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; Schmid 2022).
Adjuvant therapy: IV: 200 mg once every 3 weeks (in combination with radiation therapy) for up to 9 cycles (Schmid 2020; Schmid 2022).
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; Cortes 2022).
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, mismatch repair proficient or not microsatellite instability-high, combination therapy: 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).
Endometrial carcinoma, microsatellite instability-high or mismatch repair deficient, advanced, single-agent therapy: IV: 200 mg once every 3 weeks (O’Malley 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.
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 2022) 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.
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.
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.
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:
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 (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 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 (ASCO [Rathmell 2022]; George 2022; McDermott 2021).
IV: 200 mg once every 3 weeks (McDermott 2021) or 400 mg once every 6 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.
Renal cell carcinoma, advanced, first-line combination therapy:
Note: For use in combination with either axitinib or lenvatinib regardless of risk stratification (Motzer 2021; Rini 2019); 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 (George 2022).
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 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.
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 (ASCO [Griggs 2021]).
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.
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 (ASCO [Schneider 2021]). Refer to guideline for further information regarding management of immune-mediated adverse reactions associated with checkpoint inhibitor therapy.
|
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. | |
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/2022/125514s123lbl.pdf#page=126, 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 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 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 (as determined by an approved test) 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 (as determined by an approved test) 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; Renal cell carcinoma, advanced, first-line single-agent therapy
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). 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)
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 Sjogren syndrome-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, Sjorgren syndrome) 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 Sjogren syndrome-like symptoms is 70 days (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). 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)
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 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)
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
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 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).
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), Vogt-Koyanagi-Harada disease (Ref), and vision loss (Ref).
Onset: Varied; median onset of 5 weeks (range: 1 to 72 weeks) (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). 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; ranging from 2 to 24 months with a 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)
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)
|
Drug (Pembrolizumab) |
Comparator |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
30% |
N/A |
15% |
200 mg every 3 weeks |
Adjuvant treatment of renal cell carcinoma |
488 |
N/A |
496 |
|
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%), 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 21%) (table 4), weight loss (10% to 15%)
|
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 |
|
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 |
Gastrointestinal: Abdominal pain (11% to 22%) (table 5), constipation (12% to 22%), decreased appetite (15% to 25%), diarrhea (12% to 28%) (table 6), nausea (11% to 22%), vomiting (infants, children, adolescents: 30%; adults: 11% to 19%)
|
Drug (Pembrolizumab) |
Comparator |
Placebo |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
11% |
N/A |
13% |
200 mg every 3 weeks |
Adjuvant treatment of renal cell carcinoma |
488 |
N/A |
496 |
|
22% |
N/A |
N/A |
200 mg every 3 weeks |
Cervical cancer |
98 |
N/A |
N/A |
|
13% |
8% (Chemotherapy) |
N/A |
2 mg/kg or 10 mg/kg every 3 weeks |
Ipilimumab-refractory melanoma |
357 |
171 |
N/A |
|
13% |
13% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously treated urothelial carcinoma |
266 |
255 |
N/A |
|
11% |
13% (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) |
|---|---|---|---|---|---|---|---|
|
27% |
N/A |
23% |
200 mg every 3 weeks |
Adjuvant treatment of renal cell carcinoma |
488 |
N/A |
496 |
|
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: 0.5% to 24%) (table 7), hemorrhage (19%; grades 3/4: 5%; major hemorrhage: 4%), increased INR (19% to 27%; grade 3/4: ≤2%), leukopenia (30% to 35%; grades 3/4: 9%), lymphocytopenia (24% to 54%; grades 3/4: 2% 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)
|
Drug (Pembrolizumab) |
Comparator |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|---|
|
Grade 3: 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 |
161 |
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: 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 |
|
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 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 |
Population |
Dose |
Indication |
Number of Patients (Pembrolizumab) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|
|
All grades: 26% |
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 |
161 |
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 |
|
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 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)
|
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) |
|---|---|---|---|---|---|---|---|
|
20% |
N/A |
11% |
200 mg every 3 weeks |
Adjuvant treatment of renal cell carcinoma |
488 |
N/A |
496 |
|
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 cancer |
682 |
309 |
N/A |
|
33% |
34% (Chemotherapy) |
N/A |
200 mg every 3 weeks |
Previously untreated non–small-cell 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-Guérin-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 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 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 (infants, children, adolescents: 25%; adults: 11% to 15%), pain (22%), peripheral neuropathy (1% to 11%; grade 3/4: <1%) (table 14)
|
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 41%), myalgia (12%)
Renal: Acute kidney injury (2% to 13%), increased serum creatinine (11% to 40%) (table 15)
|
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 |
|
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%), facial edema (10%), 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)
|
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%)
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: 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, Guillain-Barre syndrome, meningitis, myasthenia (myasthenic syndrome) (Fang 2019), 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, 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), 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), sclerosing cholangitis (Matsumoto 2020, Ooi 2020), xerostomia (SITC [Brahmer 2021])
Hematologic & oncologic: Disseminated intravascular coagulation (Alberti 2020), pancytopenia (Atwal 2017), pure red cell aplasia (SITC [Brahmer 2021]; Meri-Abad 2021)
Hypersensitivity: Cytokine release syndrome (Sackstein 2021), drug reaction with eosinophilia and systemic symptoms (Lamiaux 2018)
Immunologic: Dermatomyositis (Takatsuki 2021), Sjögren syndrome (SITC [Brahmer 2021])
Infection: Cytomegalovirus disease (Kim 2020)
Nervous system: Aseptic meningitis (Lima 2019), cerebral hemorrhage (Yamazaki 2017), chronic inflammatory demyelinating polyneuropathy (Maleissye 2016), retrobulbar neuritis (optic) (Kawakado 2021), reversible posterior leukoencephalopathy syndrome (LaPorte 2017)
Neuromuscular & skeletal: Subacute cutaneous lupus erythematosus (Blakeway 2019)
Ophthalmic: Dry eye syndrome (SITC [Brahmer 2021]), maculopathy (acute exudative polymorphous vitelliform maculopathy [AEPVM]) (Lambert 2021), Vogt-Koyanagi-Harada disease (Tamura 2018), vision loss (Telfah 2019)
Renal: Focal segmental glomerulosclerosis (Kim 2021), glomerulonephritis (necrotizing) (Uner 2021), interstitial nephritis (Peláez Bejarano 2021)
Respiratory: Reactivated tuberculosis (ileitis) (Lau 2021)
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.
• 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 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: Some indications are based on PD-L1 expression, or are based on tumor specimen microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR), mispatch 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. 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).
None known.
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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetaminophen: May diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy
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 (where applicable); tumor specimen microsatellite instability-high (MSI-H) status, mismatch repair deficient (dMMR) status, mismatch repair proficient status, and/or tumor mutational burden-high (TMB-H) status (where applicable).
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.
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).
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): $1,602.53
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