Breast cancer, triple negative, high-risk, early stage:
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 (Schmid 2020).
Adjuvant therapy: IV: 200 mg once every 3 weeks (in combination with radiation therapy) for up to 9 cycles (Schmid 2020).
Breast cancer, triple negative, locally recurrent 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. Administer in combination with chemotherapy; in the clinical trial, chemotherapy consisted of paclitaxel (protein bound), paclitaxel (conventional), or gemcitabine/carboplatin (Cortes 2020).
Cervical cancer, persistent, recurrent, or metastatic, combination therapy: IV: 200 mg once every 3 weeks (Colombo 2021) 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) (Colombo 2021).
Cervical cancer, recurrent or metastatic, single-agent therapy: IV: 200 mg once every 3 weeks (Chung 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Colorectal cancer, microsatellite instability high or mismatch repair deficient, unresectable or metastatic: IV: 200 mg once every 3 weeks (André 2020; Le 2020) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Cutaneous squamous cell carcinoma, recurrent, metastatic, or locally advanced: IV: 200 mg once every 3 weeks (Grob 2020) or 400 mg once every 6 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Endometrial carcinoma, advanced: IV: 200 mg once every 3 weeks (Makker 2022) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (in combination with lenvatinib).
Esophageal cancer, recurrent locally advanced or metastatic, single-agent therapy: IV: 200 mg once every 3 weeks (Kojima 2020) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Esophageal cancer, locally advanced or metastatic, combination therapy: IV: 200 mg once every 3 weeks (Sun 2021) or 400 mg once every 6 weeks (initially 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.
Gastric cancer, locally advanced or metastatic, HER2-positive, first-line combination 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.
Head and neck cancer, squamous cell, unresectable/recurrent or metastatic, single-agent therapy: IV: 200 mg once every 3 weeks (Mehra 2018) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Head and neck cancer, squamous cell, unresectable/recurrent or metastatic, first-line combination therapy: IV: 200 mg once every 3 weeks (Burtness 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (initially in combination with 6 cycles of fluorouracil and either carboplatin or cisplatin).
Hepatocellular carcinoma, advanced: IV: 200 mg once every 3 weeks (Zhu 2018) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Hodgkin lymphoma, classical, relapsed or refractory: IV: 200 mg once every 3 weeks (Chen 2017; Chen 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Malignant pleural mesothelioma, relapsed/refractory, PD-L1+ (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 (Alley 2017; Metaxas 2018).
Melanoma, adjuvant treatment: IV: 200 mg once every 3 weeks (Eggermont 2018; Luke 2021) or 400 mg once every 6 weeks; continue until disease recurrence, unacceptable toxicity, or for up to 12 months in patients without disease recurrence.
Melanoma, unresectable or metastatic: IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks until disease progression or unacceptable toxicity.
Off-label dosing: 2 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Ribas 2015).
Merkel cell carcinoma, recurrent 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.
Off-label dosing: 2 mg/kg once every 3 weeks for up to 2 years or until complete response, or until disease progression or unacceptable toxicity (Nghiem 2016).
Microsatellite instability-high or mismatch repair-deficient cancer, unresectable or metastatic: IV: 200 mg once every 3 weeks (Marabelle 2020b) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
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 (Khodadoust 2020).
Non–small cell lung cancer, stage III or metastatic, single-agent therapy: IV: 200 mg once every 3 weeks (Mok 2019; Reck 2016) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Off-label dosing (in patients with metastatic non–small cell lung cancer (NSCLC) with disease progression following platinum-containing chemotherapy): 2 mg/kg once every 3 weeks for 24 months or until disease progression or unacceptable toxicity (Herbst 2016).
Non–small cell lung cancer, metastatic, nonsquamous, first-line combination therapy: IV: 200 mg once every 3 weeks (in combination with pemetrexed and either cisplatin or carboplatin) for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks (with or without optional indefinite pemetrexed maintenance therapy) 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 (Gandhi 2018; Langer 2016). Pembrolizumab 400 mg once every 6 weeks has been approved as an additional dosing option.
Non–small cell lung cancer, metastatic, squamous, first-line combination therapy: IV: 200 mg once every 3 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 until radiographic disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles (Paz-Ares 2018). Pembrolizumab 400 mg once every 6 weeks has been approved as an additional dosing option.
Primary mediastinal large B-cell lymphoma, relapsed or refractory: IV: 200 mg once every 3 weeks (Armand 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Renal cell carcinoma, adjuvant treatment: IV: 200 mg once every 3 weeks (Choueiri 2021) or 400 mg once every 6 weeks; continue until disease recurrence, unacceptable toxicity, or (in patients without disease recurrence) for up to 12 months.
Renal cell carcinoma, advanced, first-line combination therapy: IV: 200 mg once every 3 weeks (Motzer 2021; Powles 2020; Rini 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (in combination with axitinib or in combination with lenvatinib).
Tumor mutational burden-high cancer, unresectable or metastatic: IV: 200 mg once every 3 weeks (Marabelle 2020a) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Urothelial carcinoma, non-muscle invasive, high-risk, Bacillus Calmette-Guerin–unresponsive: IV: 200 mg once every 3 weeks (Balar 2021) 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.
Urothelial carcinoma, locally advanced or metastatic: IV: 200 mg once every 3 weeks (Bellmunt 2017; Vuky 2020) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Renal impairment prior to treatment initiation: There are no dosage adjustments provided in the manufacturer’s labeling; however, there was no clinically important effect on clearance for patients with eGFR ≥15 mL/minute/1.73 m2.
Renal toxicity during treatment:
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 prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.
Grade 4 serum creatinine elevation: Permanently discontinue pembrolizumab.
Hepatic impairment prior to treatment initiation:
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 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.
(For additional information see "Pembrolizumab: Pediatric drug information")
Note: FDA approval through an accelerated process; well-controlled trials in pediatric patients are scant and dosing based on adult efficacy and safety trials and pediatric pharmacokinetic and safety data.
Hodgkin lymphoma, classical (relapsed or refractory):
Children ≥2 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 24 months.
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 (recurrent locally advanced or metastatic):
Children ≥2 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 24 months.
Microsatellite instability-high cancer (MSI-H) (unresectable or metastatic); non-CNS solid tumors that have progressed following prior treatment without satisfactory alternative treatment options:
Children ≥2 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 24 months.
Primary mediastinal large B-cell lymphoma (PMBCL) (relapsed or refractory):
Children ≥2 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 24 months.
Tumor mutational burden-high (TMB-H) (unresectable or metastatic); non-CNS solid tumors that have progressed following prior treatment without satisfactory alternative treatment options:
Children ≥2 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 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: Children ≥2 years 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.
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. |
Children ≥2 years 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.
Children ≥ 2 years 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.
Refer to adult dosing.
Note: No dosage reductions of pembrolizumab are recommended. 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 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.
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 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 |
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. 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. 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. 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. |
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]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous:
Keytruda: 100 mg/4 mL (4 mL) [contains polysorbate 80]
Solution Reconstituted, Intravenous:
Keytruda: 50 mg ([DSC]) [contains polysorbate 80]
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125514s125lbl.pdf#page=124, must be dispensed with this medication.
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.
Cervical cancer (persistent, recurrent, or metastatic): When administered in combination with chemotherapy with or without bevacizumab, administer pembrolizumab prior to chemotherapy (± bevacizumab) when administered on the same day.
Esophageal cancer (locally advanced or metastatic), head and neck squamous cell carcinoma (unresectable/recurrent, metastatic), non-small cell lung cancer (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.
Gastric cancer (locally advanced or metastatic): When administered in combination with trastuzumab and chemotherapy, administer pembrolizumab prior to trastuzumab and chemotherapy when administered on the same day.
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.
Breast cancer, triple negative (high-risk, early stage): Treatment of high-risk early stage triple-negative breast cancer, in combination with chemotherapy as neoadjuvant therapy, then continued as a single agent as adjuvant therapy following surgery.
Breast cancer, triple negative (locally recurrent unresectable or metastatic): Treatment of locally recurrent unresectable or metastatic triple-negative breast cancer (in combination with chemotherapy) in patients whose tumors express PD-L1 (combined positive score [CPS] ≥10) as determined by an approved test.
Cervical cancer:
Treatment of persistent, recurrent, or metastatic cervical cancer (in combination with chemotherapy, with or without bevacizumab) in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test.
Treatment (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 not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) in patients who have 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 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 (in combination with platinum- and fluoropyrimidine-based chemotherapy).
Treatment (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 of locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma (in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy).
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, single-agent treatment of metastatic or unresectable recurrent HNSCC in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test.
Single-agent treatment of recurrent or metastatic HNSCC in patients with disease progression on or after platinum-containing chemotherapy.
Hepatocellular carcinoma (advanced): Treatment of hepatocellular carcinoma in patients who have been previously treated with sorafenib.
Hodgkin lymphoma, classical (relapsed or refractory):
Treatment of relapsed or refractory classical Hodgkin lymphoma in adults.
Treatment of pediatric patients with refractory classical Hodgkin lymphoma or with classical Hodgkin lymphoma that has relapsed after 2 or more lines of therapy.
Melanoma:
Adjuvant treatment of stage IIB, IIC, or III melanoma following complete resection in pediatric patients ≥12 years of age and adults.
Treatment of unresectable or metastatic melanoma.
Merkel cell carcinoma (recurrent 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 in adult and pediatric patients that have progressed following prior treatment and have no satisfactory alternate treatment options.
Limitation of use: Safety and efficacy in pediatric patients with MSI-H central nervous system cancers have not been established.
Colorectal cancer: Treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer.
Non–small cell lung cancer:
First-line, single-agent treatment of non–small cell lung cancer (NSCLC) in patients with stage III NSCLC (who are not candidates for surgical resection or definitive chemoradiation) or in patients with metastatic NSCLC, and with tumors with PD-L1 expression (tumor proportion score [TPS] ≥1%), as determined by an approved test, and 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.
Single-agent treatment of metastatic NSCLC in patients with tumors 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 of advanced renal cell carcinoma (in combination with axitinib or in combination with lenvatinib).
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 carcinoma:
Treatment 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 of locally advanced or metastatic urothelial cancer in patients who are not eligible for any platinum-containing chemotherapy.
Treatment 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.
Malignant pleural mesothelioma, relapsed/refractory, PD-L1+; Mycosis fungoides/Sézary syndrome, relapsed/refractory
Pembrolizumab may be confused with atezolizumab, dostarlimab, durvalumab, necitumumab, nivolumab, palivizumab, panitumumab, pemetrexed, pemigatinib, polatuzumab vedotin
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
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).
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).
Risk factors:
• Autoimmune disease (Ref)
• Diabetes mellitus (Ref)
• Preexisting cardiovascular disease (Ref)
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 (eg, lichenoid dermatitis), 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 sicca syndrome-like symptoms (Ref). Although most cutaneous toxicities are transient, they can cause significant morbidity and impairment of patients’ health-related quality of life (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; often occurs within the first 2 weeks of therapy and can be seen in patients with any tumor type (Ref), but has also been reported later in therapy (Ref). For most patients, dermatologic toxicity is the earliest irAE experienced (Ref).
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). 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 5.3 months (range: 26 days to 16.6 months). Hypophysitis: Median onset of 3.7 months (range: 1 day to 11.9 months). Hyperthyroidism: Median onset of 1.4 months (range: 1 day to 21.9 months). Hypothyroidism: Median onset of 3.5 months (range: 1 day to 18.9 months). Thyroiditis: Median onset of 1.2 months (range: 0.5 to 3.5 months).
Risk factors:
• Autoimmune disorders (Ref)
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, may occur (Ref). Colitis-related mortality is associated with delayed reporting, noncompliance with an antidiarrheal regimen, and delays in drug withholding (Ref).
Mechanism: Non–dose-related; immunologic (Ref).
Onset: Varied. These adverse reactions manifest 5 to 10 weeks after start of therapy (Ref). Colitis: Median onset of 3.5 months (range: 10 days to 16.2 months).
Risk factors:
• Autoimmune disorders of the GI tract (Ref)
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 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), immune thrombocytopenia (10.1 weeks), pancytopenia or aplastic anemia (21.7 weeks) (Ref).
Risk factors:
• Combination immunotherapy and chemotherapy (Ref)
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. Hepatitis: Median onset of 1.3 months (range: 8 days to 21.4 months).
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
Immune-mediated nephritis has rarely occurred. Although an increased serum creatinine is common, acute kidney injury occurs less frequently (Ref).
Mechanism: Non–dose-related; immunologic (Ref)
Onset: Varied. Increased serum creatinine: 12 to 48 weeks after initiation (Ref). Autoimmune nephritis: Onset of 3.2 to 5.1 months (range: 12 days to 12.8 months). 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 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).
Onset: Varied; typically develop within 4 months of initiation (Ref).
Uveitis 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, color changes, ocular myasthenia (Ref), photophobia (associated with aseptic meningitis) (Ref), inflammation of the eyelid (Ref), and vision loss (Ref).
Onset: Varied (Ref).
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).
Mechanism: Non–dose-related; immunologic (Ref)
Onset: Varied; ranging from 2 to 24 months with a median onset of ~3 months (Ref). Pneumonitis median time to development was 3.3 months (range: 2 days to 19.3 months).
Risk factors:
• Prior thoracic radiation in non-small cell lung cancer patients (Ref)
• Treatment-naive patients (Ref)
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 24%) (table 1) , vitiligo (13%) (table 2)
Drug (Pembrolizumab) |
Comparator |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|---|
13% |
N/A |
9% |
200 mg every 3 weeks |
Adjuvant treatment of resected melanoma |
509 |
N/A |
502 |
20% |
70% (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 |
24% |
23% (Ipilimumab) |
N/A |
10 mg/kg every 2 or 3 weeks |
Ipilimumab-naive melanoma |
555 |
256 |
N/A |
24% |
8% (Chemotherapy) |
N/A |
2 mg/kg or 10 mg/kg every 3 weeks |
Ipilimumab-refractory melanoma |
357 |
171 |
N/A |
17% |
8% (Docetaxel) |
N/A |
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 |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
N/A |
15% |
8% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously untreated non–small-cell lung cancer |
636 |
615 |
N/A |
20% |
19% (Brentuximab vedotin) |
N/A |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
N/A |
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%), 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 19%) (table 3) , weight loss (10% to 15%)
Drug (Pembrolizumab) |
Comparator |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|---|
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 |
Gastrointestinal: Abdominal pain (11% to 22%) (table 4) , constipation (12% to 22%), decreased appetite (15% to 25%), diarrhea (12% to 28%) (table 5) , nausea (11% to 22%), vomiting (11% to 19%)
Drug (Pembrolizumab) |
Comparator |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
---|---|---|---|---|---|
22% |
N/A |
200 mg every 3 weeks |
Cervical cancer |
98 |
N/A |
13% |
8% (Chemotherapy) |
2 mg/kg or 10 mg/kg every 3 weeks |
Ipilimumab-refractory melanoma |
357 |
171 |
13% |
13% (Chemotherapy) |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
11% |
13% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
Drug (Pembrolizumab) |
Comparator |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|---|
28% |
N/A |
26% |
200 mg every 3 weeks |
Adjuvant treatment of resected melanoma |
509 |
N/A |
502 |
16% |
35% (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 |
20% |
20% (Chemotherapy) |
N/A |
2 mg/kg or 10 mg/kg every 3 weeks |
Ipilimumab-refractory melanoma |
357 |
171 |
N/A |
18% |
19% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
N/A |
12% |
12% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously untreated non–small-cell lung cancer |
636 |
615 |
N/A |
22% |
17% (Brentuximab vedotin) |
N/A |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
N/A |
Genitourinary: Hematuria (12% to 19%), urinary tract infection (2% to 19%)
Hematologic & oncologic: Anemia (17% to 54%; grades 3/4: 1% to 24%) (table 6) , hemorrhage (19%; grades 3/4: 5%; major hemorrhage: 4%), increased INR (19% to 21%; grade 3/4: 2%), leukopenia (35%; grades 3/4: 9%), lymphocytopenia (24% to 54%; grades 3/4: 2% to 25%) (table 7) , neutropenia (7% to 30%; grades 3/4: 1% to 11%) (table 8) , prolonged partial thromboplastin time (14%), thrombocytopenia (12% to 34%; grades 3/4: 4% to 10%) (table 9)
Drug (Pembrolizumab) |
Comparator |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
---|---|---|---|---|---|
All grades: 35% |
N/A |
200 mg every 3 weeks |
Bacillus Calmette-Guerin-unresponsive high-risk non-muscle invasive bladder cancer |
148 |
N/A |
Grades 3/4: 1% |
N/A |
200 mg every 3 weeks |
Bacillus Calmette-Guerin-unresponsive high-risk non-muscle invasive bladder cancer |
148 |
N/A |
All grades: 54% |
N/A |
200 mg every 3 weeks |
Cervical cancer |
98 |
N/A |
Grades 3/4: 24% |
N/A |
200 mg every 3 weeks |
Cervical cancer |
98 |
N/A |
All grades: 52% |
78% (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: 7% |
19% (Cetuximab platinum FU) |
200 mg every 3 weeks |
First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer |
300 |
287 |
All grades: 35% |
33% (Ipilimumab) |
10 mg/kg every 2 or 3 weeks |
Ipilimumab-naive melanoma |
555 |
256 |
Grades 3/4: 4% |
4% (Ipilimumab) |
10 mg/kg every 2 or 3 weeks |
Ipilimumab-naive melanoma |
555 |
256 |
All grades: 52% |
68% (Chemotherapy) |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
Grades 3/4: 13% |
18% (Chemotherapy) |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
All grades: 43% |
79% (Chemotherapy) |
200 mg every 3 weeks |
Previously untreated non–small-cell lung cancer |
636 |
615 |
Grades 3/4: 4% |
19% (Chemotherapy) |
200 mg every 3 weeks |
Previously untreated non–small-cell lung cancer |
636 |
615 |
All grades: 24% |
33% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
Grades 3/4: 5% |
8% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
All grades: 17% |
N/A |
200 mg every 3 weeks |
Urothelial carcinoma |
370 |
N/A |
Grades 3/4: 7% |
N/A |
200 mg every 3 weeks |
Urothelial carcinoma |
370 |
N/A |
Drug (Pembrolizumab) |
Comparator |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|---|
All grades: 24% |
N/A |
16% |
200 mg every 3 weeks |
Adjuvant treatment of resected melanoma |
509 |
N/A |
502 |
Grades 3/4: 1% |
N/A |
1% |
200 mg every 3 weeks |
Adjuvant treatment of resected melanoma |
509 |
N/A |
502 |
All grades: 54% |
74% (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 |
Grades 3/4: 25% |
45% (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 |
All grades: 33% |
25% (Ipilimumab) |
N/A |
10 mg/kg every 2 or 3 weeks |
Ipilimumab-naive melanoma |
555 |
256 |
N/A |
Grades 3/4: 7% |
6% (Ipilimumab) |
N/A |
10 mg/kg every 2 or 3 weeks |
Ipilimumab-naive melanoma |
555 |
256 |
N/A |
All grades: 45% |
53% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
N/A |
Grades 3/4: 15% |
25% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
N/A |
All grades: 30% |
41% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously untreated non–small-cell lung lung cancer |
636 |
615 |
N/A |
Grades 3/4: 7% |
13% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously untreated non–small-cell lung cancer |
636 |
615 |
N/A |
All grades: 35% |
32% (Brentuximab vedotin) |
N/A |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
N/A |
Grades 3/4: 9% |
13% (Brentuximab vedotin) |
N/A |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
N/A |
Drug (Pembrolizumab) |
Comparator |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
---|---|---|---|---|---|
All grades: 7% |
71% (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: 1% |
42% (Cetuximab platinum FU) |
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 |
200 mg every 3 weeks |
Primary mediastinal large B-cell lymphoma |
53 |
N/A |
Grades 3/4: 11% |
N/A |
200 mg every 3 weeks |
Primary mediastinal large B-cell lymphoma |
53 |
N/A |
All grades: 28% |
43% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
Grades 3/4: 8% |
17% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
Drug (Pembrolizumab) |
Comparator |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
---|---|---|---|---|---|
All grades: 12% |
76% (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: 4% |
18% (Cetuximab platinum FU) |
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) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
Grades 3/4: 10% |
5% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
Hepatic: Hyperbilirubinemia (10% to 16%) (table 10) , increased serum alanine aminotransferase (21% to 34%) (table 11) , increased serum alkaline phosphatase (17% to 42%), increased serum aspartate aminotransferase (20% to 39%) (table 12)
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 |
Drug (Pembrolizumab) |
Comparator |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|---|
27% |
N/A |
16% |
200 mg every 3 weeks |
Adjuvant treatment of resected melanoma |
509 |
N/A |
502 |
25% |
38% (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 |
21% |
16% (Chemotherapy) |
N/A |
2 mg/kg or 10 mg/kg every 3 weeks |
Ipilimumab-refractory melanoma |
357 |
171 |
N/A |
22% |
9% (Docetaxel) |
N/A |
2 mg/kg or 10 mg/kg every 3 weeks |
Previously treated non–small-cell lung lung cancer |
682 |
309 |
N/A |
33% |
34% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously untreated non–small-cell lung lung cancer |
636 |
615 |
N/A |
34% |
45% (Brentuximab vedotin) |
N/A |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
N/A |
Drug (Pembrolizumab) |
Comparator |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|---|
24% |
N/A |
15% |
200 mg every 3 weeks |
Adjuvant treatment of resected melanoma |
509 |
N/A |
502 |
20% |
N/A |
N/A |
200 mg every 3 weeks |
Bacillus Calmette-Guerin-unresponsive high-risk non-muscle invasive bladder cancer |
148 |
N/A |
N/A |
28% |
37% (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 |
27% |
25% (Ipilimumab) |
N/A |
10 mg/kg every 2 or 3 weeks |
Ipilimumab-naive melanoma |
555 |
256 |
N/A |
24% |
16% (Chemotherapy) |
N/A |
2 mg/kg or 10 mg/kg every 3 weeks |
Ipilimumab-refractory melanoma |
357 |
171 |
N/A |
26% |
12% (Docetaxel) |
N/A |
2 mg/kg or 10 mg/kg every 3 weeks |
Previously treated non–small-cell lung lung cancer |
682 |
309 |
N/A |
28% |
20% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
N/A |
31% |
32% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously untreated non–small-cell lung lung cancer |
636 |
615 |
N/A |
39% |
41% (Brentuximab vedotin) |
N/A |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
N/A |
Infection: Infection (16%; serious infection: 4%)
Nervous system: Fatigue (20% to 43%), headache (11% to 14%), pain (22%), peripheral neuropathy (1% to 11%; grade 3/4: <1%) (table 13)
Drug (Pembrolizumab) |
Comparator |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
---|---|---|---|---|---|
All grades: 1% |
7% (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% |
1% (Cetuximab platinum FU) |
200 mg every 3 weeks |
First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer |
300 |
287 |
All grades: 2% |
N/A |
2 mg/kg or 10 mg/kg every 3 weeks |
Ipilimumab-refractory melanoma |
357 |
N/A |
All grades: 11% |
43% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
Grades 3/4: 0.7% |
7% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
Neuromuscular & skeletal: Arthralgia (10% to 18%), asthenia (10% to 11%), back pain (11% to 12%), musculoskeletal pain (19% to 32%), myalgia (12%)
Renal: Increased serum creatinine (11% to 35%) (table 14)
Drug (Pembrolizumab) |
Comparator |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
---|---|---|---|---|---|
18% |
27% (Cetuximab platinum FU) |
200 mg every 3 weeks |
First-line treatment of metastatic or unresectable, recurrent head and neck squamous cell cancer |
300 |
287 |
35% |
28% (Chemotherapy) |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
28% |
14% (Brentuximab vedotin) |
200 mg every 3 weeks |
Relapsed or refractory classical Hodgkin lymphoma |
148 |
152 |
11% |
N/A |
200 mg every 3 weeks |
Urothelial carcinoma |
370 |
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 28%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (2%), cardiac tamponade (2%), facial edema (10%), ischemic heart disease (2%), myocarditis (≤1%), pericardial effusion (2%), pericarditis (2% to 4%), pulmonary embolism (2%)
Endocrine & metabolic: Hyperthyroidism (3% to 10%) (table 15) , thyroiditis (≤2%)
Drug (Pembrolizumab) |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
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 |
Gastrointestinal: Colitis (2%), dysphagia (8%), stomatitis (3%) (table 16)
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%)
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%)
Renal: Acute kidney injury (2%)
Respiratory: Nasopharyngitis (10%), oropharyngeal pain (8%), pleural effusion (2%), respiratory failure (≥2%)
Miscellaneous: Fistula (4%), infusion related reaction (≤9%; including severe infusion related reaction)
<1%:
Cardiovascular: Vasculitis
Endocrine & metabolic: Adrenocortical insufficiency, diabetic ketoacidosis, hypoparathyroidism, hypophysitis, type 1 diabetes mellitus
Gastrointestinal: Duodenitis, gastritis, increased serum amylase, increased serum lipase, pancreatitis
Hematologic & oncologic: Aplastic anemia, hemolytic anemia, immune thrombocytopenia, immunological signs and symptoms (hemophagocytic lymphohistiocytosis) (Kalmuk 2020), lymphadenitis (histiocytic necrotizing lymphadenitis [Kikuchi lymphadenitis]), sarcoidosis
Hypersensitivity: Anaphylaxis
Immunologic: Organ transplant rejection (solid)
Infection: Systemic inflammatory response syndrome
Nervous system: Demyelinating disease, encephalitis, exacerbation of myasthenia gravis, Guillain-Barre syndrome, meningitis, myasthenia (myasthenic syndrome) (Fang 2019), myasthenia gravis, neuropathy (autoimmune), paresis (nerve)
Neuromuscular & skeletal: Myelitis, polymyalgia rheumatica, polymyositis, rhabdomyolysis
Ophthalmic: Iritis
Renal: Nephritis
Frequency not defined:
Cardiovascular: Cardiac failure, edema, septic shock
Dermatologic: Cellulitis, dermatitis
Gastrointestinal: Clostridioides difficile associated diarrhea
Genitourinary: Urinary tract infection with sepsis, uterine hemorrhage
Hematologic & oncologic: Rectal hemorrhage
Hepatic: Hepatic sinusoidal obstruction syndrome (followed by allogeneic hematopoietic stem cell transplantation)
Immunologic: Graft versus host disease (followed by allogeneic hematopoietic stem cell transplantation)
Infection: Candidiasis
Neuromuscular & skeletal: Osteomyelitis
Respiratory: Epistaxis, hemoptysis
Postmarketing:
Dermatologic: Bullous pemphigoid (Hara 2020), Stevens-Johnson syndrome (Haratake 2018), toxic epidermal necrolysis (Ran Cai 2020)
Gastrointestinal: Gastrointestinal perforation (Beck 2019), sclerosing cholangitis (Matsumoto 2020, Ooi 2020)
Hematologic & oncologic: Disseminated intravascular coagulation (Alberti 2020), pancytopenia (Atwal 2017)
Nervous system: Aseptic meningitis (Lima 2019), cerebral hemorrhage (Yamazaki 2017), chronic inflammatory demyelinating polyneuropathy (Maleissye 2016), reversible posterior leukoencephalopathy syndrome (LaPorte 2017)
Neuromuscular & skeletal: Subacute cutaneous lupus erythematosus (Blakeway 2019)
Ophthalmic: Vision loss (Telfah 2019)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to pembrolizumab or any component of the formulation.
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.
• Dermatologic toxicity: Immune-mediated rash or dermatitis may occur. Immune-mediated dermatologic adverse reactions (including grade 2 and 3 events) occurred with pembrolizumab. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis has occurred with anti-PD-1/PD-L1 monoclonal antibodies. Immune-mediated dermatologic reactions were treated with systemic corticosteroids in 40% of patients, and reactions resolved in ~80% of patients. In cases where pembrolizumab was withheld, all reinitiated treatment after symptom improvement; immune-mediated dermatologic toxicity recurred in some patients.
• Endocrinopathies: Pembrolizumab is associated with immune-mediated endocrinopathies.
- Adrenal insufficiency: Primary and secondary adrenal insufficiency have occurred, including cases of ≥ grade 2 adrenal insufficiency. Over 75% of cases were managed with systemic corticosteroids; the majority of patients remained on corticosteroid therapy. In cases where pembrolizumab was withheld for adrenal insufficiency, all reinitiated treatment after symptom improvement.
- Diabetes mellitus: Type 1 diabetes mellitus has occurred (which may present with diabetic ketoacidosis).
- Hypophysitis: Immune-mediated hypophysitis has occurred (grades 2, 3, and 4), and may present with acute mass effect symptoms (headache, photophobia, or visual field defects). Hypophysitis may lead to hypopituitarism. Most hypophysitis cases were managed with systemic corticosteroids; the majority of patients remained on corticosteroid therapy. In cases where pembrolizumab was withheld for hypophysitis, all reinitiated treatment after symptom improvement.
- Thyroid disorders: Immune-mediated thyroid disorders have occurred. Hyperthyroidism occurred in a small percentage of patients, including grade 2 and 3 events. Discontinuation or treatment interruption due to hyperthyroidism were required in a small number of patients. In cases where pembrolizumab was withheld, all reinitiated treatment after symptom improvement. Hypothyroidism has occurred, including grade 2 and 3 cases. Hypothyroidism may follow hyperthyroidism. Discontinuation or treatment interruption due to hypothyroidism were required in a small number of patients; in cases where pembrolizumab was withheld, all reinitiated treatment. Most patients required long-term thyroid replacement therapy. The incidence of new or worsening hypothyroidism was higher in patients with squamous cell cancer of the head and neck (as a single agent or in combination with chemotherapy) and in classical Hodgkin lymphoma (as a single agent). Thyroiditis may present with or without endocrinopathy. Thyroiditis occurred rarely, and did not result in permanent discontinuation, although treatment was interrupted occasionally.
• GI toxicity: Immune-mediated colitis has occurred (may present with diarrhea), including cases of grade 2 to 4 colitis. Systemic corticosteroids were administered to the majority of patients for immune-mediated colitis; additional immunosuppressant therapy was necessary in some patients. Most patients with colitis experienced resolution. In cases where pembrolizumab was withheld for colitis, all reinitiated treatment after symptom improvement; colitis recurred in ~25% of patients. Cytomegalovirus infection or reactivation has been observed in patients with corticosteroid-refractory, immune-mediated colitis. Pancreatitis (including increased serum amylase and lipase levels), gastritis, and duodenitis have also been reported.
• Hepatotoxicity: Immune-mediated hepatitis has occurred with pembrolizumab monotherapy (grades 2 to 4 hepatitis). Hepatitis has led to pembrolizumab treatment interruption or discontinuation. Systemic corticosteroids were used to manage immune-mediated hepatitis in many patients; additional immunosuppressants were necessary in some cases. Hepatitis resolved in a majority of patients. In cases where pembrolizumab was withheld for hepatitis, all reinitiated treatment after symptom improvement with no recurrence of hepatitis. Pembrolizumab/axitinib combination therapy may result in higher frequencies of grades 3 and 4 ALT and AST elevations (compared to single-agent therapy). Over half of patients with ALT elevation required systemic corticosteroids; resolution of grades 2 to 4 ALT elevation occurred in most patients. When rechallenged with either pembrolizumab, axitinib, or both, some patients experienced recurrence of ALT elevation to >3 times ULN (with subsequent recovery).
• Hypersensitivity: Hypersensitivity and anaphylaxis have been observed (rare).
• 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.
• Nephrotoxicity: Immune-mediated nephritis with kidney dysfunction has occurred, including grade 2 to grade 4 cases. Most patients required systemic corticosteroids. In cases where pembrolizumab was withheld for nephritis, all reinitiated treatment after symptom improvement with no recurrence of nephritis. Nephritis resolved in over one-half of affected patients.
• Ocular toxicity: Immune-mediated uveitis, iritis, and other ocular inflammatory toxicities may occur with pembrolizumab. Some cases can be associated with retinal detachment. Differing grades of visual impairment (including blindness) may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome.
• Pulmonary toxicity: Immune-mediated pneumonitis has been observed, including grades 2 to 4, and fatal cases. Many patients required management with systemic corticosteroids. Pneumonitis resolved in over half of the affected patients. In cases where pembrolizumab was withheld for pneumonitis, all reinitiated pembrolizumab after symptom improvement; pneumonitis recurred in ~25% of patients. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation.
• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders have been observed rarely with pembrolizumab (or other anti-PD-1/PD-L1 monoclonal antibodies) and may affect any organ system (may be fatal), including myocarditis, pericarditis, vasculitis, meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy, myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatic, hypoparathyroidism, hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection.
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 stem cell transplant: Fatal and other serious complications may occur in patients who receive allogeneic hematopoietic stem cell transplant (HSCT) 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 HSCT. 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 HSCT.
• 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]).
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 renal 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: Select patients for persistent, recurrent, or metastatic cervical cancer (as a single agent or in combination with chemotherapy ± bevacizumab), previously treated recurrent locally advanced or metastatic esophageal cancer, metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC; first-line single agent treatment), metastatic or stage III (unresectable) non–small cell lung cancer (NSCLC; single-agent treatment), or triple-negative locally recurrent unresectable or metastatic breast cancer based on PD-L1 expression. Select patients for microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) cancers (including colorectal cancer), or tumor mutational burden-high (TMB-H) cancer based on MSI-H/dMMR or TMB-H status, respectively, in tumor specimens. The effect of prior chemotherapy on test results for TMB-H, MSI-H, or dMMR in patients with high-grade gliomas is unclear; it is recommended to test for these markers in the primary tumor specimens obtained prior to temozolomide initiation (in patients with high-grade gliomas). For non–MSI-H/dMMR endometrial carcinoma, select patients for treatment based on tumor specimen MSI or MMR status. Information on approved tests may be found at http://www.fda.gov/companiondiagnostics.
In clinical trials, the following adverse effects were reported more frequently (≥15% difference in incidence in pediatric patients [≥2 years of age] than adults): Fatigue, vomiting, abdominal pain, hypertransaminasemia, and hyponatremia.
None known.
Antibiotics: May diminish the therapeutic effect of Immune Checkpoint Inhibitors. 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. 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. Risk C: Monitor therapy
Ketoconazole (Systemic): Immune Checkpoint Inhibitors may enhance the hepatotoxic effect of Ketoconazole (Systemic). 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
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 at least 4 months after the last pembrolizumab dose.
Pembrolizumab is a humanized monoclonal antibody (IgG4). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).
Based on the mechanism of action, pembrolizumab may cause fetal harm if administered during pregnancy; an alteration in the immune response or immune mediated disorders may develop following in utero exposure.
It is not known if pembrolizumab is present in breast milk. 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 final pembrolizumab dose. Immunoglobulins are excreted in breast milk; therefore, pembrolizumab may be expected to appear in breast milk.
PD-L1 expression status in patients with cervical cancer (single-agent or combination therapy), esophageal cancer, first-line (single agent) treatment of head and neck squamous cell carcinoma, metastatic or stage III (unresectable) non–small cell lung cancer (when used as single-agent therapy), or triple-negative locally recurrent unresectable or metastatic breast cancer; microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) status in MSI-H/dMMR cancers (including colorectal cancer); tumor mutational burden-high (TMB-H) status in TMB-H cancer; tumor specimen MSI or MMR status for non–MSI-H/dMMR endometrial carcinoma.
Monitor LFTs (AST, ALT, and total bilirubin; at baseline and periodically during treatment; consider monitoring more frequently in patients receiving pembrolizumab/axitinib); renal 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 stem 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.
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).
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.
Solution (Keytruda Intravenous)
100 mg/4 mL (per mL): $1,540.31
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