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  • CLASSES

    Monoclonal Antibodies that Target the Programmed Death-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Pathways

    DEA CLASS

    Rx

    DESCRIPTION

    Programmed death receptor-1 (PD-1) blocking human monoclonal antibody
    Used for certain types of lymphoma, skin cancer, solid tumors, and tumors with genomic instability or a high mutational burden
    Serious immune-mediated adverse reactions (e.g., pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism/hyperthyroidism) have been reported

    COMMON BRAND NAMES

    Keytruda

    HOW SUPPLIED

    Keytruda Intravenous Inj Pwd F/Sol: 50mg
    Keytruda Intravenous Inj Sol: 1mL, 25mg

    DOSAGE & INDICATIONS

    For the treatment of malignant melanoma.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for the treatment of stage IIB-IV melanoma.
    For the treatment of unresectable or metastatic melanoma in patients with ipilimumab refractory disease.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. The primary endpoint of median progression-free survival (PFS), evaluated by independent central review, was significantly improved with pembrolizumab 2 mg/kg IV (n = 180) every 3 weeks (2.9 months) and pembrolizumab 10 mg/kg IV (n = 181) every 3 weeks (2.9 months) compared with investigator-choice chemotherapy (ICC) (n = 179; 2.7 months) in patients with unresectable stage III or IV melanoma who had disease progression following ipilimumab and had received prior treatment with a BRAF- and/or MEK-inhibitor (if BRAF V600 mutant-positive) in a second interim analysis of a multinational, randomized, phase 2 trial (the KEYNOTE-002 trial). ICC consisted of carboplatin/paclitaxel (n = 42) or single-agent carboplatin (n = 13), paclitaxel (n = 28), dacarbazine (n = 45), or temozolomide (n = 43). Ipilimumab-refractory melanoma was defined as progression within 24 weeks after at least 2 doses of ipilimumab. At a median follow-up time of 10 months, the 6-month PFS rates were 34% and 38% in the pembrolizumab 2 mg/kg and 10 mg/kg arms, respectively, compared with 16% in the ICC arm; additionally, the 9-month PFS rates were 24% and 29% compared with 8%, respectively. Treatment crossover to pembrolizumab occurred in 48% of patients who received ICC. Overall survival (OS) data are not yet mature.

    For the treatment of unresectable or metastatic melanoma in patients who had not received prior ipilimumab therapy.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions.

    For the adjuvant treatment of melanoma following complete resection in patients with lymph node involvement.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease recurrence or for up to 12 months in patients without disease recurrence. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions.[57889]

    For the treatment of non-small cell lung cancer (NSCLC).
    For the first-line treatment of patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 (Tumor Proportion Score (TPS) 1% or higher) and are EGFR- and ALK-negative, as monotherapy.
    NOTE: For monotherapy with pembrolizumab, select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in NSCLC is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, open-label clinical trial (KEYNOTE-042; n = 1,274), treatment of PD-L1 positive (1% or more), EGFR and ALK-negative, stage III NSCLC in patients who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC with pembrolizumab significantly improved median overall survival compared with investigator's choice of platinum-based chemotherapy (16.7 vs. 12.1 months); survival was higher in patients with TPS of 50% or more (20 months). Progression-free survival (PFS) was not significantly improved in patients with TPS of 1% or more (5.4 months vs. 6.5 months) or 50% or more (7.1 vs. 6.4 months). In patients with TPS 1% or more, the objective response rate was 27% in each arm; however, more prolonged responses were seen in patients who received pembrolizumab. A response of 12 months or longer was seen in 47% of responding patients treated with pembrolizumab compared with 16% of those who received chemotherapy; a response duration of 18 months or more was seen in 26% versus 6% of patients, respectively. Another clinical trial with a similar design to KEYNOTE-042 but only enrolling patients with TPS of 50% or more (KEYNOTE-024) was stopped early by an independent data and safety monitoring committee after demonstrating superiority of pembrolizumab compared with platinum-based chemotherapy with regard to PFS (10.3 vs. 6 months), despite a large percentage of patients (66%) in the chemotherapy arm crossing over to receive second-line therapy with pembrolizumab.[61268] [57889] After 5 years of follow-up, treatment with pembrolizumab significantly improved median overall survival (OS) in KEYNOTE-024 compared with platinum-based chemotherapy (26.3 months vs. 13.4 months); the estimated 5-year OS rate was 31.9% versus 16.3%, respectively.

    For the treatment of PD-L1-expressing (TPS 1% or higher), metastatic NSCLC with disease progression on or after platinum-containing chemotherapy, and after progression on EGFR- or ALK-targeted therapy if applicable, as monotherapy.
    NOTE: For monotherapy with pembrolizumab, select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in NSCLC is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, randomized, open-label clinical trial, treatment with pembrolizumab (n = 346) improved overall survival (OS) and progression-free survival (PFS) compared with docetaxel (n = 343) in patients with PD-L1-expressing (TPS, 1% or greater), platinum-resistant, metastatic NSCLC. In the subgroup of patients with TPS greater than or equal to 1%, OS in patients treated with pembrolizumab was 10.4 months compared with 8.5 months in those who received docetaxel and the objective response rate (ORR) was 18% versus 9%, respectively; PFS was not significantly different. Results were stronger in patients with TPS greater than or equal to 50%, with median OS of 14.9 months in the pembrolizumab arm versus 8.2 months in the docetaxel arm, and ORR 30% compared with 8%, respectively; the improvement in PFS was small but statistically significant in this subgroup (5.2 months vs. 4.1 months).

    For the first-line treatment of metastatic, EGFR- and ALK-negative, nonsquamous NSCLC, in combination with pemetrexed and platinum chemotherapy.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression in combination with pemetrexed (500 mg/m2 IV) on day 1 plus either carboplatin (AUC 5 IV) or cisplatin (75 mg/m2 IV) on day 1 repeated every 21 days for 4 cycles. Administer pembrolizumab prior to pemetrexed and chemotherapy when given on the same day. After the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Following completion of platinum-based therapy, pembrolizumab may be continued as maintenance therapy for up to 24 months, either alone or in combination with pemetrexed, until disease progression or unacceptable toxicity. In a multicenter double-blind clinical trial (KEYNOTE-189), patients with previously untreated metastatic, EGFR- and ALK-negative, nonsquamous NSCLC, regardless of PD-L1 status, were randomized to treatment with pemetrexed plus either cisplatin or carboplatin, in combination with either pembrolizumab (n = 410) or placebo (n = 206). After a median follow-up of 31 months, the median overall survival (22 months vs. 10.6 months), progression-free survival (9 months vs. 4.9 months), and overall response rate (48.3% vs. 19.9%) were significantly improved in the pembrolizumab arm. The median duration of response was 12.5 months for patients who received pembrolizumab plus pemetrexed/platinum chemotherapy compared with 7.1 months in those receiving placebo plus pemetrexed/platinum chemotherapy.

    For the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC), in combination with carboplatin and either paclitaxel or nab-paclitaxel.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression in combination with carboplatin (AUC 6 IV on day 1) plus either paclitaxel (200 mg/m2 IV on day 1) or nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) repeated every 3 weeks for 4 cycles. Administer pembrolizumab prior to chemotherapy when given on the same day. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, randomized, double-blind clinical trial (KEYNOTE-407), treatment with pembrolizumab plus carboplatin and either paclitaxel or nab-paclitaxel (n = 278) significantly improved median overall survival (17.1 months vs. 11.6 months) and progression-free survival (6.4 months vs. 4.8 months) compared with placebo plus carboplatin and paclitaxel/nab-paclitaxel (n = 281) in patients with metastatic squamous NSCLC. The objective response rate was also significantly improved in the pembrolizumab arm (58% vs. 35%), for a median duration of 7.2 months and 4.9 months, respectively.[57889]

    For the treatment of Merkel cell carcinoma.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for the treatment of Merkel cell carcinoma.
    For the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions.[57889] In a nonrandomized phase 2 study, treatment with pembrolizumab (median duration of treatment, 27 weeks; range, 3 to 57 weeks) resulted in an objective response rate (ORR) of 56% in 25 evaluable patients with stage IIIB or IV Merkel cell carcinoma who progressed following standard treatment and had not previously received systemic therapy. At a median follow-up time of 33 weeks (range, 7 to 53 weeks), the median progression-free survival time was 9 months and the 6-month PFS rate was 67%. Tumor cell PD-L1 expression did not correlate with clinical response.[60891] The ORR was 56% in 50 patients (median age, 71 years; range, 46 to 91 years) enrolled in the previous study; the complete response rate was 24%. The median duration of response had not yet been reached (range, 5.9 to greater than 34.5 months).[57889]

    Adolescents, Children, and Infants 6 months and older

    2 mg/kg (not to exceed 200 mg) IV repeated every 3 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult Merkel cell carcinoma patients.[57889]

    For the treatment of head and neck cancer.
    For the treatment of recurrent or metastatic head and neck cancer (squamous cell) with disease progression on or after platinum-containing chemotherapy, as monotherapy.
    NOTE: For monotherapy with pembrolizumab, select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in head and neck cancer is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. After a median follow-up of 8.9 months, treatment with pembrolizumab resulted in an objective response rate (ORR) of 16% (95% CI, 11% to 22%), with a complete response rate of 5% in a multicenter, non-randomized, open-label clinical trial of patients with platinum-resistant, recurrent or metastatic head and neck squamous cell carcinoma (n = 174). The median duration of response was not reached, but ranged from 2.4 months to more than 27.7 months; 23 of 28 responses lasted 6 months or longer. The ORR and duration of response were similar regardless of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.[57889]

    For the first-line treatment of metastatic or unresectable, recurrent head and neck cancer (squamous cell), in combination with carboplatin and fluorouracil.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression in combination with carboplatin (AUC 5 IV on day 1) and fluorouracil (1,000 mg/m2 per day continuous IV infusion on days 1 to 4) repeated every 3 weeks for 6 cycles. Administer pembrolizumab prior to chemotherapy when given on the same day. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue pembrolizumab for severe or life-threatening infusion-related reactions. Treatment with pembrolizumab plus fluorouracil and either carboplatin or cisplatin significantly improved median overall survival  (13 months vs. 10.7 months) compared with cetuximab plus fluorouracil and carboplatin/cisplatin in patients with previously untreated metastatic or unresectable, recurrent squamous cell head and neck cancer in a randomized, open-label trial (KEYNOTE-048); hazard ratios were similar in the intent-to-treat population (0.72), in patients with PD-L1 CPS of 1 or more (0.65), and in patients with CPS of 20 or more (0.6). Progression-free survival (PFS) was not significantly different between arms (4.9 months vs. 5.1 months). The objective response rate was 36% in each arm for a median duration of 6.7 months in the pembrolizumab arm and 4.3 months in the cetuximab arm; there were more complete responses in patients who received pembrolizumab (6% vs. 3%), respectively.

    For the first-line treatment of metastatic or unresectable, recurrent head and neck cancer (squamous cell), in combination with cisplatin and fluorouracil.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression in combination with cisplatin (100 mg/m2 IV on day 1) and fluorouracil (1,000 mg/m2 per day continuous IV infusion on days 1 to 4) repeated every 3 weeks for 6 cycles. Administer pembrolizumab prior to chemotherapy when given on the same day. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue pembrolizumab for severe or life-threatening infusion-related reactions. Treatment with pembrolizumab plus fluorouracil and either carboplatin or cisplatin significantly improved median overall survival  (13 months vs. 10.7 months) compared with cetuximab plus fluorouracil and carboplatin/cisplatin in patients with previously untreated metastatic or unresectable, recurrent squamous cell head and neck cancer in a randomized, open-label trial (KEYNOTE-048); hazard ratios were similar in the intent-to-treat population (0.72), in patients with PD-L1 CPS of 1 or more (0.65), and in patients with CPS of 20 or more (0.6). Progression-free survival (PFS) was not significantly different between arms (4.9 months vs. 5.1 months). The objective response rate was 36% in each arm for a median duration of 6.7 months in the pembrolizumab arm and 4.3 months in the cetuximab arm; there were more complete responses in patients who received pembrolizumab (6% vs. 3%), respectively.

    For the first-line treatment of metastatic or unresectable, recurrent head and neck cancer (squamous cell) in patients whose tumors express PD-L1 (combined positive score (CPS), 1 or more), as monotherapy.
    NOTE: For monotherapy with pembrolizumab, select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in head and neck cancer is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with pembrolizumab monotherapy significantly improved median overall survival (12.3 months vs. 10.3 months) in patients with metastatic or unresectable, recurrent squamous cell head and neck cancer and CPS of 1 or more compared with cetuximab plus fluorouracil and carboplatin/cisplatin in a randomized, open-label clinical trial (KEYNOTE-048); in patients with CPS of 20 or more, median overall survival was 14.9 months versus 10.7 months, respectively. At the time of the interim and final analyses, there was no significant difference in OS for the overall population. Median progression-free survival (PFS) was not significantly different between treatment arms (3.2 months vs. 5 months). The objective response rate was 19% in patients who received pembrolizumab compared with 35% in the cetuximab arm, for a median duration of 20.9 months versus 4.5 months, respectively; complete responses occurred in 5% and 3% of patients, respectively.[57889]

    For the treatment of Hodgkin lymphoma.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for the treatment of Hodgkin lymphoma.
    For the treatment of classical Hodgkin lymphoma that has relapsed or progressed after an autologous stem-cell transplant and post-transplant brentuximab vedotin†.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks for up to 24 months was evaluated in a phase 2 trial (KEYNOTE-087 trial). Alternatively, pembrolizumab 400 mg IV every 6 weeks until disease progression or up to 24 months in patients without progression may be used. There does not appear to be any clinically significant differences in efficacy and safety between pembrolizumab dosages of 200 mg IV every 3 weeks or 400 mg IV every 6 weeks based on pharmacokinetic data and model-based simulations. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions.

    For the treatment of classical Hodgkin lymphoma (cHL) in pediatric patients with refractory disease or who have relapsed after 2 or more prior lines of therapy.
    Intravenous dosage
    Adolescents, Children, and Infants 6 months and older

    2 mg/kg (not to exceed 200 mg) IV repeated every 3 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult classical Hodgkin lymphoma patients. Treatment with pembrolizumab significantly improved median progression-free survival compared with brentuximab vedotin in patients with relapsed or refractory cHL in a randomized, open-label clinical trial (KEYNOTE-204) (13.2 months vs. 8.3 months). The objective response rate (ORR) in patients treated with pembrolizumab was 66% (complete response [CR], 25%) for a median duration of 20.7 months. Patients in this study received a median of 2 prior therapies; 42% were refractory to the last prior therapy, 29% previously received an autologous stem-cell transplant (auto-SCT), 5% received prior brentuximab therapy, and 39% received prior radiation therapy. In a multicenter, nonrandomized trial (KEYNOTE-087), treatment with pembrolizumab resulted in an ORR of 69% (CR, 22%) for a median duration of 11.1 months in patients with relapsed or refractory cHL. Patients in this study received a median of 4 prior therapies; 61% had previously received an auto-SCT, 83% received prior brentuximab therapy, and 36% received prior radiation therapy.

    For the treatment of relapsed or refractory classical Hodgkin lymphoma (cHL).
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with pembrolizumab significantly improved median progression-free survival compared with brentuximab vedotin in patients with relapsed or refractory cHL in a randomized, open-label clinical trial (KEYNOTE-204) (13.2 months vs. 8.3 months). The objective response rate (ORR) in patients treated with pembrolizumab was 66% (complete response [CR], 25%) for a median duration of 20.7 months. Patients in this study received a median of 2 prior therapies; 42% were refractory to the last prior therapy, 29% previously received an autologous stem-cell transplant (auto-SCT), 5% received prior brentuximab therapy, and 39% received prior radiation therapy. In a multicenter, nonrandomized trial (KEYNOTE-087), treatment with pembrolizumab resulted in an ORR of 69% (CR, 22%) for a median duration of 11.1 months in patients with relapsed or refractory cHL. Patients in this study received a median of 4 prior therapies; 61% had previously received an auto-SCT, 83% received prior brentuximab therapy, and 36% received prior radiation therapy.

    For the treatment of urothelial carcinoma.
    For the treatment of locally advanced or metastatic urothelial carcinoma in patients who progress during or following platinum-containing chemotherapy, as monotherapy.
    NOTE: Select patients with metastatic urothlial carcimona for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in urothelial carcinoma is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, randomized clinical trial (KEYNOTE-045), treatment with pembrolizumab significantly improved median overall survival (10.3 vs. 7.4 months) and objective response rates (21% vs. 11%; complete response, 7% vs. 3%; partial response, 14% vs. 8%) for patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy treated with pembrolizumab (n = 270) compared with investigator's choice of chemotherapy (paclitaxel, n = 84; docetaxel, n = 84; vinflunine, n = 87); the median duration of response was not reached in the pembrolizumab arm, compared with 4.3 months in the chemotherapy arm. There was no significant difference in progression-free survival between treatment arms.

    For the treatment of locally advanced or metastatic urothelial carcinoma in patients who progress within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy, as monotherapy.
    NOTE: Select patients with metastatic urothlial carcimona for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in urothelial carcinoma is available at: www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, randomized clinical trial (KEYNOTE-045), treatment with pembrolizumab significantly improved median overall survival (10.3 vs. 7.4 months) and objective response rates (21% vs. 11%; complete response, 7% vs. 3%; partial response, 14% vs. 8%) for patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy treated with pembrolizumab (n = 270) compared with investigator's choice of chemotherapy (paclitaxel, n = 84; docetaxel, n = 84; vinflunine, n = 87); the median duration of response was not reached in the pembrolizumab arm, compared with 4.3 months in the chemotherapy arm. There was no significant difference in progression-free survival between treatment arms. Fifteen percent of patients in this trial had disease progression following platinum-based neoadjuvant or adjuvant chemotherapy.

    For the treatment of locally advanced or metastatic urothelial carcinoma in patients who are ineligible for platinum-containing chemotherapy, as monotherapy.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, open-label, single-arm clinical trial (n = 370; KEYNOTE-052), treatment with pembrolizumab resulted in an objective response rate of 29% (95% CI, 24% to 34%), with 10% complete responses and 20% partial responses, in patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. The median duration of response was 30.1 months, with 67% of responses lasting 12 months and 52% lasting 24 months. The median overall survival was 11.3 months. In a multicenter, randomized trial, previously untreated patients with metastatic urothelial carcinoma who were eligible for platinum-containing chemotherapy (KEYNOTE-361) were randomized to treatment with pembrolizumab monotherapy, pembrolizumab with platinum-based chemotherapy to platinum-based chemotherapy alone. This study did not meet its major efficacy measures of improved progression-free survival or overall survival in the pembrolizumab plus chemotherapy arm. In an exploratory analysis, overall survival was similar in patients receiving pembrolizumab monotherapy versus chemotherapy in both the total population (15.6 months vs. 14.3 months) and in patients with CPS of 10% or higher (16.1 months vs. 15.2 months). The monotherapy arm of this trial was closed to accrual for patients with low PD-L1 expression (CPS less than 10%) upon the recommendation of the independent Data Monitoring Committee based on concerning survival data for PD-L1 inhibitor monotherapy in this trial and the IMvigor130 trial.

    For the treatment of unresectable or metastatic microsatellite instability-high solid tumors or mismatch repair deficient solid tumors.
    NOTE: Select patients for treatment based on MSI-H/dMMR status in tumor specimens. Because the effect of prior chemotherapy on test results for 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 initiation of temozolomide chemotherapy in patients with high-grade gliomas. An FDA-approved test for the detection of MSI-H or dMMR is not currently available.
    For the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In pooled data from 5 multicenter, uncontrolled, open-label, multicohort, single-arm trials (KEYNOTE-016, KEYNOTE-164, KEYNOTE-028, KEYNOTE-012, and KEYNOTE-158), patients with MSI-H or dMMR solid tumors treated with pembrolizumab (10 mg/kg every 2 weeks or 200 mg every 3 weeks; n = 149) had an objective response rate of 39.6% (complete response, 7.4%; partial response, 32.2%) with a median duration of response not reached (range, 1.6+ to 22.7+ months); 78% of patients had a duration of response greater than or equal to 6 months.

    Adolescents and Children 2 years and older

    2 mg/kg (not to exceed 200 mg) IV repeated every 3 weeks until disease progression or up to 24 months in patients without progression; the safety and efficacy of pembrolizumab in pediatric patients with MSI-H central nervous system cancers have not been established. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult MSI-H patients. In pooled data from 5 multicenter, uncontrolled, open-label, multicohort, single-arm trials (KEYNOTE-016, KEYNOTE-164, KEYNOTE-028, KEYNOTE-012, and KEYNOTE-158), adult patients with MSI-H or dMMR solid tumors treated with pembrolizumab (10 mg/kg every 2 weeks or 200 mg every 3 weeks; n = 149) had an objective response rate of 39.6% (complete response, 7.4%; partial response, 32.2%) with a median duration of response not reached (range, 1.6+ to 22.7+ months); 78% of patients had a duration of response greater than or equal to 6 months.

    For the treatment of gastric cancer.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for the treatment of gastric cancer, including gastroesophageal junction adenocarcinoma
    For the treatment of recurrent, PD-L1 positive (combined positive score [CPS] 1 or higher), locally advanced or metastatic gastric cancer, including gastroesophageal junction adenocarcinoma (GEJ), with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy, as monotherapy.
    NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining a tumor biopsy for PD-L1 testing. Information on FDA-approved tests for the detection of PD-L1 expression in gastric cancer is available at: www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, open-label multicohort trial of patients with gastric or GEJ adenocarcinoma who progressed on at least 2 prior systemic treatments for advanced disease, the objective response rate of patients treated with pembrolizumab was 13.3% (95% CI, 8.2% to 20%); 1.4% had a complete response (CR) and 11.9% had a partial response (PR). For responding patients, the duration of response ranged from 2.8 to 19.4+ months; 58% of responding patients had a duration of response of at least 6 months and 26% had responses of 12 months or longer. Four (4) of 7 patients with microsatellite instability-high (MSI-H) tumors had objective responses, including one CR; the duration of response in these patients ranged from 5.3 months to 14.1+ months.[57889]

    For the first-line treatment of HER2-negative, PD-L1 positive (combined positive score [CPS], 1 or higher) advanced gastric cancer†.
    Intravenous dosage
    Adults

    200 mg IV every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a randomized, controlled, phase 3 trial (the KEYNOTE-062 trial), first-line treatment of HER2-negative, PD-L1 positive, locally advanced/unresectable or metastatic gastric or GEJ cancer with pembrolizumab monotherapy was noninferior to cisplatin plus fluoropyrimidine chemotherapy for overall survival; the effect on overall survival was greater in patients with PD-L1 CPS of 10 or higher although due to protocol design, this outcome was not statistically analyzed. Patients receiving pembrolizumab monotherapy also experienced fewer treatment-related adverse reactions.

    For the first-line treatment of HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with trastuzumab, cisplatin, and fluorouracil.
    Intravenous dosage
    Adults

    200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression. Administer in combination with trastuzumab (8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles) followed by cisplatin (80 mg/m2 IV every 3 weeks for up to 6 cycles) and fluorouracil (800 mg/m2 per day by continuous IV infusion on days 1 to 5 every 3 weeks). In the clinical trial, treatment with fluorouracil could continue after completion of 6 cycles of cisplatin, per protocol. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis of a multicenter, randomized phase 3 trial (KEYNOTE-811). The median duration of response was 10.6 months in the pembrolizumab arm compared with 9.5 months in the placebo arm; 65% versus 53% of patients, respectively, had a duration of response of at least 6 months.

    For the first-line treatment of HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with trastuzumab, oxaliplatin, and capecitabine (XELOX; CapeOx).
    Intravenous dosage
    Adults

    200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression. Administer in combination with trastuzumab (8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles) followed by oxaliplatin (130 mg/m2 IV every 3 weeks for up to 6 to 8 cycles) and capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14 every 3 weeks). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis of a multicenter, randomized phase 3 trial (KEYNOTE-811). The median duration of response was 10.6 months in the pembrolizumab arm compared with 9.5 months in the placebo arm; 65% versus 53% of patients, respectively, had a duration of response of at least 6 months. 

    For the treatment of non-Hodgkin's lymphoma (NHL).
    For the treatment of refractory primary mediastinal large B-cell lymphoma (PMBCL) in patients who have relapsed after 2 or more prior lines of therapy.
    NOTE: Pembrolizumab is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for the treatment of PMBCL.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. The overall response rate was 45% in patients with relapsed or refractory PMBCL who received pembrolizumab in a multicenter, nonrandomized trial (n = 53; KEYNOTE-170). Additionally, a complete response was achieved in 11% of patients. At a median follow-up time of 9.7 months, the median duration of response was not reached (range, 1.1 to 19.2+ months). Patients (median age, 33 years; range, 20 to 61 years) in this study had received a median of 3 prior therapies (range, 2 to 8 therapies); 26% of patients had previously received an autologous stem-cell transplant and 32% of patients had received prior radiation therapy.

    Adolescents, Children, and Infants 6 months and older

    2 mg/kg (not to exceed 200 mg) IV repeated every 3 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult PMBCL patients.

    For the treatment of cervical cancer.
    For the treatment of recurrent or metastatic PD-L1-expressing (combined positive score [CPS] 1 or higher) cervical cancer in patients who had disease progression on or after chemotherapy, as monotherapy.
    NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in cervical cancer is available at: www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. The overall response rate was 14.3% in a cohort of 77 patients with recurrent or metastatic PD-L1-expressing cervical cancer who received pembrolizumab in a multi-cohort, nonrandomized trial (KEYNOTE-158). Additionally, a complete response was achieved in 2.6% of patients. At a median follow-up time of 11.7 months, the median duration of response was not reached (range, 4.1 to 18.6+ months); 91% of patients had a response duration lasting 6 months or longer. Patients (median age, 45 years; range, 27 to 75 years) in this study had received 1 (35%) or 2 (65%) lines of prior therapy.

    For the treatment of persistent, recurrent, or metastatic PD-L1-expressing (CPS 1 or higher) cervical cancer, in combination with chemotherapy with or without bevacizumab.
    NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in cervical cancer is available at: www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Use in combination with chemotherapy (paclitaxel 175 mg/m2 IV once on day 1 plus either cisplatin 50 mg/m2 IV once on day 1 or 2 OR carboplatin AUC of 5 IV once on day 1) with or without bevacizumab (15 mg/kg IV once on day 1). Repeat treatment cycles every 3 weeks. Administer pembrolizumab prior to chemotherapy when given on the same day. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. At a median follow-up of 22 (range, 15.1 to 29.4) months, the median progression-free survival (PFS) time was significantly improved in patients with persistent, recurrent, or metastatic cervical cancer who received pembrolizumab plus chemotherapy compared with placebo plus chemotherapy (10.4 months vs. 8.2 months; hazard ratio (HR) = 0.65; 95% CI, 0.53 to 0.79) in the first interim analysis of a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (KEYNOTE-826; intention-to-treat (ITT) population, n = 617). Bevacizumab was added to treatment in 63% of patients in this trial. PFS was also significantly improved with the addition of pembrolizumab therapy (HR = 0.62; 95% CI, 0.5 to 0.77) in a subgroup of patients who had a PD-L1 combined positive score (CPS) of 1 or higher (n = 548). The median overall survival time was significantly longer in the ITT population (24.4 months; HR = 0.67; 95% CI, 0.54 to 0.84) and the PD-L1 CPS of 1 or higher subgroup (median not reached; HR = 0.64; 95% CI, 0.5 to 0.81) treated with pembrolizumab plus chemotherapy compared with placebo plus chemotherapy (16.3 to 16.5 months). Patients (median age, 50 years; range, 22 to 82 years) in this study had adenocarcinoma, adenosquamous carcinoma, or squamous-cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment. At study entry, 56.4% of patients had received previous chemoradiotherapy with or without surgery and 19% of patients had previously untreated metastatic disease.

    For the treatment of hepatocellular cancer.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for this indication.
    For the treatment of hepatocellular cancer in patients who have been previously treated with sorafenib.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a single-arm, multicenter trial in patients with hepatocellular cancer (HCC) who had disease progression on or after sorafenib, or were intolerant to sorafenib (n = 104), treatment with pembrolizumab resulted in an objective response rate of 17% (95% CI, 11% to 25%); a complete response was achieved in 1% of patients. The duration of response, as assessed by a blinded independent review, was 6 months or longer in 89% of patients and 12 months or longer in 56% of patients.

    For the treatment of renal cell cancer (RCC).
    For the first-line treatment of advanced RCC, in combination with axitinib.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression in combination with axitinib (initial dose, 5 mg PO twice daily). The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily at intervals of 6 weeks or longer in normotensive patients (BP less than or equal to 150/90) who tolerate the lower dosage for at least 2 consecutive weeks with no greater than grade 2 adverse reactions. Continue axitinib until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions. In the first interim analysis of an open-label phase 3 clinical trial (KEYNOTE-426), combination therapy with pembrolizumab and axitinib significantly improved overall survival and progression-free survival in patients with advanced renal cell cancer compared with sunitinib; the benefit may be greatest in poor or intermediate IMDC risk group patients with PD-L1 expression of 1% or more. In an exploratory analysis with extended follow-up (median, 30.6 months), patients treated with pembrolizumab and axitinib continued to have significantly improved overall survival compared with sunitinib (not reached vs. 35.7 months).

    For the first-line treatment of advanced RCC, in combination with lenvatinib.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks in combination with lenvatinib (20 mg orally once daily), continue treatment until disease progression or for up to 24 months in patients without progression. After 2 year of combination therapy, lenvatinib may be continued as a single agent until disease progression or unacceptable toxicity. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions.  The primary outcome of investigator-assessed median progression-free survival time was significantly improved with lenvatinib plus pembrolizumab compared with sunitinib (23.9 months vs. 9.2 months; hazard ratio (HR) = 0.39; 95% CI, 0.32 to 0.49; p less than 0.001) in patients with previously untreated advanced RCC with a clear-cell component in a 3-arm, randomized (1:1:1), phase 3 trial (the CLEAR/KEYNOTE-581 trial; n = 1,069). At a median follow-up time of 26.6 month, the overall survival time was significantly longer in the lenvatinib plus pembrolizumab arm compared with the sunitinib arm (median time not reached in either arm; HR = 0.66; 95% CI, 0.49 to 0.88; P = 0.005).

    For the treatment of small cell lung cancer (SCLC)†.
    For the treatment of metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy†.
    NOTE: FDA approval was removed for this indication in March 2021 after initial accelerated approval due to failure to significantly improve overall survival in patients with extensive-stage SCLC in a confirmatory phase 3 clinical trial (KEYNOTE-604).
    Intravenous dosage
    Adults

    Dosage not established.

    For the treatment of esophageal cancer.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for the treatment of esophageal cancer.
    For the treatment of PD-L1 positive (CPS 10 or higher), locally advanced or metastatic esophageal cancer, including gastroesophageal junction carcinoma (GEJ), with an epicenter located 1 to 5 cm above the GEJ and squamous cell histology, not amenable to surgical resection or definitive chemoradiation, with disease progression after 1 or more prior lines of systemic therapy, as monotherapy.
    NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in previously treated, recurrent, locally advanced or metastatic esophageal cancer is available at: www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with pembrolizumab significantly improved the median overall survival (OS) (9.3 months vs. 6.7 months) and progression-free survival (3.2 months vs. 2.3 months) compared with investigators' choice of chemotherapy (i.e., paclitaxel, docetaxel, or irinotecan monotherapy) in patients with recurrent, progressive, PD-L1 positive (CPS 10 or higher), locally advanced or metastatic esophageal or GEJ cancer in a randomized clinical trial (KEYNOTE-181); the estimated 12-month survival was 43% versus 20%, respectively; median OS was 8.2 versus 7.1 months, respectively, in patients with squamous cell carcinoma, and was unchanged (7.1 months) in all patients. The objective response rate was 21.5% in the pembrolizumab arm compared with 6.1% in the chemotherapy arm (complete response, 3.7% vs. 0.9%); the median duration of response was 9.3 months versus 7.7 months, respectively.

    For the treatment of locally advanced or metastatic esophageal cancer, including gastroesophageal junction carcinoma (GEJ), with an epicenter located 1 to 5 cm above the GEJ, not amenable to surgical resection or definitive chemoradiation, in combination with cisplatin and fluorouracil.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Administer pembrolizumab prior to chemotherapy when given on the same day. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Administer in combination with cisplatin (80 mg/m2 IV on day 1 every 3 weeks for up to 6 cycles) and fluorouracil (800 mg/m2 IV per day continuously on days 1 to 5, every 3 weeks for up to 24 months). In a randomized clinical trial (KEYNOTE-590), treatment with pembrolizumab plus cisplatin and fluorouracil significantly improved median overall survival (12.4 months vs. 9.8 months) and median progression-free survival (6.3 months vs. 5.8 months) compared with placebo plus cisplatin and fluorouracil in patients with locally advanced or metastatic esophageal/GEJ tumors who were not candidates for surgical resection or definitive chemoradiation. In a prespecified formal test in patients with PD-L1 CPS of 10 or higher, the median overall survival was 13.5 months in pembrolizumab-treated patients compared with 9.4 months for those who received placebo; in an exploratory analysis, the median overall survival was 10.5 months versus 10.6 months, respectively, for patients with PD-L1 CPS less than 10. The overall response rate was also significantly improved in intent-to-treat patients who received pembrolizumab (45% for a median duration of 8.3 months; complete response [CR], 6%) compared with placebo (29% for a median duration of 6 months; CR, 2.4%).

    For the treatment of endometrial cancer.
    For the treatment of advanced endometrial cancer that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) in patients who are not candidates for curative surgery or radiation, with disease progression following prior systemic therapy in any setting, in combination with lenvatinib.
    NOTE: Select patients for treatment based on MSI or MMR status in tumor specimens.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or for up to 24 months in patients without disease progression in combination with lenvatinib (20 mg PO once daily until disease progression). Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with pembrolizumab plus lenvatinib significantly improved the median progression-free survival (6.6 months vs. 3.8 months) and overall survival (17.4 months vs. 12 months) compared with doxorubicin or paclitaxel in patients with advanced endometrial cancer who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting and were not MSI-H or dMMR in a multicenter, randomized, open-label clinical trial (KEYNOTE-775). The objective response rate was also significantly improved in the pembrolizumab/lenvatinib arm (30% vs. 15%; complete response, 5% vs. 3%) for a median duration of 9.2 months versus 5.7 months, respectively.

    For the treatment of bladder cancer.
    For the treatment of Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ, with or without papillary tumors, in patients who are ineligible for or have elected not to undergo cystectomy.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until persistent or recurrent high-risk NMIBC, disease progression, or for up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Treatment of BCG-unresponsive, high-risk NMIBC with pembrolizumab resulted in a complete response rate of 41% for a median duration of 16.2 months in a multicenter, noncomparative trial (n = 96).

    For the treatment of tumor mutational burden-high solid tumors.
    For the treatment of unresectable or metastatic tumor mutational high-burden (TMB-H) solid tumors (at least 10 mutations per megabase (mut/Mb) that have progressed after prior treatment and have no alternative treatment options.
    NOTE: Select patients for treatment based on TMB-H status in tumor specimens. Because the effect of prior chemotherapy on test results for TMB-H in patients with high-grade gliomas is unclear, it is recommended to test for these markers in the primary tumor specimens obtained prior to initiation of temozolomide in patients with high-grade gliomas. An FDA-approved test for the detection of TMB status is available at www.fda/gov/CompanionDiagnostics.
    NOTE: The safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Pembrolizumab was administered to 10 cohorts of patients with various previously-treated unresectable or metastatic solid tumors with TMB-H in a prospectively-planned, retrospective analysis of a multicenter, noncomparative trial (KEYNOTE-158). For patients with at least 13 mut/Mb, the objective response rate was 37% (complete response [CR], 3%) for a median duration that was not reached; 58% of patients had a duration of response of at least 12 months, and 50% had a duration of at least 24 months. For patients with at least 10 mut/Mb, the objective response rate was 29% (complete response [CR], 4%) for a median duration that was not reached; 57% of patients had a duration of response of at least 12 months, and 50% had a duration of at least 24 months. The highest response rates were seen in patients with endometrial cancer (n = 15; 47%), neuroendocrine cancer (n = 5; 40%), cervical cancer (n = 16; 31%), and small cell lung cancer (n = 34; 29%); two patients with thyroid cancer were treated and both achieved complete response for a duration of 8.2 months and more than 33.2 months at last follow-up.

    Adolescents, Children, and Infants 6 months and older

    2 mg/kg (not to exceed 200 mg) IV repeated every 3 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. The use of pembrolizumab in pediatric patients is supported by evidence from adequate and well-controlled studies of pembrolizumab in adults with additional pharmacokinetic and safety data in pediatric patients. Pembrolizumab was administered to 10 cohorts of patients with various previously-treated unresectable or metastatic solid tumors with TMB-H in a prospectively-planned, retrospective analysis of a multicenter, noncomparative trial (KEYNOTE-158). For patients with at least 13 mut/Mb, the objective response rate was 37% (complete response [CR], 3%) for a median duration that was not reached; 58% of patients had a duration of response of at least 12 months, and 50% had a duration of at least 24 months. For patients with at least 10 mut/Mb, the objective response rate was 29% (complete response [CR], 4%) for a median duration that was not reached; 57% of patients had a duration of response of at least 12 months, and 50% had a duration of at least 24 months. The highest response rates were seen in patients with endometrial cancer (n = 15; 47%), neuroendocrine cancer (n = 5; 40%), cervical cancer (n = 16; 31%), and small cell lung cancer (n = 34; 29%); two patients with thyroid cancer were treated and both achieved complete response for a duration of 8.2 months and more than 33.2 months at last follow-up.

    For the treatment of squamous cell skin carcinoma.
    For the treatment of recurrent, metastatic, or locally advanced cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a nonrandomized, phase 2 (KEYNOTE-629) trial, treatment with pembrolizumab resulted in objective response rates of 35% (complete response (CR), 11%) and 50% (CR, 17%) in patients with recurrent or metastatic cSCC (n = 105; 1 or more prior lines of therapy, 87%) or locally advanced cSCC (n = 54; 1 or more prior lines of therapy, 22%), respectively. In patients with recurrent or metastatic cSCC, the median duration of response was not reached (range, 2.7 months to more than 30.4 months) at a median follow-up time of 23.8 months; the duration of response was at least 12 months in 68% of patients. In patients with locally advanced cSCC, the median duration of response was not reached (range, 1 month to more than 17.2 months) at a median follow-up time of 13.4 months; the duration of response was at least 12 months in 37% of patients.

    For the treatment of colorectal cancer.
    For the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer.
    NOTE: Select patients for treatment based on MSI-H/dMMR status in tumor specimens. An FDA-approved test for the detection of MSI-H or dMMR is not currently available.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions. At a median follow-up time of 27.6 months (range, 0.2 to 48.3 months), the median progression-free survival time was significantly improved in patients with previously untreated unresectable or metastatic MSI-H or dMMR colorectal cancer who received pembrolizumab compared with standard chemotherapy (16.5 months vs. 8.2 months) in a randomized, phase 3 trial (KEYNOTE-177). The overall survival data were not mature at the time of this analysis. In this trial, patients in the standard chemotherapy arm received therapy every 2 weeks that consisted of either mFOLFOX6 (oxaliplatin 85 mg/m2 IV on day 1; leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2) IV on day 1; and fluorouracil 400 mg/m2 IV bolus on day 1, then fluorouracil 2,400 mg/m2 IV over 46 to 48 hours) or FOLFIRI (irinotecan 180 mg/m2 IV on day 1; leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2) IV on day 1; and fluorouracil 400 mg/m2 IV bolus on day 1, then fluorouracil 2,400 mg/m2 IV over 46 to 48 hours). Bevacizumab (5 mg/kg IV on day 1) or cetuximab (400 mg/m2 IV on first infusion, then 250 mg/m2 once weekly) were added to mFOLFOX6 or FOLFIRI in some patients. In pooled data from 4 multicenter, uncontrolled, open-label, multicohort, single-arm trials (KEYNOTE-016, KEYNOTE-164, KEYNOTE-028, and KEYNOTE-158), the objective response rate was 36% in 90 patients with MSI-H or dMMR colorectal cancer who received pembrolizumab (10 mg/kg every 2 weeks or 200 mg every 3 weeks). The median duration of response ranged from 1.6+ to 22.7+ months in these patients. Most (84%) patients with colorectal cancer had received 2 or more prior lines of therapy.

    For the treatment of breast cancer.
    For the neoadjuvant treatment of high-risk, early-stage hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with sequential paclitaxel/carboplatin followed by cyclophosphamide/doxorubicin.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks for 8 doses OR 400 mg IV repeated every 6 weeks for 4 doses (up to 24 weeks or until disease progression or unacceptable toxicity). Administer pembrolizumab in combination with paclitaxel (80 mg/m2 IV once weekly) plus carboplatin (AUC 5 IV on day 1 every 3 weeks) for 4 cycles (12 weeks); alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. After completion of 4 cycles of paclitaxel and carboplatin, continue neoadjuvant pembrolizumab in combination with doxorubicin (60 mg/m2 IV) plus cyclophosphamide (600 mg/m2 IV) on day 1 every 3 weeks for 4 cycles, followed by surgery. Administer pembrolizumab prior to chemotherapy when given on the same day. After surgery, administer pembrolizumab 200 mg IV every 3 weeks for up to 9 doses OR 400 mg IV repeated every 6 weeks for up to 5 doses or until disease progression or unacceptable toxicity. Do not administer adjuvant pembrolizumab monotherapy to patients with disease progression or unacceptable toxicity related to neoadjuvant treatment with pembrolizumab plus chemotherapy. Pembrolizumab may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with high-risk (tumor size more than 1 cm but up to and including 2 cm in diameter with nodal involvement; or tumor size more than 2 cm in diameter regardless of nodal involvement), early stage triple-negative breast cancer were randomized to neoadjuvant treatment with pembrolizumab or placebo in combination with carboplatin and paclitaxel, followed by anthracycline and cyclophosphamide in a phase 3 clinical trial (KEYNOTE-522); after definitive surgery, patients received adjuvant pembrolizumab or placebo. Treatment with pembrolizumab plus chemotherapy significantly improved the rate of pathologic complete response (pCR) (63% vs. 55.6%) compared with placebo plus chemotherapy. The median event-free survival (EFS) was not reached in either arm, although EFS at 18 months was 91.3% in patients who received pembrolizumab compared with 85.3% in those who received placebo (HR 0.63; 95% CI, 0.43 to 0.93); overall survival results are immature.

    For the neoadjuvant treatment of high-risk, early-stage hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with sequential paclitaxel/carboplatin followed by cyclophosphamide/epirubicin.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks for 8 doses OR 400 mg IV repeated every 6 weeks for 4 doses (up to 24 weeks or until disease progression or unacceptable toxicity). Administer pembrolizumab in combination with paclitaxel (80 mg/m2 IV once weekly) plus carboplatin (AUC 5 IV on day 1 every 3 weeks) for 4 cycles (12 weeks); alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. After completion of 4 cycles of paclitaxel and carboplatin, continue neoadjuvant pembrolizumab in combination with epirubicin (90 mg/m2 IV) plus cyclophosphamide (600 mg/m2 IV) on day 1 every 3 weeks for 4 cycles, followed by surgery. Administer pembrolizumab prior to chemotherapy when given on the same day. After surgery, administer pembrolizumab 200 mg IV every 3 weeks for up to 9 doses OR 400 mg IV repeated every 6 weeks for up to 5 doses or until disease progression or unacceptable toxicity. Do not administer adjuvant pembrolizumab monotherapy to patients with disease progression or unacceptable toxicity related to neoadjuvant treatment with pembrolizumab plus chemotherapy. Pembrolizumab may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Neoadjuvant treatment with pembrolizumab in combination with carboplatin and paclitaxel, followed by neoadjuvant pembrolizumab plus anthracycline and cyclophosphamide significantly improved the rate of pathologic complete response (pCR) (63% vs. 55.6%) compared with placebo plus chemotherapy in patients with high-risk TNBC (tumor size more than 1 cm but up to and including 2 cm in diameter with nodal involvement; or tumor size more than 2 cm in diameter regardless of nodal involvement) in a phase 3 trial (KEYNOTE-522). The median event-free survival (EFS) was not reached in either arm, although EFS at 18 months was 91.3% in patients who received pembrolizumab compared with 85.3% in those who received placebo (HR 0.63; 95% CI, 0.43 to 0.93); overall survival results are immature.

    For the treatment of locally recurrent unresectable or metastatic, PD-L1 positive (CPS 10 or more), triple negative breast cancer (TNBC) in combination with nab-paclitaxel.
    NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in TNBC is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression in combination with nab-paclitaxel (100 mg/m2 on days 1, 8, and 15, every 28 days); the number of cycles of nab-paclitaxel was not specified.  Administer pembrolizumab prior to chemotherapy when given on the same day. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, double-blind clinical trial (KEYNOTE-355), patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting were randomized to treatment with either pembrolizumab or placebo in combination with paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin regardless of tumor PD-L1 expression. The addition of pembrolizumab to chemotherapy significantly improved the median progression-free survival (9.7 months vs. 5.6 months) compared with placebo plus chemotherapy in the subgroup of patients with a CPS of 10 or more. The objective response rate was 53% compared with 40%, respectively (complete response, 17% vs. 13%) for a median duration of 19.3 months in the pembrolizumab arm and 7.3 months in the placebo arm.

    For the treatment of locally recurrent unresectable or metastatic, PD-L1 positive (CPS 10 or more), triple negative breast cancer (TNBC) in combination with paclitaxel.
    NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in TNBC is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression in combination with paclitaxel (90 mg/m2 on days 1, 8, and 15, every 28 days); the number of cycles of paclitaxel was not specified.  Administer pembrolizumab prior to chemotherapy when given on the same day. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine 50 mg IV (or equivalent) 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, double-blind clinical trial (KEYNOTE-355), patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting were randomized to treatment with either pembrolizumab or placebo in combination with paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin regardless of tumor PD-L1 expression. The addition of pembrolizumab to chemotherapy significantly improved the median progression-free survival (9.7 months vs. 5.6 months) compared with placebo plus chemotherapy in the subgroup of patients with a CPS of 10 or more. The objective response rate was 53% compared with 40%, respectively (complete response, 17% vs. 13%) for a median duration of 19.3 months in the pembrolizumab arm and 7.3 months in the placebo arm.

    For the treatment of locally recurrent unresectable or metastatic, PD-L1 positive (CPS 10 or more), triple negative breast cancer (TNBC) in combination with gemcitabine and carboplatin.
    NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in TNBC is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression in combination with gemcitabine (1,000 mg/m2 IV on days 1 and 8, every 21 days) and carboplatin (AUC 2 IV on days 1 and 8, every 21 days); the number of cycles of gemcitabine plus carboplatin was not specified.  Administer pembrolizumab prior to chemotherapy when given on the same day. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, double-blind clinical trial (KEYNOTE-355), patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting were randomized to treatment with either pembrolizumab or placebo in combination with paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin regardless of tumor PD-L1 expression. The addition of pembrolizumab to chemotherapy significantly improved the median progression-free survival (9.7 months vs. 5.6 months) compared with placebo plus chemotherapy in the subgroup of patients with a CPS of 10 or more. The objective response rate was 53% compared with 40%, respectively (complete response, 17% vs. 13%) for a median duration of 19.3 months in the pembrolizumab arm and 7.3 months in the placebo arm.

    For the adjuvant treatment of high-risk, early-stage hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, as monotherapy, after completion of neoadjuvant chemotherapy (paclitaxel/carboplatin followed by cyclophosphamide/doxorubicin or epirubicin) and surgery.
    NOTE: Do not administer adjuvant pembrolizumab monotherapy to patients with disease progression or unacceptable toxicity related to neoadjuvant treatment with pembrolizumab plus chemotherapy.
    Intravenous dosage
    Adults

    200 mg IV every 3 weeks until disease progression or unacceptable toxicity for up to 9 doses; OR 400 mg IV repeated every 6 weeks until disease progression or unacceptable toxicity for up to 5 doses. Pembrolizumab may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions. Patients with high-risk (tumor size more than 1 cm but up to and including 2 cm in diameter with nodal involvement; or tumor size more than 2 cm in diameter regardless of nodal involvement), early stage triple-negative breast cancer were randomized to neoadjuvant treatment with pembrolizumab or placebo in combination with carboplatin and paclitaxel, followed by anthracycline and cyclophosphamide in a phase 3 clinical trial (KEYNOTE-522); after definitive surgery, patients received adjuvant pembrolizumab or placebo. Treatment with pembrolizumab plus chemotherapy significantly improved the rate of pathologic complete response (pCR) (63% vs. 55.6%) compared with placebo plus chemotherapy. The median event-free survival (EFS) was not reached in either arm, although EFS at 18 months was 91.3% in patients who received pembrolizumab compared with 85.3% in those who received placebo (HR 0.63; 95% CI, 0.43 to 0.93); overall survival results are immature.

    MAXIMUM DOSAGE

    Adults

    200 mg IV every 3 weeks OR 400 mg IV every 6 weeks.

    Geriatric

    200 mg IV every 3 weeks OR 400 mg IV every 6 weeks.

    Adolescents

    2 mg/kg (Max: 200 mg) IV every 3 weeks.

    Children

    2 mg/kg (Max: 200 mg) IV every 3 weeks.

    Infants

    2 mg/kg (Max: 200 mg) IV every 3 weeks.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Treatment-Related Immune-Mediated Hepatitis
    Monotherapy
    No Tumor Involvement of the LiverAST or ALT level of more than 3 to 8 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold pembrolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue pembrolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. AST or ALT level more than 8 times the ULN or a total bilirubin level more than 3 times the ULN: Permanently discontinue pembrolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).Tumor Involvement of the LiverBaseline AST or ALT level at the ULN or less: Hold or permanently discontinue pembrolizumab based on recommendations for hepatitis with no tumor involvement of the liver.Baseline AST or ALT level of more than 1 to 3 times the ULNAST or ALT level of more than 5 to 10 times the ULN: Hold pembrolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue pembrolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Baseline AST or ALT level of more than 3 to 5 times the ULNAST or ALT level of more than 8 to 10 times the ULN: Hold pembrolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue pembrolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Any Baseline AST or ALT levelAST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3 times the ULN: Permanently discontinue pembrolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
    Combination Therapy with Axitinib
    AST or ALT level of 3 to less than 10 times the ULN and a total bilirubin level of less than 2 times the ULN: Hold both pembrolizumab and axitinib and consider corticosteroid therapy. Consider rechallenge with pembrolizumab or axitinib (or sequential rechallenge with both) when hepatic enzymes recover to grade 1 or less. Per axitinib manufacturer guidance, consider a dose reduction if rechallenging with axitinib.AST or ALT level of 10 times the ULN or more OR an AST or ALT level more than 3 times the ULN and a total bilirubin level 2 times the ULN or more: Permanently discontinue pembrolizumab and axitinib and consider corticosteroid therapy.

    Renal Impairment

    Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction Grade 2 or 3 increased serum creatinine (SCr) level: Hold pembrolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue pembrolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Grade 4 increased SCr level: Permanently discontinue pembrolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Pembrolizumab is available as a single-use lyophilized powder vial and a single-use 25 mg/mL solution vial.
    Dilution is required prior to administration.
    Do not administer other drugs through the same infusion line.
    Administer pembrolizumab prior to chemotherapy when given on the same day.
     
    Lyophilized powder single-use vials
    Reconstitution:
    Add 2.3 mL of sterile water for injection, USP (SWI) to the 50 mg lyophilized powder vial for a reconstituted concentration of 25 mg/mL; inject SWI along the walls of the vial and not directly on the powder.
    Gently swirl the vial and allow up to 5 minutes for bubbles to clear. Do not shake the vial. The reconstituted solution will be a clear to slightly opalescent, colorless to slightly yellow solution. Discard if visible particles are observed.
    Storage following reconstitution: Store at room temperature for up to 6 hours or refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours (includes room temperature storage of reconstituted vials, storage of the diluted solution, and the duration of infusion). Do not freeze. If refrigerated, allow the diluted solution to warm to room temperature prior to administration. Discard after 6 hours at room temperature or 24 hours under refrigeration.
     
    Pembrolizumab single-use solution or reconstituted lyophilized powder:
    Dilution:
    Add the required amount of drug to a bag of 0.9% sodium chloride injection, USP or 5% dextrose injection, USP to a final diluted concentration between 1 mg/mL and 10 mg/mL. Mix by gentle inversion. Do not shake.
    Discard any unused reconstituted solution left in the vial.
    Storage following dilution: Store at room temperature for up to 6 hours or refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 96 hours (includes room temperature storage of reconstituted vials, storage of the diluted infusion solution, and the duration of infusion). Do not freeze. If refrigerated, allow the diluted solution to warm to room temperature prior to administration. Discard after 6 hours at room temperature or 96 hours under refrigeration.
     
    Intravenous Infusion:
    Administer the diluted solution intravenously over 30 minutes.
    Use a sterile, nonpyrogenic, low-protein binding 0.2 to 5 micron in-line or add-on filter.

    STORAGE

    Keytruda:
    - Diluted product should be used within 6 hours if stored at room temperature or within 24 hours if stored at 36 to 46 degrees F
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerated product should reach room temperature before administration
    - Store in original carton in refrigerator (35 to 46 degrees F) until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Immune-mediated reactions

    Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), thus removing inhibition of the immune response, such as pembrolizumab. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously. Although usually occurring during treatment with PD-1/PD-L1 inhibitors, immune-mediated reactions can occur at any time after starting therapy including after discontinuation of therapy. Because early identification and management is critical to safe usage of PD-1/PD-L1 inhibitors, closely monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated reactions. Initiate an appropriate workup to exclude alternative etiologies including infection in cases of suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of pembrolizumab therapy may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary, administer systemic corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy.

    Colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, viral infection

    Immune-mediated colitis has been reported with pembrolizumab therapy. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Use pembrolizumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Pembrolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

    Hepatitis, hepatotoxicity

    Immune-mediated hepatitis has been reported with pembrolizumab therapy. The incidence of hepatotoxicity was higher in patients treated with pembrolizumab in combination with axitinib compared with pembrolizumab alone. Monitor hepatic function at baseline and periodically during treatment; consider more frequent monitoring in patients receiving pembrolizumab with axitinib. Pembrolizumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary.[57889]

    Hyperthyroidism, hypothyroidism

    Pembrolizumab can cause immune-mediated thyroid disorders. The incidence of new or worsening hypothyroidism was higher in patients with squamous cell cancer of the head and neck and classical Hodgkin lymphoma compared to other populations. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Pembrolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.[57889]

    Renal failure, renal impairment

    Immune-mediated nephritis and renal failure have been reported with pembrolizumab therapy. Monitor renal function at baseline and periodically during treatment. Pembrolizumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.[57889]

    Pneumonitis, radiation therapy

    Immune-mediated pneumonitis has been reported with pembrolizumab therapy; some cases were fatal. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation therapy, except in patients with classical Hodgkin lymphoma, where pneumonitis rates were similar regardless of prior thoracic radiation. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, pembrolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary.

    Diabetic ketoacidosis, hyperglycemia, type 1 diabetes mellitus

    Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, has been reported with pembrolizumab therapy. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold pembrolizumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.

    Infusion-related reactions

    Severe and sometimes fatal hypersensitivity or infusion-related reactions have occurred with pembrolizumab. Monitor patients for signs and symptoms of infusion reactions including anaphylaxis, rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild or moderate infusion related reactions (grade 1 or 2); stop the infusion and permanently discontinue pembrolizumab for severe or life-threatening infusion-related reactions (grade 3 or 4).

    Adrenal insufficiency, hypophysitis, hypopituitarism

    Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with pembrolizumab. Monitor blood cortisol at baseline, prior to surgery, and as clinically indicated for patients with triple-negative breast cancer receiving pembrolizumab in the neoadjuvant setting. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Pembrolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.

    Allogeneic stem cell transplant

    Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with a PD-1/PD-L1 blocking antibody, such as pembrolizumab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.

    Anemia, neutropenia, thrombocytopenia

    Severe hematologic toxicity (e.g., anemia, neutropenia, and thrombocytopenia) has been reported with pembrolizumab use in patients with relapsed or refractory classical Hodgkin lymphoma (cHL). In cHL patients, monitor complete blood counts and withhold therapy for grade 4 hematologic toxicity.

    Serious rash

    Immune-mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1 inhibitors. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Pembrolizumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary.

    Multiple myeloma, treatment outside of a clinical trial

    The use of a PD-1 or PDL1 blocking antibody with a thalidomide analogue plus dexamethasone is not recommended for multiple myeloma treatment outside of a clinical trial. Two clinical trials were halted due to an increased risk of death in patients who received pembrolizumab and dexamethasone in combination with an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of multiple myeloma.

    Autoimmune disease, organ transplant, systemic lupus erythematosus (SLE)

    Use pembrolizumab with caution in patients who have previously had an organ transplant or who have autoimmune disease such as systemic lupus erythematosus (SLE). Immune-mediated organ transplant rejection has been reported with PD-1/PD-L1 inhibitor therapy.

    Guillain-Barre syndrome, myasthenia gravis, neurological disease

    Immune-mediated neurotoxicity has been reported with pembrolizumab or other PD-1/PD-L1 inhibitors. Use pembrolizumab with caution in patients who have a history of neurological disease such as myasthenia gravis or Guillain-Barre syndrome. Pembrolizumab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.

    Children, infants

    The safety and effectiveness of pembrolizumab have been established in adolescents, children, and infants with classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, Merkel cell carcinoma, microsatellite instability-high (MSI-H) cancer, and tumor mutational burden-high (TMB-H) cancer based on evidence from well-controlled studies of pembrolizumab in adult patients, with additional pharmacokinetic and safety data in pediatric patients. Treatment with pembrolizumab resulted in a higher rate of fever, vomiting, upper respiratory tract infection, headache, leukopenia, neutropenia, and grade 3 anemia in pediatric patients (range, 6 months to 17 years; n = 161) with various cancers compared with adults. The safety and effectiveness of pembrolizumab in pediatric patients have not been established in the other approved indications.[57889]

    Geriatric

    Treatment with pembrolizumab resulted in a higher incidence of serious adverse reactions in geriatric patients aged 65 years and older with classical Hodgkin lymphoma (50%) compared with patients younger than 65 years of age (24%).

    Pregnancy

    Based on its mechanism of action, pembrolizumab may cause fetal harm if used during pregnancy. Pembrolizumab is an immunoglobulin G4 antibody and may cross the placental barrier. Fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Advise pregnant women of the potential risk to a fetus. The PD-1 pathway is associated with decidual CD8-positive T-cell function and the PD1/PD-L1 interaction may be important in maintaining fetal tolerance during pregnancy. PD1/PDL1 Inhibitors, such as pembrolizumab, may impair maternal immune tolerance resulting in spontaneous abortion, intrauterine growth restriction, or early-onset preeclampsia.

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during pembrolizumab treatment. Pembrolizumab can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 4 months after treatment with pembrolizumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of treatment. Women who become pregnant while receiving pembrolizumab should be apprised of the potential hazard to the fetus. Fertility studies have not been performed in humans; therefore, the risk of infertility is unknown.

    Breast-feeding

    Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during pembrolizumab therapy and for 4 months after the final dose. It is not known if pembrolizumab is present in human milk or if it has effects on the breastfed child or on milk production. Use pembrolizumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because pembrolizumab is a large protein molecule (molecular weight of 149,000 Daltons), the amount of drug in milk is likely to be very low. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 0-49.0
    hypertension / Early / 0-39.0
    anemia / Delayed / 0-35.0
    lymphopenia / Delayed / 0-33.0
    leukopenia / Delayed / 0-30.0
    hepatotoxicity / Delayed / 0-20.0
    hyponatremia / Delayed / 0-20.0
    thrombocytopenia / Delayed / 0-19.0
    fatigue / Early / 0-17.0
    hyperamylasemia / Delayed / 0-17.0
    hypertriglyceridemia / Delayed / 0-15.0
    hypophosphatemia / Delayed / 0-12.0
    hypokalemia / Delayed / 0-12.0
    dyspnea / Early / 0-11.0
    atrial fibrillation / Early / 0-11.0
    weight loss / Delayed / 0-10.0
    infection / Delayed / 0-9.0
    hyperkalemia / Delayed / 0-9.0
    stomatitis / Delayed / 0-8.0
    nausea / Early / 0-7.0
    vomiting / Early / 0-7.0
    anorexia / Delayed / 0-7.0
    abdominal pain / Early / 0-6.0
    hypomagnesemia / Delayed / 0-6.0
    proteinuria / Delayed / 0-6.0
    hypoalbuminemia / Delayed / 0-5.0
    asthenia / Delayed / 0-5.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-5.0
    rash / Early / 0-5.0
    musculoskeletal pain / Early / 0-5.0
    hypercholesterolemia / Delayed / 0.7-5.0
    bleeding / Early / 0-5.0
    hypocalcemia / Delayed / 0-4.7
    hypercalcemia / Delayed / 0-4.6
    peripheral neuropathy / Delayed / 0-4.2
    pleural effusion / Delayed / 0-4.0
    pericarditis / Delayed / 0-4.0
    supraventricular tachycardia (SVT) / Early / 0-4.0
    sinus tachycardia / Rapid / 0-4.0
    myocardial infarction / Delayed / 0-3.0
    hematuria / Delayed / 0-3.0
    dysphagia / Delayed / 0-2.9
    cough / Delayed / 0-2.0
    peripheral edema / Delayed / 0-2.0
    hypermagnesemia / Delayed / 0-2.0
    headache / Early / 0-2.0
    cardiac tamponade / Delayed / 0-2.0
    pericardial effusion / Delayed / 0-2.0
    prolonged bleeding time / Delayed / 0-2.0
    pulmonary embolism / Delayed / 0-2.0
    back pain / Delayed / 0-1.5
    arthralgia / Delayed / 0.4-1.4
    myocarditis / Delayed / 0-1.4
    pneumonitis / Delayed / 1.0-1.3
    constipation / Delayed / 0-1.1
    hypothyroidism / Delayed / 0-1.0
    Guillain-Barre syndrome / Delayed / 0-1.0
    myelitis / Delayed / 0-1.0
    myasthenia gravis / Delayed / 0-1.0
    myalgia / Early / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    hemophagocytic lymphohistiocytosis / Delayed / 0-1.0
    organ transplant rejection / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    renal failure / Delayed / 0-1.0
    rhabdomyolysis / Delayed / 0-1.0
    alopecia / Delayed / 0-0.8
    pruritus / Rapid / 0-0.7
    metabolic acidosis / Delayed / 0-0.4
    dizziness / Early / 0-0.4
    interstitial nephritis / Delayed / 0.3-0.3
    adrenocortical insufficiency / Delayed / 0-0.3
    hypophysitis / Delayed / 0.3-0.3
    hyperthyroidism / Delayed / 0-0.2
    infusion-related reactions / Rapid / 0.2-0.2
    dysphonia / Delayed / 0-0.2
    graft-versus-host disease (GVHD) / Delayed / 1.0
    hepatic failure / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    azotemia / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    lethargy / Early / Incidence not known
    malaise / Early / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    atopic dermatitis / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    erythema / Early / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    retinopathy / Delayed / Incidence not known
    hypertensive crisis / Early / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    Vogt-Koyanagi-Harada syndrome / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    retinal detachment / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 2.1-2.1
    tumor flare / Delayed / 0-1.4
    meningitis / Delayed / 0-1.0
    paresis / Delayed / 0-1.0
    angina / Early / 0-1.0
    ocular inflammation / Early / 0-1.0
    iritis / Delayed / 0-1.0
    gastritis / Delayed / 0-1.0
    confusion / Early / 2.0
    cholangitis / Delayed / Incidence not known
    flank pain / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    interstitial lung disease / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    psoriaform rash / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    osteomyelitis / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    migraine / Early / Incidence not known
    photophobia / Early / Incidence not known
    hematoma / Early / Incidence not known
    melena / Delayed / Incidence not known
    subdural hematoma / Early / Incidence not known

    Mild

    skin hypopigmentation / Delayed / 0-13.0
    influenza / Delayed / 0-11.0
    weakness / Early / 0-2.0
    syncope / Early / 0-2.0
    purpura / Delayed / 0-1.0
    pelvic pain / Delayed / Incidence not known
    cheilitis / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    dysesthesia / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known
    seborrhea / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    dental pain / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    rhinorrhea / Early / Incidence not known
    petechiae / Delayed / Incidence not known
    ecchymosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Based on its mechanism of action, pembrolizumab may cause fetal harm if used during pregnancy. Pembrolizumab is an immunoglobulin G4 antibody and may cross the placental barrier. Fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Advise pregnant women of the potential risk to a fetus. The PD-1 pathway is associated with decidual CD8-positive T-cell function and the PD1/PD-L1 interaction may be important in maintaining fetal tolerance during pregnancy. PD1/PDL1 Inhibitors, such as pembrolizumab, may impair maternal immune tolerance resulting in spontaneous abortion, intrauterine growth restriction, or early-onset preeclampsia.

    Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during pembrolizumab therapy and for 4 months after the final dose. It is not known if pembrolizumab is present in human milk or if it has effects on the breastfed child or on milk production. Use pembrolizumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because pembrolizumab is a large protein molecule (molecular weight of 149,000 Daltons), the amount of drug in milk is likely to be very low. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.

    MECHANISM OF ACTION

    Pembrolizumab is a human monoclonal IgG4 kappa antibody that binds to the programmed death receptor-1 (PD-1) found on T-cells and blocks the interaction of PD-1 with its ligands, PD-L1 and PD-L2, on the tumor cell. Melanoma and some other solid tumors suppress cytotoxic T-cell activity by over-expressing PD-L1 on the cell surface. Blocking the PD-1/PD-L1 pathway prevents T-cell inactivation. In mice, inhibiting PD-1 activity deceased tumor growth.[57889] Pembrolizumab differs from ipilimumab, another monoclonal antibody that binds to the cytotoxic T-lymphocyte Antigen-4 (CTLA-4) and blocks the interaction of CTLA-4 with its ligands, in that pembrolizumab blocks the PD-1/PD-L1 interaction peripherally at the tumor site whereas ipilimumab blocks the CTLA4/ligand interaction primarily in the lymphoid organs.[57904]

    PHARMACOKINETICS

    Pembrolizumab is administered intravenously. In a population pharmacokinetic analysis (n = 2,993), pembrolizumab clearance was approximately 23% lower at steady state (geometric mean, 195 mL/day; coefficient of variation (CV), 40%) than after the first dose (252 mL/day; CV, 37%); this difference is not considered clinically important. The geometric mean steady-state volume of distribution (Vd) was 6 L (CV, 20%), and the mean terminal half-life was 22 days (CV, 32%).

    Intravenous Route

    In a population pharmacokinetic analysis, steady-state pembrolizumab concentrations were reached by 16 weeks following an every 3-week regimen; the systemic accumulation was approximately 2.1-fold. The pembrolizumab Cmax, Cmin, and AUC at steady state increased proportionally in the dose range of 2 to 10 mg/kg IV every 3 weeks. In a multicenter, randomized, open-label, dose comparative, phase I study (n = 173), patients with ipilimumab-refractory advanced melanoma received pembrolizumab 2 mg/kg IV or 10 mg/kg IV every 3 weeks. The AUC values were 0.643 grams X day/L (coefficient of variation (CV), 28%) and 3.77 grams X day/L (CV, 33%) in the 2 mg/kg and 10 mg/kg arms, respectively. Pembrolizumab exposure was 5.9 times higher in the 10 mg/kg arm. A pembrolizumab dosage regimen of 400 mg IV every 6 weeks was compared with 200 mg IV every 3 weeks and 2 mg/kg IV every 3 weeks regimens in a model-based analysis using concentration-time profile simulations from 2,993 subjects from 5 clinical trials. At steady state (days 169 to 210), the average pembrolizumab concentration over the dosage interval (AUC) following the 400 mg IV every 6 weeks regimen was similar to the 200 mg IV every 3 weeks (difference from mean value, 0.7%) and higher than the 2 mg/kg IV every 3 weeks regimen (difference in mean value, 35%). Based on observed pharmacokinetic data from an interim analysis of 41 patients with melanoma treated with pembrolizumab 400 mg every 6 weeks, there does not appear to be any clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks.