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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, melanoma, Merkel cell carcinoma, microsatellite instability-high or mismatch repair deficient solid tumors, and cancers of the bladder, cervix, head and neck, kidneys, liver, lung, and stomach
    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 over 30 minutes repeated every 3 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 II 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 over 30 minutes repeated every 3 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 over 30 minutes repeated every 3 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 http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes 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. 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 in the chemotherapy arm crossing over to receive second-line therapy with pembrolizumab. Pembrolizumab also significantly improved overall survival compared with chemotherapy in the final overall survival analysis (30 vs. 14.2 months), occurring 14 months after the interim analysis.[61268] [57889]

    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 http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes 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. 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 over 30 minutes, followed by pemetrexed (500 mg/m2 IV over 10 minutes), followed by either carboplatin (AUC 5 IV over 15 to 60 minutes) or cisplatin (75 mg/m2 IV) on day 1, 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. To prevent or minimize toxicities, all patients should also receive the following concomitant medications: dexamethasone 4 mg PO twice daily for 3 consecutive days, beginning the day before each pemetrexed dose; folic acid 400 to 1,000 mcg PO daily beginning 7 days prior to the first pemetrexed dose and continuing until 21 days after the last pemetrexed dose; and vitamin B12 injection 1 mg IM one week prior to the first dose of pemetrexed and every 3 cycles (every 9 weeks) thereafter (do not substitute oral vitamin B12 for the IM injection). After the first vitamin B12 injection, subsequent injections may be given on the same day as pemetrexed treatment. 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). Median overall survival (not reached vs. 11.3 months), progression-free survival (8.8 months vs. 4.9 months), and objective response rate (48% vs. 19%) were significantly improved in the pembrolizumab arm. The median duration of response was 11.2 months for patients who received pembrolizumab plus pemetrexed/platinum chemotherapy compared with 7.8 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 over 30 minutes on day 1, in combination with carboplatin (AUC 6 IV on day 1) and either paclitaxel (200 mg/m2 IV on day 1) or nab-paclitaxel (100 mg/m2 IV on days 1, 8, and 15), every 3 weeks for 4 cycles. Administer pembrolizumab prior to chemotherapy when given on the same day. Following completion of platinum-based therapy, pembrolizumab may be continued as maintenance therapy until disease progression or unacceptable toxicity, for up to 24 months. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-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 (15.9 months vs. 11.3 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 over 30 minutes 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.[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 and Children 2 years and older

    2 mg/kg (not to exceed 200 mg) IV over 30 minutes 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 http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes 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. 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 over 30 minutes on day 1, 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), every 3 weeks for 6 cycles. Administer pembrolizumab prior to chemotherapy when given on the same day. After completion of 6 cycles of pembrolizumab, carboplatin, and fluorouracil, continue pembrolizumab 200 mg IV over 30 minutes every 3 weeks until disease progression or for 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 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 for all populations regardless of PD-L1 expression. 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 over 30 minutes on day 1, 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), every 3 weeks for 6 cycles. Administer pembrolizumab prior to chemotherapy when given on the same day. After completion of 6 cycles of pembrolizumab, cisplatin, and fluorouracil, continue pembrolizumab 200 mg IV over 30 minutes every 3 weeks until disease progression or for 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 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 for all populations regardless of PD-L1 expression. 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 http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes 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. 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. The most benefit may be in patients with a CPS of 20 or more; in an exploratory subgroup analysis of patients with a CPS of 1 to 19, the median overall survival was 10.8 months in the pembrolizumab arm versus 10.1 months in the cetuximab arm, which was not statistically significant. 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 II trial (KEYNOTE-087 trial). 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 in patients with refractory disease or who have relapsed after 3 or more prior lines of therapy.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes 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. The overall response rate was 69% in patients with relapsed or refractory classical Hodgkin lymphoma who received pembrolizumab in a multicenter, nonrandomized trial (n = 210; KEYNOTE-087). Additionally, a complete remission was achieved in 22% of patients. At a median follow-up time of 9.4 months, the median duration of response was 11.1 months. Patients (median age, 35 years; range, 18 to 76 years) in this study had received a median of 4 prior therapies (range, 1 to 12 therapies); 61% of patients had previously received an autologous stem-cell transplant, 83% of patients had received prior brentuximab therapy, and 36% of patients had received prior radiation therapy.

    Adolescents, Children, and Infants

    2 mg/kg (not to exceed 200 mg) IV over 30 minutes 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.

    For the treatment of locally advanced or metastatic 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: 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 urothelial carcinoma is available at: http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes every 3 weeks until disease progression or 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 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: 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 urothelial carcinoma is available at: http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes every 3 weeks until disease progression or 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 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 whose tumors express PD-L1 (Combined Positive Score (CPS), 10% or more) and who are not eligible for cisplatin-containing chemotherapy or in patients who are ineligible for any platinum-containing chemotherapy regardless of level of tumor PD-L1 expression, as monotherapy.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes every 3 weeks until disease progression or 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 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 7% complete responses and 22% 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 not reached (95% CI, 1.4+ months to 17.8+ months). In an ongoing multicenter, randomized trial in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy (KEYNOTE-361), patients having low PD-L1 expression (CPS less than 10%) had decreased survival with pembrolizumab monotherapy compared to those who received platinum-based chemotherapy; the monotherapy arm of this trial was closed to accrual for patients with low PD-L1 expression upon the recommendation of the independent Data Monitoring Committee.

    For the treatment of unresectable or metastatic microsatellite instability-high solid tumors or mismatch repair deficient solid tumors.
    For the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes every 3 weeks until disease progression or 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 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 colorectal cancer treated with pembrolizumab (10 mg/kg every 2 weeks or 200 mg every 3 weeks; n = 90) had an objective response rate of 36% (95% CI, 26% to 46%) with a median duration of response ranging from 1.6+ to 22.7+ months.

    Adolescents and Children 2 years and older

    2 mg/kg (not to exceed 200 mg) IV over 30 minutes 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 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 colorectal treated with pembrolizumab (10 mg/kg every 2 weeks or 200 mg every 3 weeks; n = 90) had an objective response rate of 36% (95% CI, 26% to 46%) with a median duration of response ranging from 1.6+ to 22.7+ months.

    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 over 30 minutes every 3 weeks until disease progression or 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 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 over 30 minutes 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 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: For monotherapy with pembrolizumab, 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: http://www.fda.gov/CompanionDiagnostics.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for the treatment of gastric cancer, including gastroesophageal junction adenocarcinoma
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes, every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. 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.

    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 over 30 minutes 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. 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 and Children 2 years and older

    2 mg/kg (not to exceed 200 mg) IV over 30 minutes 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: 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 cervical cancer is available at: http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes 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. 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 hepatocellular cancer in patients who have been previously treated with sorafenib.
    NOTE: The FDA has designated pembrolizumab as an orphan drug for this indication.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes, 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 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.
    For the first-line treatment of advanced renal cell cancer, in combination with axitinib.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes on day 1 repeated every 3 weeks, 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 treatment until disease progression or unacceptable toxicity, or for pembrolizumab, up to 24 months in patients without progression. 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.

    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.
    Intravenous dosage
    Adults

    200 mg IV over 30 minutes, every 3 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression. Treatment with pembrolizumab resulted in an objective response rate of 19% (complete response, 2%) in patients with SCLC that progressed on or after platinum-based chemotherapy and at least one other prior line of therapy in one of 2 multicenter, multicohort, nonrandomized, open-label trials (KEYNOTE-028 or KEYNOTE-158). The duration of response was at least 6 months in 94% of patients who obtained a response, at least 12 months in 63%, and at least 18 months in 56% of patients who obtained a response.

    MAXIMUM DOSAGE

    Adults

    200 mg IV every 3 weeks.

    Geriatric

    200 mg IV every 3 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

    Baseline Hepatic Impairment
    Mild hepatic impairment (total bilirubin level less than or equal to the upper limit of normal (ULN) and AST level greater than ULN OR total bilirubin level greater than 1 to 1.5 times the ULN and any AST level): No pembrolizumab dosage adjustment is necessary, based on a population pharmacokinetic analysis.
    Moderate to severe hepatic impairment: Insufficient information is available regarding the clearance of pembrolizumab in patients with moderate to severe hepatic impairment.[57889]
     
    Treatment-Related Hepatotoxicity
    Immune-mediated hepatitis in patients WITHOUT hepatocellular cancer or renal cell carcinoma (RCC) receiving combination therapy with axitinib
    AST/ALT 3.1 to 5 times the upper limit of normal (ULN) or a total bilirubin level 1.6 to 3 times the ULN: Hold pembrolizumab therapy and administer corticosteroids (initial dose of 0.5 to 1 mg/kg per day prednisone or equivalent, followed by a taper); resume therapy when the adverse event recovers to grade 1 or less. Permanently discontinue therapy if there is no recovery to less than or equal to grade 1 within 12 weeks or if the corticosteroid dose cannot be reduced to 10 mg per day of prednisone (or equivalent) or less within 12 weeks.
    AST/ALT greater than 5 times the ULN or a total bilirubin level greater than 3 times the ULN: Permanently discontinue therapy. Administer corticosteroids (initial dose of 1 to 2 mg/kg per day prednisone or equivalent, followed by a taper).
    Liver metastases and grade 2 AST/ALT elevations at baseline, with AST/ALT increases of greater than or equal to 50% relative to baseline lasting at least 1 week: Permanently discontinue pembrolizumab therapy.[57889]
     
    Immune-mediated hepatitis in patients with hepatocellular cancer
    If baseline AST/ALT was less than 2 times ULN and AST/ALT increases to greater than or equal to 5 times ULN: Hold pembrolizumab therapy and administer corticosteroids. Resume treatment when AST or ALT recovers to grade 1 or less, or to baseline.
    If baseline AST/ALT was greater than or equal to 2 times ULN and AST/ALT increases to greater than 3 times baseline: Hold pembrolizumab therapy and administer corticosteroids. Resume treatment when AST or ALT recovers to grade 1 or less, or to baseline.
    AST/ALT greater than 10 times ULN regardless of baseline: Permanently discontinue pembrolizumab therapy.
    Total bilirubin greater than 2 mg/dL if baseline was less than 1.5 mg/dL OR total bilirubin greater than 3 mg/dL regardless of baseline: Hold pembrolizumab therapy and administer corticosteroids. Resume treatment when total bilirubin recovers to grade 1 or less, or to baseline.
    Child-Pugh score greater than or equal to 9 points: Permanently discontinue pembrolizumab therapy.
    Gastrointestinal bleeding suggestive of portal hypertension: Permanently discontinue pembrolizumab therapy.
    New onset of clinically detectable ascites, or encephalopathy: Permanently discontinue pembrolizumab therapy.[57889]
     
    Hepatotoxicity in patients with RCC receiving combination therapy with axitinib
    ALT/AST 3 to less than 10 times ULN WITHOUT concurrent total bilirubin 2 times ULN or more: Hold both pembrolizumab and axitinib therapy and consider treatment with corticosteroids. When liver function tests recover to grade 1 or less, consider rechallenge with a single drug (i.e., pembrolizumab or axitinib), or a sequential rechallenge with both drugs. If rechallenging with axitinib, consider dose reduction as per the axitinib prescribing information.
    ALT/AST 10 times ULN or more, or greater than 3 times ULN with concurrent total bilirubin 2 times ULN or more: Permanently discontinue both pembrolizumab and axitinib and consider corticosteroid therapy.[57889]

    Renal Impairment

    Baseline Renal Impairment
    eGFR, 15 to 89 mL/min/1.73 m2: No dosage adjustment is necessary, based on a population pharmacokinetic analysis.
     
    Treatment-Related Nephritis
    Grade 2 nephritis: Hold pembrolizumab therapy and administer corticosteroids (initial dose of 1 to 2 mg/kg per day prednisone or equivalent, followed by a taper); resume therapy when the adverse event recovers to grade 1 or less. Permanently discontinue therapy if there is no recovery to less than or equal to grade 1 within 12 weeks or if the corticosteroid dose cannot be reduced to 10 mg per day of prednisone (or equivalent) or less within 12 weeks.
    Grade 3 or 4 nephritis: Permanently discontinue pembrolizumab therapy. Administer corticosteroids (initial dose of 1 to 2 mg/kg per day prednisone or equivalent, followed by a taper).

    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.
    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 24 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 24 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

    Colitis

    Immune-mediated colitis has been reported with pembrolizumab therapy. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Therapy may need to be temporarily withheld or permanently discontinued. Corticosteroids should be administered in patients who develop grade 2 or greater immune-mediated colitis. The median time to onset of colitis was 3.5 months and the median duration was 1.3 months.

    Hepatic disease, hepatitis, hepatotoxicity

    Immune-mediated hepatitis has been reported with pembrolizumab therapy; the median time to onset was 1.3 months with a median duration of 1.8 months. Pembrolizumab in combination with axitinib can cause hepatotoxicity with higher than expected frequencies compared to pembrolizumab alone. Monitor patients for changes in liver function; consider more frequent monitoring in patients receiving pembrolizumab with axitinib compared to when the drugs are used as monotherapy. Treatment may need to be temporarily withheld or permanently discontinued if signs of hepatitis or hepatotoxicity occur. Treatment with corticosteroids may also be necessary. No initial pembrolizumab dosage adjustments are necessary for patients with mild hepatic impairment; pembrolizumab has not been studied in patients with moderate or severe hepatic disease.[57889]

    Hyperthyroidism, hypothyroidism

    Thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis, have been reported with pembrolizumab therapy across clinical trials (n = 2,799). Monitor patients for changes in thyroid function at baseline, periodically during therapy, and as clinically indicated. Therapy may need to be temporarily withheld or permanently discontinued. Medically manage hyperthyroidism per standard therapy (e.g., thionamides, beta-blockers). The median time to onset of hyperthyroidism was 1.4 months, thyroiditis was 1.2 months, and hypothyroidism was 3.5 months. The median duration was 2.1 months for hyperthyroidism and the median duration was not reached for patients with hypothyroidism.[57889]

    Renal failure, renal impairment

    Immune-mediated nephritis and renal failure have been reported with pembrolizumab therapy. Monitor renal function in patients who receive pembrolizumab. Therapy may need to be temporarily withheld or permanently discontinued. Corticosteroids should be administered in patients who develop grade 2 or greater immune-mediated nephritis. No initial dosage adjustments are necessary in patients with renal impairment. The median time to onset of nephritis was 5.1 months, and the median duration was 3.3 months.[57889]

    Asthma, chronic obstructive pulmonary disease (COPD), pneumonitis, radiation therapy

    Immune-mediated pneumonitis has been reported with pembrolizumab therapy; some cases were fatal. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If this adverse event is suspected, confirm with radiographic imaging. Therapy may need to be temporarily withheld or permanently discontinued. Corticosteroids should be administered in patients who develop grade 2 or greater immune-mediated pneumonitis. Pneumonitis occurred approximately two times more often in patients with a history of prior thoracic radiation therapy than in patients who did not receive radiation therapy; the risk is also higher in patients with non-small cell lung cancer (NSCLC). Use pembrolizumab with caution in these patients, as well as patients with asthma or chronic obstructive pulmonary disease (COPD) who may also be at increased risk.

    Guillain-Barre syndrome, hemolytic anemia, immune-mediated reactions, myasthenia gravis, myocarditis, pancreatitis, sarcoidosis, uveitis, vasculitis

    Immune-mediated reactions have occurred during and after treatment with pembrolizumab and may affect any organ system; some cases were severe or fatal. Clinically significant immune-mediated reactions include arthritis, encephalitis, hemolytic anemia, Guillain-Barre syndrome, myasthenia gravis, myelitis, myocarditis, myositis, pancreatitis, sarcoidosis, vasculitis, and uveitis. Monitor patients for signs and symptoms of immune-mediated reactions; confirm etiology or exclude other causes. Therapy may need to be temporarily withheld or permanently discontinued; administer corticosteroids as clinically indicated. Based on limited clinical data, consider the use of other systemic immunosuppressants in patients with immune-related adverse reactions that cannot be controlled with corticosteroids.

    Diabetes mellitus, diabetic ketoacidosis, hyperglycemia, type 1 diabetes mellitus

    Pembrolizumab should be used with caution in patients with diabetes mellitus. Type 1 diabetes mellitus, including 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 for type 1 diabetes.

    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. Stop the infusion and permanently discontinue pembrolizumab therapy for severe (grade 3) or life-threatening (grade 4) infusion-related reactions, and provide medical treatment.

    Adrenal insufficiency, hypophysitis, hypopituitarism

    Hypophysitis has been reported with pembrolizumab therapy across clinical trials (n = 2,799). Monitor patients for signs and symptoms of hypophysitis, including hypopituitarism, adrenal insufficiency, persistent or worsening headache, dizziness or fainting, vision changes, extreme weakness. Therapy may need to be temporarily withheld or permanently discontinued; administer corticosteroids and hormone replacement as clinically indicated. The median time to onset was 3.7 months, and the median duration was 4.7 months.

    Allogeneic stem cell transplant, sinusoidal obstruction syndrome (SOS), veno-occlusive disease (VOD)

    Serious adverse events including graft versus host disease (GVHD) and sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) occurred in patients with classical Hodgkin lymphoma who received an allogeneic stem cell transplant (SCT) after treatment with pembrolizumab; fatalities have been reported. Monitor patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe acute GVHD, steroid-requiring febrile syndrome, SOS, and other immune-mediated adverse events; treat adverse events promptly. These complications may occur despite intervening therapy between PD-1 blockade with pembrolizumab and allogeneic transplantation. Additionally, acute cases of GVHD, some fatal, have been reported in patients who received an allogeneic SCT prior to pembrolizumab. Patients who experienced a prior episode of GVHD may be increased risk for developing this complication after pembrolizumab therapy. Perform a risk/benefit analysis prior to starting treatment with pembrolizumab in patients who have a history of undergoing an allogeneic SCT.

    Organ transplant

    Use pembrolizumab with caution in patients who have received a solid organ transplant, as rejection has been reported in the postmarketing setting in patients treated with pembrolizumab. Treatment with pembrolizumab may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with pembrolizumab versus the risk of possible organ rejection in these patients.

    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 Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and exclude other causes. Based on the severity of the reaction, hold or permanently discontinue pembrolizumab therapy, and administer corticosteroids. For signs or symptoms of SJS or TEN, hold pembrolizumab therapy and refer the patient for specialized care for assessment and treatment; permanently discontinue therapy if a diagnosis of SJS or TEN is confirmed.

    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.

    Children

    Experience with pembrolizumab therapy is limited in adolescents, children, and infants. The safety and effectiveness of pembrolizumab have been established in pediatric patients with classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), and microsatellite instability-high (MSI-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 fatigue, vomiting, abdominal pain, elevated transaminase levels, and hyponatremia in pediatric patients (range, 2 to 18 years; n = 40) with various cancers compared with adults less than 65 years of age; pembrolizumab plasma concentrations were comparable to those observed in adult patients at the same dose regimen (2 mg/kg IV every 3 weeks). The safety and effectiveness of pembrolizumab in pediatric patients have not been established in the other approved indications.[57889]

    Pregnancy

    Based on animal studies and its mechanism of action, fetal harm can occur if pembrolizumab is administered to a pregnant woman. Females of reproductive potential should avoid becoming pregnant during pembrolizumab therapy. These women should be instructed to utilize highly effective contraceptive methods during therapy and for 4 months after the completion of treatment. Advise these women to contact their healthcare provider if pregnancy is suspected or confirmed. If pembrolizumab is used during pregnancy or if a woman becomes pregnant while receiving pembrolizumab, the patient should be apprised of the potential hazard to the fetus. The programmed death receptor-1 (PD-1)/PD-1 ligand (PDL-1) pathway helps to preserve pregnancy by maintaining maternal tolerance to the fetus. Although there are no human or animal reproduction studies with pembrolizumab, inhibiting PD-1/PDL-1 binding and signaling led to an increase in fetal loss in murine models. Potential risks for blocking the PD-1/PDL-1 pathway include an increased incidence of abortion or stillbirths. Pembrolizumab is also an IgG4 immunoglobulin; this immunoglobulin type is known to cross the placenta and there may be drug exposure to the developing fetus. This exposure may result in an increased risk of immune-disorders or altered immune response.

    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

    It is not known whether pembrolizumab is excreted into human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with pembrolizumab and for 4 months after the last dose.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 0-34.0
    graft-versus-host disease (GVHD) / Delayed / 0-26.0
    lymphopenia / Delayed / 1.0-25.0
    anemia / Delayed / 0-24.0
    hypertension / Early / 0-24.0
    hepatotoxicity / Delayed / 0-20.0
    hyperglycemia / Delayed / 1.3-19.0
    hyponatremia / Delayed / 4.1-17.0
    dyspnea / Early / 0.5-11.0
    neutropenia / Delayed / 0-11.0
    atrial fibrillation / Early / 0-11.0
    hypophosphatemia / Delayed / 0-10.0
    leukopenia / Delayed / 0-9.0
    infection / Delayed / 2.0-9.0
    sinusoidal obstruction syndrome (SOS) / Delayed / 9.0-9.0
    veno-occlusive disease (VOD) / Delayed / 9.0-9.0
    fatigue / Early / 0.9-6.0
    hypokalemia / Delayed / 0-6.0
    hypoalbuminemia / Delayed / 0.5-5.0
    musculoskeletal pain / Early / 0-5.0
    bleeding / Early / 0-5.0
    hypercalcemia / Delayed / 0-4.6
    thrombocytopenia / Delayed / 0-4.0
    hypocalcemia / Delayed / 0-4.0
    supraventricular tachycardia (SVT) / Early / 0-4.0
    sinus tachycardia / Rapid / 0-4.0
    pericarditis / Delayed / 0-4.0
    anorexia / Delayed / 0-3.8
    pneumonitis / Delayed / 1.3-3.2
    abdominal pain / Early / 0-3.1
    hematuria / Delayed / 0-3.0
    weight loss / Delayed / 0-2.9
    dysphagia / Delayed / 0-2.9
    hypertriglyceridemia / Delayed / 0-2.6
    diarrhea / Early / 0-2.4
    rash / Early / 0.2-2.3
    pleural effusion / Delayed / 0-2.2
    cough / Delayed / 0-2.0
    peripheral edema / Delayed / 1.1-2.0
    asthenia / Delayed / 0-2.0
    headache / Early / 0-2.0
    myocardial infarction / Delayed / 0-2.0
    pericardial effusion / Delayed / 0-2.0
    cardiac tamponade / Delayed / 0-2.0
    prolonged bleeding time / Delayed / 0-2.0
    back pain / Delayed / 0-1.5
    nausea / Early / 0-1.3
    stomatitis / Delayed / 0-1.3
    hypoglycemia / Early / 0-1.3
    colitis / Delayed / 1.1-1.2
    arthralgia / Delayed / 0.4-1.2
    hypercholesterolemia / Delayed / 0.7-1.2
    constipation / Delayed / 0-1.1
    vomiting / Early / 0-1.0
    myalgia / Early / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    Guillain-Barre syndrome / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / 0-1.0
    insomnia / Early / 0-0.7
    hypothyroidism / Delayed / 0-0.5
    myocarditis / Delayed / 0-0.5
    myelitis / Delayed / 0-0.5
    metabolic acidosis / Delayed / 0-0.4
    hypomagnesemia / Delayed / 0-0.4
    hypophysitis / Delayed / 0-0.4
    pruritus / Rapid / 0-0.3
    dizziness / Early / 0-0.3
    hyperthyroidism / Delayed / 0.1-0.2
    interstitial nephritis / Delayed / 0.1-0.2
    infusion-related reactions / Rapid / 0.2-0.2
    dysphonia / Delayed / 0-0.2
    enterocolitis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    malaise / Early / Incidence not known
    lethargy / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    erythema / Early / Incidence not known
    atopic dermatitis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    organ transplant rejection / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    hypertensive crisis / Early / Incidence not known

    Moderate

    peripheral neuropathy / Delayed / 1.0-10.0
    antibody formation / Delayed / 2.1-2.1
    myasthenia / Delayed / 0-1.0
    diabetes mellitus / Delayed / 0.2-0.2
    confusion / Early / 2.0
    flank pain / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    bullous rash / Early / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    osteomyelitis / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    hypopituitarism / Delayed / Incidence not known

    Mild

    skin hypopigmentation / Delayed / 0-13.0
    influenza / Delayed / 0-11.0
    pelvic pain / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    dysesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    seborrhea / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    dental pain / Delayed / Incidence not known
    rhinorrhea / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known

    DRUG INTERACTIONS

    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.
    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 animal studies and its mechanism of action, fetal harm can occur if pembrolizumab is administered to a pregnant woman. Females of reproductive potential should avoid becoming pregnant during pembrolizumab therapy. These women should be instructed to utilize highly effective contraceptive methods during therapy and for 4 months after the completion of treatment. Advise these women to contact their healthcare provider if pregnancy is suspected or confirmed. If pembrolizumab is used during pregnancy or if a woman becomes pregnant while receiving pembrolizumab, the patient should be apprised of the potential hazard to the fetus. The programmed death receptor-1 (PD-1)/PD-1 ligand (PDL-1) pathway helps to preserve pregnancy by maintaining maternal tolerance to the fetus. Although there are no human or animal reproduction studies with pembrolizumab, inhibiting PD-1/PDL-1 binding and signaling led to an increase in fetal loss in murine models. Potential risks for blocking the PD-1/PDL-1 pathway include an increased incidence of abortion or stillbirths. Pembrolizumab is also an IgG4 immunoglobulin; this immunoglobulin type is known to cross the placenta and there may be drug exposure to the developing fetus. This exposure may result in an increased risk of immune-disorders or altered immune response.

    It is not known whether pembrolizumab is excreted into human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with pembrolizumab and for 4 months after the last dose.

    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.