LV) Latvia: Keytruda;
  • (MA) Morocco: Keytruda;
  • (MX) Mexico: Keytruda;
  • (MY) Malaysia: Keytruda;
  • (NL) Netherlands: Keytruda;
  • (NO) Norway: Keytruda;
  • (NZ) New Zealand: Keytruda;
  • (PE) Peru: Keytruda;
  • (PH) Philippines: Keytruda;
  • (PL) Poland: Keytruda;
  • (PR) Puerto Rico: Keytruda;
  • (PT) Portugal: Keytruda;
  • (PY) Paraguay: Keytruda;
  • (QA) Qatar: Keytruda;
  • (RO) Romania: Keytruda;
  • (RU) Russian Federation: Keytruda | Kitruda;
  • (SA) Saudi Arabia: Keytruda;
  • (SE) Sweden: Keytruda;
  • (SG) Singapore: Keytruda;
  • (SI) Slovenia: Keytruda;
  • (SK) Slovakia: Keytruda;
  • (TH) Thailand: Keytruda;
  • (TN) Tunisia: Keytruda;
  • (TR) Turkey: Keytruda;
  • (TW) Taiwan: Keytruda;
  • (UA) Ukraine: Keytruda;
  • (UY) Uruguay: Keytruda;
  • (ZA) South Africa: Keytruda
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Topic 96957 Version 332.0

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