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Pembrolizumab

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Feb.02.2024

Pembrolizumab

Indications/Dosage

Labeled

  • biliary tract cancer
  • bladder cancer
  • breast cancer
  • cervical cancer
  • colorectal cancer
  • endometrial cancer
  • esophageal cancer
  • gastric cancer
  • head and neck cancer
  • hepatocellular cancer
  • Hodgkin lymphoma
  • malignant melanoma
  • Merkel cell carcinoma
  • microsatellite instability-high solid tumors
  • mismatch repair deficient solid tumors
  • non-Hodgkin's lymphoma (NHL)
  • non-small cell lung cancer (NSCLC)
  • renal cell cancer
  • small cell lung cancer (SCLC)
  • squamous cell skin carcinoma
  • tumor mutational burden-high solid tumors
  • urothelial carcinoma

NOTE: Use of a PD-1 or PDL1 blocking antibody such as pembrolizumab with a thalidomide analogue plus dexamethasone is not recommended in patients with multiple myeloma unless it is being evaluated in a controlled clinical trial.[57889] Two clinical trials (KEYNOTE-183 and KEYNOTE-185) 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 (off-label use).[62286]

Off-Label

    † Off-label indication

    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.[57889] 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.[59863]

    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.[57889]

    for the adjuvant treatment of stage IIB, IIC, or III melanoma following complete resection

    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] The investigator-assessed median relapse-free survival (RFS; HR 0.62) and distant metastases-free survival (DMFS; HR 0.59) times were not reached in either arm after a median follow-up time of 39.4 months in patients with previously untreated, stage IIB or IIC melanoma after complete resection who received up to 1 year of adjuvant pembrolizumab or placebo in interim analyses of a randomized, placebo-controlled, phase 3 trial (KEYNOTE-716). The DMFS at 36 months was 84.4% with adjuvant pembrolizumab compared with 74.7% with placebo; the 36-month RFS rate was 76.2% versus 63.4%, respectively.[67512] [69434] In the 5-year analysis of another randomized, double-blind, phase 3 trial (EORTC 1325/KEYNOTE 054), up to 1 year of adjuvant therapy with pembrolizumab significantly improved the 5-year rate of RFS (55.4% vs. 38.3%) and DMFS (60.6% vs. 44.5%) compared with placebo in patients with resected high-risk stage III cutaneous melanoma. Of note, 70% of patients in the placebo arm with locoregional recurrence crossed over to an anti-PD-1/PD-L1-based treatment and 23% of patients in the pembrolizumab arm were rechallenged with pembrolizumab.[67178] [69435]

    Children 12 years and Adolescents

    2 mg/kg (not to exceed 200 mg) IV 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] The investigator-assessed median relapse-free survival (RFS; HR 0.62) and distant metastases-free survival (DMFS; HR 0.59) times were not reached in either arm after a median follow-up time of 39.4 months in patients with previously untreated, stage IIB or IIC melanoma after complete resection who received up to 1 year of adjuvant pembrolizumab or placebo in interim analyses of a randomized, placebo-controlled, phase 3 trial (KEYNOTE-716). The DMFS at 36 months was 84.4% with adjuvant pembrolizumab compared with 74.7% with placebo; the 36-month RFS rate was 76.2% versus 63.4%, respectively. Pediatric patients aged 12 years and older were eligible for study enrollment; 2 pediatric patients were randomized (1 patient in the pembrolizumab arm and 1 patient in the placebo arm) in this trial.[67512] [69434] Efficacy for pediatric patients with stage III melanoma has been extrapolated from clinical trial data in adults with melanoma.[57889]

    For the treatment of non-small cell lung cancer (NSCLC)

    for the perioperative treatment of resectable non-small cell lung cancer (NSCLC) (tumors greater than or equal to 4 cm or node positive), in combination with cisplatin and pemetrexed

    Intravenous dosage

    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks for 12 weeks as neoadjuvant treatment or until disease progression that precludes definitive surgery or unacceptable toxicity, in combination with cisplatin (75 mg/m2 IV on day 1) and pemetrexed (500 mg/m2 IV on day 1) every 3 weeks for up to 4 cycles. Administer pembrolizumab prior to chemotherapy when given on the same day. Within 4 to 12 weeks after surgery, resume adjuvant pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks as monotherapy for 39 weeks or until disease recurrence or unacceptable toxicity. 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-671), perioperative treatment with pembrolizumab plus neoadjuvant platinum-based chemotherapy significantly improved the median overall survival (not reached vs. 52.4 months) and median event-free survival (not reached vs. 17 months) compared with perioperative placebo plus platinum-based chemotherapy in patients with previously untreated and resectable stage II, IIIA, or IIIB (N2) NSCLC. Platinum-based chemotherapy included cisplatin plus gemcitabine for patients with squamous histology and cisplatin plus pemetrexed for patients with nonsquamous histology.[69675] [57889]

    for the perioperative treatment of resectable non-small cell lung cancer (NSCLC) (tumors greater than or equal to 4 cm or node positive), in combination with cisplatin and gemcitabine

    Intravenous dosage

    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks for 12 weeks as neoadjuvant treatment or until disease progression that precludes definitive surgery or unacceptable toxicity, in combination with cisplatin (75 mg/m2 IV on day 1) and gemcitabine (1,000 mg/m2 IV on days 1 and 8) every 3 weeks for up to 4 cycles. Administer pembrolizumab prior to chemotherapy when given on the same day. Within 4 to 12 weeks after surgery, resume adjuvant pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks as monotherapy for 39 weeks or until disease recurrence or unacceptable toxicity. 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-671), perioperative treatment with pembrolizumab plus neoadjuvant platinum-based chemotherapy significantly improved the median overall survival (not reached vs. 52.4 months) and median event-free survival (not reached vs. 17 months) compared with perioperative placebo plus platinum-based chemotherapy in patients with previously untreated and resectable stage II, IIIA, or IIIB (N2) NSCLC. Platinum-based chemotherapy included cisplatin plus gemcitabine for patients with squamous histology and cisplatin plus pemetrexed for patients with nonsquamous histology.[69675] [57889]

    for the adjuvant treatment of stage IB (T2a, 4 cm or more), II, or IIIA NSCLC following resection and platinum-based chemotherapy

    Intravenous dosage

    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease recurrence, unacceptable toxicity, 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. In a multicenter, randomized, triple-blind, phase 3 clinical trial (KEYNOTE-091), adjuvant treatment with pembrolizumab after resection and 4 cycles of platinum-based chemotherapy significantly improved disease-free survival (DFS) compared with placebo in the subgroup of patients with stage 1B, II, or IIIA NSCLC which comprised 86% of the study population (58.7 months vs. 34.9 months); in the 14% of patients who did not receive adjuvant chemotherapy, the impact of adjuvant pembrolizumab on DFS was not statistically significant. Overall survival results were not mature.[57889] [68574]

    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

    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.[66632]

    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.[57889] [28376] [66703]

    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] [66530]

    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

    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 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).[61369] [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] The overall response rate (ORR) was 58% (complete response (CR) rate, 30%) in 50 patients with advanced Merkel cell carcinoma who received pembrolizumab in a multicenter, phase 2 (KEYNOTE-017) trial. At a median follow-up of 31.8 (range, 0.4 to 56.9) months, the median progression-free survival time was 16.8 months and the median duration of response and overall survival time were not reached.[69693] In another multicenter, phase 2 (KEYNOTE-913) trial, the ORR was 49% (CR rate, 16%) in 55 patients with advanced Merkel cell carcinoma who received pembrolizumab. In these 2 trials, eligible patients (median age, 71 years; range, 46 to 91 years) were not amenable to definitive surgery or radiation therapy and had not previously received systemic therapy; 14% of patients had stage IIIB disease and 86% of patients had stage IV disease.[57889]

    Infants, Children, and Adolescents 6 months to 17 years

    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 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.[57889] [64769]

    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.[57889] [64769]

    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

    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] [64769]

    for the treatment of recurrent or metastatic head and neck cancer (squamous cell) with disease progression on or after 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 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 treatment of Hodgkin lymphoma

    NOTE: The FDA has designated pembrolizumab as an orphan drug for the treatment of Hodgkin lymphoma.

    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.[57889] The median progression-free survival (PFS) time was significantly improved in patients with relapsed or refractory cHL who received pembrolizumab compared with brentuximab vedotin (13.2 months vs. 8.3 months; hazard ratio (HR) = 0.65; 95% CI, 0.48 to 0.88) in a multicenter, randomized, phase 3 (KEYNOTE-204) trial (n = 304). Patients (median age, 36 years) in this trial received a median of 2 prior therapies and were ineligible for (37%) or had relapsed after (63%) autologous hematopoietic stem-cell transplantation (ASCT).[69216] At a median follow-up of 63.7 months, the objective response rate (ORR) was 71.4% (complete response [CR] rate, 27.6%) in 210 patients with relapsed or refractory cHL who received pembrolizumab in a multicenter, multicohort, phase 2 (KEYNOTE-087) trial. The median duration of response (DOR) was 16.6 months, the median PFS time was 13.7 months, and the median overall survival time was not reached. Patients who achieved a CR and had received at least 6 months of pembrolizumab including 2 cycles beyond CR were allowed to discontinue therapy; these patients could receive a second course of pembrolizumab for up to 1 year if they subsequently experienced progressive disease. In 19 evaluable patients who received a second course of pembrolizumab, the ORR was 73.7% (CR, 36.8%) and the median DOR was 15.2 months. Patients (median age, 35 years; range, 18 to 76 years) in this trial had progressed after the most recent therapy or without a response their most recent ASCT and received a median of 4 (range, 1 to 12) prior systemic therapies; 83.3% had received prior brentuximab vedotin therapy.[69217]

    for the treatment of classical Hodgkin lymphoma (cHL) in patients with refractory disease or who have relapsed after 2 or more prior lines of therapy

    Intravenous dosage

    Infants, Children, and Adolescents

    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 cHL patients.[57889]

    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).[61092] 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.[57889]

    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

    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.[61782] [57889]

    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

    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.[61782] [57889]

    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.[66073] [57889] 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.[66963] [57889]

    for the treatment of locally advanced or metastatic urothelial cancer, in combination with enfortumab vedotin

    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, in combination with enfortumab vedotin (1.25 mg/kg [maximum, 125 mg] IV on days 1 and 8, every 21 days until disease progression or unacceptable toxicity). Administer pembrolizumab after completion of enfortumab vedotin when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. 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 (KEYNOTE-A39), treatment with pembrolizumab plus enfortumab vedotin significantly improved overall survival (31.5 months vs. 16.1 months), progression-free survival (12.5 months vs. 6.3 months), and objective response rate (68% vs. 44%; complete response [CR], 29% vs. 12%) compared with platinum-based chemotherapy in patients with locally advanced or metastatic urothelial cancer with no prior systemic treatment for advanced disease. In an open-label, multicohort trial (KEYNOTE-869), treatment with pembrolizumab plus enfortumab vedotin resulted in a confirmed overall response rate of 68% (CR, 12%) in 3 cohorts of patients with previously untreated locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy; the median duration of response was 22.1 months in 2 cohorts and was not reached in the third.[64845] [68834] [70064] [57889]

    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 subclonal dMMR mutations and microsatellite instability may arise in high-grade gliomas during temozolomide therapy, it is recommended to test for MSI-H and dMMR in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in these patients. It is recommended to confirm local MSI-H or dMMR results with an FDA-approved test if feasible, due to discordance between results. If confirmatory testing is not able to be done, the presence of TMB of 10 mut/Mb or higher may be used to select patients for treatment. Information on FDA-approved tests for patient selection is available at www.fda.gov/CompanionDiagnostics.[57889]

    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.[57889]

    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.[57889]

    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 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.[65919]

    for the first-line treatment of HER2-positive, PD-L1 positive (combined positive score [CPS] 1 or higher), locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with trastuzumab and platinum- and fluoropyrimidine-containing chemotherapy

    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 fluoropyrimidine- and platinum-containing chemotherapy. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (ORR) (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in the overall population of 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); in the clinical trial, treatment with fluorouracil could continue after completion of 6 cycles of cisplatin, per protocol. In a prespecified subgroup analysis, the ORR in patients with PD-L1 positive disease was 76% in the pembrolizumab arm versus 51% in the control arm; in patients who were PD-L1 negative, the ORR was 63% versus 58%, respectively. In a subsequent interim analysis, the hazard ratios for progression-free survival and overall survival were nonsignificant in patients with PD-L1 negative disease.[69837] [57889] [66655]

    for the first-line treatment of HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with platinum- and fluoropyrimidine-containing chemotherapy

    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 fluoropyrimidine- and platinum-containing chemotherapy; administer pembrolizumab prior to chemotherapy when given on the same day. Treatment with pembrolizumab plus investigator's choice of chemotherapy (cisplatin and 5FU [FP] or oxaliplatin and capecitabine [CapeOx]) significantly improved overall survival (12.9 months vs. 11.5 months), progression-free survival (6.9 months vs. 5.6 months), and objective response rate (51% vs. 42%; complete response, 9% vs. 6%) compared with placebo plus chemotherapy in patients with HER2-negative advanced gastric or GEJ cancer who had not previously received systemic therapy for metastatic disease in a planned interim analysis of a multicenter, randomized, double-blind, phase 3 clinical trial (KEYNOTE-859); 86% of patients received CapeOx. The median duration of response was 8 months versus 5.7 months, respectively. Seventy-eight percent of patients had PD-L1 positive tumors with a CPS greater than or equal to 1. Differences in response were more pronounced in the subgroups of patients with tumors that had PD-L1 CPS greater than or equal to 1, and in those with PD-L1 CPS greater than or equal to 10.[57889] [69908]

    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†

    Intravenous dosage

    Adults

    Dosage not available.

    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

    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 (KEYNOTE-170) trial, the primary endpoint of objective response rate (assessed by blinded central review) was 45% (complete response (CR) rate, 13%) following pembrolizumab therapy in 53 patients with PMBCL who had relapsed or refractory disease after at least 2 prior lines of therapy. At a median follow-up time of 48.7 (range, 41.2 to 56.2) months, the investigator-assessed best overall response rate was 41.5% (CR rate, 20.8%) in patients who received pembrolizumab in the KEYNOTE-170 trial. The median progression-free survival (PFS) and overall survival (OS) times were 4.3 months and 22.3 months, respectively. In this study, patients (median age, 33 years; range, 20 to 61 years) had received a median of 3 (range, 2 to 8) prior therapies including rituximab; 26% of patients had previously received an autologous stem-cell transplant and 32% of patients had received prior radiation therapy.[70186] [70187] At a median follow-up time of 29.1 months, the objective response rate was 48% (CR rate, 33%) in a cohort of patients with PMBCL who experienced relapse after or were ineligible for autologous stem-cell transplantation (n = 21) in a phase 1b (KEYNOTE-013) trial. After an additional 26 months of follow-up, the median PFS and OS times were 19 months and 37.1 months, respectively.[70186] [70189]

    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.[57889]

    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

    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.[57889]

    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

    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 paclitaxel 175 mg/m2 IV on day 1 plus either cisplatin 50 mg/m2 IV on day 1 or 2 OR carboplatin AUC of 5 IV on day 1, with or without bevacizumab 15 mg/kg IV on day 1 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.[57889] At the first interim analysis of a multicenter, randomized, double-blind, phase 3 trial (KEYNOTE-826), treatment with pembrolizumab plus chemotherapy significantly improved the median progression-free survival compared with placebo plus chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer (10.4 months vs. 8.2 months); bevacizumab was added to treatment in 63% of patients in this trial. The objective response rate was 68% in the pembrolizumab arm compared with 50% in the placebo arm, respectively (complete response, 23% vs. 14%); the median duration of response was 18 months versus 10.4 months, respectively. In the final overall survival (OS) analysis, treatment with pembrolizumab plus chemotherapy significantly improved the median OS compared with placebo plus chemotherapy in the intent-to-treat population (26.4 months vs. 16.8 months), the PD-L1 CPS of greater than or equal to 1 population (28.6 months vs. 16.5 months), and in the PD-L1 CPS greater than or equal to 10 population (29.6 months vs. 17.4 months).[67047] [69855]

    for the treatment of FIGO 2014 stage III to IVA cervical cancer, in combination with chemoradiotherapy (CRT)

    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. Administer in combination with cisplatin (40 mg/m2 IV once weekly for 5 cycles) and radiotherapy (external beam radiation therapy [ERBT] followed by brachytherapy [BT]). Administer pembrolizumab prior to chemoradiotherapy 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. Treatment with pembrolizumab plus cisplatin and ERBT followed by BT (chemoradiotherapy [CRT]) was compared with placebo plus CRT in a multicenter, randomized, double-blind clinical trial (KEYNOTE-A18) which included patients with cervical cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer; of these patients (n = 1,060), 56% had FIGO 2014 stage III to IVA disease and 44% had FIGO 2014 stage 1B2 to IIB node positive disease. In the subset of patients with FIGO 2014 stage III to IVA disease, the addition of pembrolizumab to CRT significantly improved the median progression-free survival PFS by investigator, which was not reached in both arms with a lower level of the 95% confidence interval not reached in the pembrolizumab arm compared with 18.8 months in the placebo arm; the 12-month rate of PFS was 81% versus 70%, respectively. Overall survival results were not mature at the time of the PFS analysis.[57889] [70191]

    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 secondary to hepatitis B in patients who have received prior systemic therapy other than a PD-1 or PD-L1 inhibitor-containing regimen

    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. Treatment with pembrolizumab significantly improved median overall survival (13.9 months vs. 13 months) compared with placebo in patients with previously-treated Barcelona Clinical Liver Cancer (BCLC) Stage B or C hepatocellular cancer in a multicenter, randomized clinical trial conducted in Asia; 79% of patients had active hepatitis B. The median progression-free survival was 2 months in the pembrolizumab arm compared with 2.3 months in the placebo arm; the objective response rate was 11% versus 1.6%, respectively, with a median duration of 23.9 months in patients who received pembrolizumab and 5.6 months in those who received placebo. Complete responses were achieved by 0.9% of patients in the pembrolizumab arm and 0.8% of those in the placebo arm.[70283] [57889]

    For the treatment of renal cell cancer (RCC)

    for the adjuvant treatment of renal cell cancer at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions, as monotherapy

    Intravenous dosage

    Adults

    200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease recurrence, unacceptable toxicity, 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. Adjuvant treatment with pembrolizumab significantly improved disease-free survival (DFS) compared with placebo in patients with renal cell cancer with an intermediate-high or high risk of recurrence after nephrectomy or M1 with no evidence of disease after nephrectomy in a randomized clinical trial (KEYNOTE-564); the 24-month DFS rate was 77% versus 68%, respectively.[57889] [67129]

    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.[63966] [57889] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[48494] 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.[57889] Combination therapy with pembrolizumab and axitinib significantly improved median overall survival (45.7 months vs. 40.1 months) and median progression-free survival (15.7 months vs. 11.1 months) compared with sunitinib in patients with advanced renal cell cancer in the final analysis of an open-label, phase 3 clinical trial (KEYNOTE-426). The objective response rate was 60.4% (complete response [CR], 10%) versus 39.6% (CR, 3.5%), respectively; the median duration of response was 23.6 months in patients receiving combination therapy compared with 15.3 months for patients treated with sunitinib.[67485] [63966] [57889]

    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.[57889] [58782] 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) in patients with previously untreated advanced RCC with a clear-cell component in a 3-arm, randomized (1:1:1), phase 3 trial (CLEAR/KEYNOTE-581); the objective response rate was 71% versus 36%, respectively (complete response, 16% vs. 4%).[66893] In an updated overall survival analysis, the median overall survival for patients treated with pembrolizumab plus lenvatinib was 53.7 months compared with 54.3 months for those who received sunitinib.[69686]

    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

    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

    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.[57889] [66536]

    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%).[57889] [66945]

    For the treatment of endometrial cancer

    for the treatment of advanced endometrial cancer that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) 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

    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.[57889] [58782] [67484]

    for the treatment of advanced endometrial cancer that is 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, 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 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 2 cohorts of a multicenter, open-label, noncomparative, multicohort, phase II trial (KEYNOTE-158), the objective response rate was 46% (complete response, 12%) for a median duration that was not reached in patients with unresectable or metastatic MSI-H or dMMR endometrial cancer received at least 1 dose of pembrolizumab; of patients who responded, 68% had a response duration of at least 12 months and 44% had a response duration of at least 24 months.[57889] [67483]

    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).[57889]

    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

    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.[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, 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.[57889]

    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.[57889]

    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

    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.[57889]

    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.[66036] [57889]

    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.[66036] [57889]

    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

    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.[66036] [57889]

    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

    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.[66122] [66123] [57889] 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 in a prespecified interim analysis. At the prespecified final analysis, the median overall survival was also significantly improved in the pembrolizumab arm (23 months versus 16.1 months, respectively). 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.[57889] [66123]

    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

    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.[66122] [66123] [57889] 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.[29200] 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 in a prespecified interim analysis. At the prespecified final analysis, the median overall survival was also significantly improved in the pembrolizumab arm (23 months versus 16.1 months, respectively). 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.[57889] [66123]

    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

    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.[66122] [66123] [57889] 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 in a prespecified interim analysis. At the prespecified final analysis, the median overall survival was also significantly improved in the pembrolizumab arm (23 months versus 16.1 months, respectively). 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.[57889] [66123]

    For the treatment of biliary tract cancer

    NOTE: Pembrolizumab is designated by the FDA as an orphan drug for the treatment of biliary tract carcinoma.

    for the treatment of locally advanced unresectable or metastatic biliary tract cancer, in combination with gemcitabine and cisplatin

    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 in combination with cisplatin (25 mg/m2 IV) plus gemcitabine (1,000 mg/m2 IV) on days 1 and 8, every 3 weeks; in KEYNOTE-966, treatment with cisplatin was limited to 8 cycles and there was no limit to the number of cycles of gemcitabine. 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, randomized, double-blind phase 3 clinical trial (KEYNOTE-966), treatment with pembrolizumab in combination with cisplatin and gemcitabine significantly improved the median overall survival compared with placebo plus cisplatin and gemcitabine (12.7 months vs. 10.9 months) in patients with locally advanced unresectable or metastatic biliary tract cancer who had not received prior systemic therapy in the advanced disease setting. The median progression-free survival was 6.5 months in the pembrolizumab arm compared with 5.6 months in the placebo arm, and the median objective response rate was 29% in each arm (complete response, 2.1% vs. 1.3%); the median duration of response was 8.3 months vs. 6.8 months, respectively.[57889] [69750]

    Therapeutic Drug Monitoring

    Management of Treatment-Related Toxicity
    Immune-Mediated Reactions
    NOTE: Corticosteroid therapy consists of 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. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. 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.
    Colitis
    Grade 2 or 3 toxicity: Hold pembrolizumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
    Grade 4 toxicity: Permanently discontinue pembrolizumab and administer corticosteroids.
    Endocrinopathies (including Type 1 diabetes, Hypophysitis, Hypothyroidism, Hyperthyroidism, and Adrenal Insufficiency)
    Grade 3 or 4 toxicity: Hold pembrolizumab until the patient is clinically stable; administer appropriate treatment (e.g., hormone replacement therapy, corticosteroids, insulin). Permanently discontinue pembrolizumab for severe toxicity.
    Exfoliative Skin Reactions
    Suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS): Hold pembrolizumab and administer corticosteroids as applicable.
    Confirmed SJS, TEN, or DRESS: Permanently discontinue pembrolizumab and administer corticosteroids.
    Hematologic Toxicity (patients with classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma only)
    Grade 4 toxicity: Hold pembrolizumab. Resume therapy when the adverse event recovers to grade 1 or less.
    Infusion-Related Reactions
    Grade 1 or 2 toxicity: Hold pembrolizumab or slow the infusion rate.
    Grade 3 or 4 toxicity: Permanently discontinue pembrolizumab.
    Myocarditis
    Grade 2, 3, or 4 toxicity: Permanently discontinue pembrolizumab and administer corticosteroids.
    Neurologic Toxicity
    Grade 2 toxicity: Hold pembrolizumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
    Grade 3 or 4 toxicity: Permanently discontinue pembrolizumab and administer corticosteroids.
    Pneumonitis
    Grade 2 toxicity: Hold pembrolizumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
    Grade 3 or 4 toxicity: Permanently discontinue pembrolizumab and administer corticosteroids.
    Other Immune-Mediated Adverse Reactions
    Grade 3 toxicity: Hold pembrolizumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
    Recurrent grade 3 toxicity that requires treatment with other systemic immunosuppressants: Permanently discontinue pembrolizumab.
    Grade 4 toxicity: Permanently discontinue pembrolizumab and administer corticosteroids.[57889]

    Maximum Dosage Limits

    • 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.

    Patients with Hepatic Impairment Dosing

    Treatment-Related Immune-Mediated Hepatitis

    • Monotherapy

    No Tumor Involvement of the Liver
    AST 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 Liver
    Baseline 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 ULN
    AST 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 ULN
    AST 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 level
    AST 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.[57889]

    Patients with Renal Impairment Dosing

    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).[57889]

    † Off-label indication
    Revision Date: 02/02/2024, 02:33:12 PM

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NEJM 2019. Epub ahead of print, doi: 10.1056/NEJMoa1816714.64769 - Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394:1915-1928.64845 - Padcev (enfortumab vedotin-ejfv) injection package insert. Northbrook, Illinois: Astellas Pharma US, Inc; 2023 Dec.65919 - Shitara K, Cutsem EV, Bang YJ, et al. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncology 2020. Epub before print, doi:10.1001/jamaoncol.2020.3370.66036 - Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. NEJM. 2020;382(9):810-821.66073 - Vuky J, Balar AV, Castellano D, et al. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2020;38(23):2658-2666.66122 - Cortes Castan J, Guo Z, Karantza V, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC). Annals of Oncology. 2017;28(10):x25.66123 - Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Journal of Clinical Oncology. 2020;38(15_suppl):1000.66530 - Paz-Ares L, Vicente D, Tafreshi A, et al. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. Journal of Thoracic Oncology. 2020;15(10):1657-1669.66536 - Kojima T, Shah MA, Muro K, et al. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020;38(35):4138-4148.66570 - Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol. 2020;38(21):2369-2379.66632 - Reck M, Rodriguez-Abreu D, Robinson AG, et al. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score >= 50%. J Clin Oncol 2021. Epub ahead of print, doi.org/10.1200/JCO.21.00174.66655 - Chung HC, Bang YJ, Fuchs CS, et al. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol. 2021;17(5):491-501.66703 - Rodriguez-Abreu1 D, Powell SF, Hochmair MJ, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Annals of Oncology. 2021. Epub ahead of print, doi: 10.1016/j.annonc.2021.04.00866893 - Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021;384(14):1289-1300.66945 - Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398:759-771.66963 - Powles T, Csoszi T, Ozguroglu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:931-945.67047 - Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med 2021. Epub ahead of print, doi: 10.1056/NEJMoa2112435.67129 - Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. NEJM. 2021;385(8):683-694.67178 - Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22(5):643-654.67407 - Merck Press Release, July 1, 2021. Merck provides update on KEYTRUDA (pembrolizumab) indication in third-line gastric cancer in the US.67483 - Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/ Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10.67484 - Makker V, Colombo N, Casado Herraez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. NEJM. 2022;386(5):437-448.67485 - Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(15_suppl):4500.67512 - Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet 2022. Epub ahead of print, doi: 10.1016/S0140-6736(22)00562-1.68574 - O’Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022;23:1274-1286.68834 - Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2022;41(1):22-31.69216 - Kuruvilla J, Ramchandren R, Santoro A, et al. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Lancet Oncol 2021;22(4):512-524.69217 - Armand P, Zinzani PL, Lee HJ, et al. Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy in relapsed/refractory classical Hodgkin lymphoma. Blood 2023; Epub ahead of print, doi: 10.1182/blood.2022019386.69434 - Luke JJ, Ascierto PA, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase 3 KEYNOTE-716 study. J Clin Oncol. 2023;41(17 suppl):oral abstract LBA9505.69435 - Eggermont AMM, Kicinski M, Blank CU, et al. Five-Year Analysis of Adjuvant Pembrolizumab or Placebo in Stage III Melanoma. NEJM Evidence. 2023;1(11). Epub ahead of print, doi: 10/1056/EVIDoa2200214.69675 - Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. NEJM. 2023;389(6):491-503.69686 - Choueiri TK, Eto M, Motze R, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023;24:228-238.69693 - Nghiem P, Bhatia S, Lipson EJ, et al. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. J Immunother Cancer 2021;9(4):e002478.69750 - Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401:1853-1865.69837 - Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023. Epub ahead of print, doi: 10.1016/S0140-6736(23)02033-0.69855 - Monk BJ, Colombo N, Tewari KS, et al. KEYNOTE-826: Final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer. J Clin Oncol. 2023;41(16 suppl):5500.69908 - Rha SY, Oh DY, Yanez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24:1181-1195.70064 - Powles TB, Valderrama BP, Gupta S, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Annals of Oncology. 2023;34(S2):S1340.70186 - Armand P, Rodig S, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol 2019;37(34):3291-3299.70187 - Zinzani PL, Thieblemont C, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: final analysis of KEYNOTE-170. Blood 2023;142(2):141-145.70189 - Kuruvilla J, Armand P, Hamadani M, et al. Pembrolizumab for patients with non-Hodgkin lymphoma: phase 1b KEYNOTE-013 study. Leuk Lymphoma 2023;64(1):130-139.70191 - Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: A randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Annals of Oncology. 2023;32(2):S1279-1280.70283 - Qin S, Chen Z, Fang W, et al. Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2023;41(7):1434-1443.

    How Supplied

    Pembrolizumab Lyophilisate for solution for injection

    Keytruda 50mg Powder for Injection (00006-3029) (Merck Sharp & Dohme Corp., a Subsidiary of Merck & Co., Inc.) nullKeytruda 50mg Powder for Injection package photo

    Pembrolizumab Solution for injection

    Keytruda 100mg/4mL Solution for Injection (00006-3026) (Merck Sharp & Dohme Corp., a Subsidiary of Merck & Co., Inc.) nullKeytruda 100mg/4mL Solution for Injection package photo

    Description/Classification

    Description

    Pembrolizumab is a programmed death receptor-1 (PD-1) blocking monoclonal antibody that works by preventing the interaction between PD-1 and the PD-L1 and PD-L2 ligands. It is indicated for the treatment of certain types of breast cancer, cervical cancer, cutaneous squamous cell carcinoma, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, Hodgkin lymphoma, melanoma, Merkel cell carcinoma, microsatellite instability-high or mismatch repair deficient solid tumors (including colorectal cancer), lung cancer, primary mediastinal large B-cell lymphoma (PMBCL), renal cell carcinoma, tumor mutational burden-high solid tumors, and urothelial carcinoma. Immune-mediated adverse reactions including colitis, pneumonitis, hepatitis, hypophysitis, nephritis, hypothyroidism/hyperthyroidism, and encephalitis have been reported with pembrolizumab use; treatment with high-dose corticosteroids may be necessary for patients who develop immune-mediated toxicity.[57889]

    Classifications

    • Antineoplastic and Immunomodulating Agents
      • Antineoplastics
        • Antineoplastic Monoclonal Antibodies
          • Immunomodulatory Monoclonal Antibodies
            • Antineoplastic Monoclonal Antibodies Targeting Programmed Death-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Pathways
    Revision Date: 11/30/2020, 08:53:44 PM

    References

    57889 - Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2024 Jan.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Emetic Risk

    • Minimal [67389]

    Route-Specific 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.[57889]

     

    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.[64928]

     

    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.[57889]

     

    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.[57889]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

    Pembrolizumab

    pH Range
    pH is 5.5.
      Revision Date: 03/25/2022, 01:41:22 PMCopyright 2004-2024 by Lawrence A. Trissel. All Rights Reserved.

      References

      57889 - Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2024 Jan.64928 - Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2019 Sept.67389 - Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797.

      Adverse Reactions

      Mild

      • abdominal pain
      • acneiform rash
      • alopecia
      • anorexia
      • arthralgia
      • asthenia
      • back pain
      • cheilitis
      • chills
      • cough
      • dental pain
      • diarrhea
      • dizziness
      • dysesthesia
      • dysgeusia
      • ecchymosis
      • epistaxis
      • fatigue
      • fever
      • flushing
      • folliculitis
      • headache
      • hypoesthesia
      • infection
      • influenza
      • injection site reaction
      • insomnia
      • lethargy
      • maculopapular rash
      • malaise
      • musculoskeletal pain
      • myalgia
      • nausea
      • paresthesias
      • pelvic pain
      • petechiae
      • pharyngitis
      • pruritus
      • purpura
      • rash
      • rhinitis
      • rhinorrhea
      • seborrhea
      • sinusitis
      • skin discoloration
      • skin hypopigmentation
      • syncope
      • urticaria
      • vomiting
      • weakness
      • weight loss
      • xerophthalmia
      • xerosis

      Moderate

      • adrenocortical insufficiency
      • anemia
      • angina
      • antibody formation
      • atopic dermatitis
      • bleeding
      • blurred vision
      • bone pain
      • bullous rash
      • candidiasis
      • cholangitis
      • colitis
      • confusion
      • constipation
      • contact dermatitis
      • cystitis
      • diabetes mellitus
      • dysphagia
      • dysphonia
      • dyspnea
      • edema
      • elevated hepatic enzymes
      • erythema
      • flank pain
      • gastritis
      • hematoma
      • hematuria
      • hemoptysis
      • hepatitis
      • hepatotoxicity
      • hyperamylasemia
      • hyperbilirubinemia
      • hypercalcemia
      • hypercholesterolemia
      • hyperglycemia
      • hyperkalemia
      • hypermagnesemia
      • hypertension
      • hyperthyroidism
      • hypertriglyceridemia
      • hypoalbuminemia
      • hypocalcemia
      • hypoglycemia
      • hypokalemia
      • hypomagnesemia
      • hyponatremia
      • hypophosphatemia
      • hypophysitis
      • hypotension
      • hypothyroidism
      • infusion-related reactions
      • interstitial lung disease
      • interstitial nephritis
      • iritis
      • leukopenia
      • lymphopenia
      • melena
      • meningitis
      • metabolic acidosis
      • migraine
      • neutropenia
      • ocular inflammation
      • oral ulceration
      • osteomyelitis
      • palmar-plantar erythrodysesthesia (hand and foot syndrome)
      • paresis
      • peripheral edema
      • peripheral neuropathy
      • photophobia
      • pneumonitis
      • prolonged bleeding time
      • proteinuria
      • psoriaform rash
      • sinus tachycardia
      • stomatitis
      • subdural hematoma
      • supraventricular tachycardia (SVT)
      • thrombocytopenia
      • tumor flare
      • urinary retention
      • vaginal bleeding
      • wheezing

      Severe

      • abdominal pain
      • acneiform rash
      • adrenocortical insufficiency
      • alopecia
      • anaphylactoid reactions
      • anemia
      • anorexia
      • aplastic anemia
      • arthralgia
      • ascites
      • asthenia
      • atopic dermatitis
      • atrial fibrillation
      • azotemia
      • back pain
      • bleeding
      • cardiac arrest
      • cardiac tamponade
      • colitis
      • constipation
      • contact dermatitis
      • cough
      • diabetic ketoacidosis
      • diarrhea
      • disseminated intravascular coagulation (DIC)
      • dizziness
      • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
      • dysphagia
      • dysphonia
      • dyspnea
      • elevated hepatic enzymes
      • enterocolitis
      • erythema
      • exfoliative dermatitis
      • fatigue
      • fever
      • folliculitis
      • GI bleeding
      • GI perforation
      • graft-versus-host disease (GVHD)
      • Guillain-Barre syndrome
      • headache
      • heart failure
      • hematemesis
      • hematuria
      • hemolytic anemia
      • hemophagocytic lymphohistiocytosis
      • hepatic failure
      • hepatitis
      • hepatotoxicity
      • hyperamylasemia
      • hyperbilirubinemia
      • hypercalcemia
      • hypercholesterolemia
      • hyperglycemia
      • hyperkalemia
      • hypermagnesemia
      • hypertension
      • hypertensive crisis
      • hyperthyroidism
      • hypertriglyceridemia
      • hypoalbuminemia
      • hypocalcemia
      • hypoglycemia
      • hypokalemia
      • hypomagnesemia
      • hyponatremia
      • hypophosphatemia
      • hypophysitis
      • hypothyroidism
      • infection
      • infusion-related reactions
      • interstitial nephritis
      • intracranial bleeding
      • lethargy
      • leukoencephalopathy
      • leukopenia
      • lymphopenia
      • maculopapular rash
      • malaise
      • metabolic acidosis
      • musculoskeletal pain
      • myalgia
      • myasthenia gravis
      • myelitis
      • myocardial infarction
      • myocarditis
      • nausea
      • nephrotic syndrome
      • neutropenia
      • oliguria
      • organ transplant rejection
      • palmar-plantar erythrodysesthesia (hand and foot syndrome)
      • pancreatitis
      • pericardial effusion
      • pericarditis
      • peripheral edema
      • peripheral neuropathy
      • pleural effusion
      • pneumonitis
      • prolonged bleeding time
      • proteinuria
      • pruritus
      • pulmonary embolism
      • rash
      • renal failure
      • retinal detachment
      • retinopathy
      • rhabdomyolysis
      • sinus tachycardia
      • sinusoidal obstruction syndrome (SOS)
      • Stevens-Johnson syndrome
      • stomatitis
      • supraventricular tachycardia (SVT)
      • thrombocytopenia
      • thrombotic thrombocytopenic purpura (TTP)
      • toxic epidermal necrolysis
      • uveitis
      • vasculitis
      • veno-occlusive disease (VOD)
      • visual impairment
      • Vogt-Koyanagi-Harada syndrome
      • vomiting
      • weight loss

      Immune-mediated hepatitis occurred in 0.7% (grade 3 or 4, 0.4%) of patients receiving pembrolizumab in clinical trials (n = 2,799). Of patients that experienced hepatitis, 68% received systemic corticosteroids and 11% of these patients required additional immunosuppressant therapy. Hepatitis resolved in 79% of patients. All patients who had treatment held for hepatitis resumed therapy with pembrolizumab after symptom improvement; of these, no patient had a recurrence of hepatitis. Monitor hepatic function at baseline and periodically during treatment. 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 and other systemic immunosuppressants may be necessary. In randomized trials, hepatotoxicity occurred in 14% (grade 3 or 4, 3.7%) of patients with renal cell cancer (RCC) treated with pembrolizumab monotherapy in a randomized clinical trial including increased transaminases, immune-mediated and autoimmune hepatitis, hepatic failure, increased bilirubin level, increased gamma glutamyl transferase level, and drug-induced liver injury. Hepatotoxicity occurred in 39% (grade 3 or 4, 20%) and 25% (grade 3 or 4, 9%) of patients with RCC who received pembrolizumab plus axitinib and pembrolizumab plus lenvatinib, respectively. Consider more frequent monitoring in patients receiving pembrolizumab with axitinib. Fatal autoimmune hepatitis occurred in 1 (0.3%) patient who received pembrolizumab plus lenvatinib. Elevated hepatic enzymes including increased ALT (20% to 34%; grade 3 or 4, 1.8% to 9%) and AST (20% to 39%; grade 3 or 4, 1.6% to 20%) levels occurred in patients who received single-agent pembrolizumab in clinical studies for cancers other than hepatocellular cancer. Increased AST (54% vs. 44%; grade 3 or 4, 14% vs. 12%), increased bilirubin (47% vs. 36%; grade 3 or 4, 11% vs. 7%), increased ALT (47% vs. 32%; grade 3 or 4, 7% vs. 4.6%), increased GGT (40% vs. 39%; grade 3 or 4, 20% vs. 15%), and increased alkaline phosphatase (39% vs. 34%; grade 3 or 4, 4.1% vs. 4%) occurred more often in previously treated patients with hepatocellular cancer who received pembrolizumab monotherapy compared with placebo in a clinical trial. The incidence of increased ALT (22% to 75%; grade 3 or 4, 1.6% to 11%) and increased AST (24% to 73%; grade 3 or 4, 1% to 9%) was increased when pembrolizumab was administered in combination with other drugs in clinical trials. While the overall incidence of transaminitis when pembrolizumab was administered in combination with axitinib was toward the upper range of other combination therapies (57% to 60%), grade 3 or 4 increases in ALT (20%) and AST (13%) were higher in this population. Increased alkaline phosphatase occurred in 17% to 48% (grade 3 or 4, 7% or less) of patients who received pembrolizumab as monotherapy or in combination with other drugs in clinical trials. Hyperbilirubinemia occurred in up to 32% (grade 3 or 4, 10% or less) of patients who received pembrolizumab monotherapy or in combination. Additionally, grade 3 or 4 ascites occurred in 8% of patients with hepatocellular carcinoma received single-agent pembrolizumab in a clinical trial. Cholangitis (2.8%) and biliary obstruction (2.3%) occurred in patients with advanced biliary tract cancer treated with pembrolizumab in combination with other drugs in clinical trials. Sclerosing cholangitis has been reported in postmarketing experience with pembrolizumab.[57889]

      Hypoalbuminemia was reported in 16% to 60% (grade 3 or 4, 5% or less) of patients who received pembrolizumab as monotherapy or in combination with other drugs in clinical trials.[57889]

      Constipation occurred in up to 21% (grade 3 or 4, 1.1% or less) of patients who received single-agent pembrolizumab and in 18% to 42% (grade 3 or 4, 1% or less) of patients who received pembrolizumab in combination with other drugs in clinical trials. Nausea was reported in 11% to 28% (grade 3 or 4, 1.6% or less) of patients who received pembrolizumab monotherapy or in combination with axitinib. The incidence was higher when administered in combination with lenvatinib or cytotoxic chemotherapy (36% to 67%; grade 3 or 4, 7% or less). Vomiting occurred in 19.8% or fewer (grade 3 or 4, 1.4% or less) patients who received single-agent pembrolizumab and in 12% to 37% (grade 3 or 4, 7% or less) of patients who received pembrolizumab plus lenvatinib or cytotoxic chemotherapy. The incidence of vomiting (29%) in pediatric patients (age range, 6 months to 17 years) with various cancers who received pembrolizumab 2 mg/kg IV every 3 weeks was at least 10% higher compared with adults. Abdominal pain was reported in 24% or fewer (grade 3 or 4, 3.1% or less) patients who received pembrolizumab as monotherapy or in combination with chemotherapy including pediatric patients, and in 27% to 34% (grade 3 or 4, 22.6%) of patients who received pembrolizumab plus lenvatinib in clinical trials. The term abdominal pain included pelvic pain, flank pain, tumor pain, bladder pain, hepatic pain, suprapubic pain, and abdominal discomfort in some studies.[57889]

      Stomatitis occurred in 3% and mucosal inflammation in 4.3% (grade 3 or 4, 1.3%) of patients with locally advanced or metastatic head and neck cancer treated with pembrolizumab monotherapy in a randomized, open-label trial. The incidence of stomatitis was higher (26% to 43%; grade 3 or 4, 1.6% to 8%) in patients who received pembrolizumab in combination with axitinib, lenvatinib, or platinum-based chemotherapy for various indications; the term stomatitis included aphthous ulcer, oral ulceration, cheilitis, and tongue ulceration. Oropharyngeal pain was reported in 8% of patients with classical Hodgkin lymphoma who received pembrolizumab monotherapy in a randomized trial. The addition of pembrolizumab to axitinib or platinum-based chemotherapy increased the incidence of grade 3 or 4 stomatitis/mucosal inflammation by 2.2% to 5% compared with control arms.[57889]

      Decreased appetite (including early satiety and anorexia) was reported in 15% to 44% (grade 3 or 4, 7% or less) of patients treated with pembrolizumab as monotherapy or in combination with other drugs in clinical trials. Decreased weight/weight loss occurred in 15% to 48% (grade 3 or 4, 10% or less) of pembrolizumab-treated patients.[57889]

      Dysphagia occurred in 8% to 12% (grade 3 or 4, 2.3% to 2.9%) of patients with locally advanced or metastatic head and neck cancer receiving pembrolizumab as a single agent or in combination with platinum-based chemotherapy in a randomized, open-label clinical trial; this was similar to the incidence in patients receiving platinum-based chemotherapy without pembrolizumab (10%; grade 3 or 4, 2.1%). Dysgeusia was reported in 21% to 35% of patients who received treatment with pembrolizumab in combination with enfortumab vedotin.[57889]

      Immune-mediated thyroid disorders including hyperthyroidism have been reported with pembrolizumab therapy. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin medical management as clinically indicated. Pembrolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary. Hyperthyroidism occurred in 12% or fewer patients who received pembrolizumab in randomized clinical trials (grade 3 or 4, 0.1% to 0.3%).[57889]

      Immune-mediated thyroid disorders including hypothyroidism and thyroiditis have been reported with pembrolizumab therapy. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement as clinically indicated. Pembrolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary. Thyroiditis may present with or without endocrinopathy; hypothyroidism may follow hyperthyroidism. Hypothyroidism occurred in 8% to 22% (grade 3, 0.7% or less) of patients treated with pembrolizumab as monotherapy or in combination with cytotoxic chemotherapy; thyroiditis occurred in 0.6% to 2% of patients receiving pembrolizumab monotherapy. Hypothyroidism was reported in 35% (grade 3 or 4, 0.2%) of patients who received pembrolizumab plus axitinib and in 57% to 67% (grade 3 or 4, 0.9% go 1%) of patients who received pembrolizumab plus lenvatinib in clinical trials. Immune-mediated hypoparathyroidism was reported in less than 1% of patients who received pembrolizumab or other PD-1/PD-L1 blocking antibodies.[57889]

      Immune-mediated interstitial nephritis occurred in 0.3% (grade 3 or 4, 0.1%) of patients who received pembrolizumab in clinical trials (n = 2,799). 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 and other systemic immunosuppressants may be necessary. In clinical trials, 89% of patients who experienced nephritis received systemic corticosteroids; nephritis resolved in 56% of patients. All patients who had pembrolizumab therapy held for nephritis resumed therapy after symptoms improvement; of these, none had a recurrence of nephritis. Increased serum creatinine was reported in 11% to 71% (grade 3 or 4, 6% or less) of patients who received pembrolizumab in clinical trials. Acute kidney injury (AKI) including azotemia, increased creatinine, renal failure, renal impairment, oliguria, decreased glomerular filtration rate, and toxic nephropathy occurred in 13% to 21% (grade 3 or 4, 1.2 to 5%) of patients with renal cell cancer (RCC) treatment with pembrolizumab as monotherapy or in combination with lenvatinib; it was reported in at least 1% and up to 7% of patients treated with pembrolizumab as monotherapy or in combination with chemotherapy in other clinical trials. Serious cases of urinary retention occurred in 2.5% of patients with advanced urothelial cancer who received treatment with pembrolizumab in combination with enfortumab vedotin.[57889]

      Severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis/anaphylactoid reactions occurred in 0.2% of patients who received pembrolizumab across clinical trials (n = 2,799). Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, itching, flushing, rash, hypotension, hypoxemia, and fever. Stop the infusion and permanently discontinue pembrolizumab in patients who develop grade 3 or 4 infusion-related reactions. Hypersensitivity (4.1%) and infusion reactions (9% or less) were reported in patients with classical Hodgkin lymphoma who received pembrolizumab monotherapy in clinical trials. Allergic reactions led to a discontinuation of therapy in 0.4% of patients with unresectable or metastatic melanoma in another clinical trial.[57889]

      Immune-mediated pneumonitis occurred in 3.4% (grade 3 or 4, 1.2%; grade 5, 0.1%) of patients who received pembrolizumab in clinical trials (n = 2,799). The incidence of pneumonitis is higher in patients who have received prior thoracic radiation therapy, except in patients with classical Hodgkin lymphoma (cHL). Monitor patients for signs and symptoms of pneumonitis. If confirmed, pembrolizumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Of patients who experienced pneumonitis after single-agent pembrolizumab therapy, 67% received systemic corticosteroids, with resolution occurring in 59% of patients. All patients who had pembrolizumab therapy held for pneumonitis resumed therapy after symptoms improvement; of these, 23% had a recurrence of pneumonitis. Pneumonitis/interstitial lung disease (ILD) was reported in 7% to 10% (grade 3 or higher, 1% to 9%) of pembrolizumab-treated patients in individual clinical trials.[57889]

      Cough was reported in 11% to 26% (grade 3 or 4, 2% or less) of patients who received pembrolizumab as monotherapy or in combination with cytotoxic chemotherapy, axitinib, or lenvatinib in clinical trials. Dyspnea occurred in 23% or less (grade 3 or 4, 11% or less) of patients who received single-agent pembrolizumab and in 10% to 21% (grade 3 or 4, 1.8% to 3.7%) of patients who received pembrolizumab plus platinum-containing chemotherapy in clinical trials. In some studies, the term cough included upper-airway cough syndrome; the term dyspnea included wheezing. Pleural effusion was reported in 2.2% of patients with non-small cell lung cancer who received single-agent pembrolizumab (n = 636) and in 2% or more of patients with head and neck squamous cell cancer who received single-agent pembrolizumab (n = 192) in clinical trials. One fatality due to pleural effusion was reported in a patient with renal cell carcinoma who received pembrolizumab plus axitinib.[57889]

      Fever was reported in 11% to 28% (grade 3 or 4, 1.3% or less) of adult patients treated with pembrolizumab monotherapy or in combination with chemotherapy at doses ranging from a 200 mg flat dose to 10 mg/kg across various clinical trials in multiple disease states. Fever (3%) was among the most common serious adverse reactions reported in patients with endometrial cancer who were treated with pembrolizumab plus lenvatinib in a nonrandomized, multicohort study. The incidence of fever (33%) in pediatric patients (age range, 6 months to 17 years) with various cancers who received pembrolizumab 2 mg/kg IV every 3 weeks was at least 10% higher compared with adults.[57889]

      Peripheral edema was reported in 11% to 15% (grade 3 or 4, 2% or less) of patients with urothelial cancer, bladder, cancer, or cervical cancer treated with pembrolizumab monotherapy in separate clinical trials. Peripheral edema occurred in 26% of patients who received treatment with pembrolizumab in combination with enfortumab vedotin, and was responsible for an interruption of therapy in 2% of patients with endometrial cancer treated with pembrolizumab plus lenvatinib in a nonrandomized, multicohort study. Generalized edema was responsible for discontinuation of therapy in 1% of patients with ipilimumab-refractory melanoma receiving pembrolizumab monotherapy in a randomized clinical trial (n = 357). Additionally, facial edema occurred in 10% (grade 3 or 4, 2.1) of pembrolizumab-treated patients with head and neck cancer (n = 192).[57889]

      Fatigue was reported in 20% to 43% (grade 3 or 4, 6% or less) of patients who received pembrolizumab monotherapy in clinical trials; the incidence was higher in patients who received pembrolizumab plus cytotoxic chemotherapy (26% to 70%; grade 3 or 4, 1% to 12%) or axitinib, lenvatinib, or enfortumab vedotin (51% to 58%; grade 3 or 4, 5% to 11%). The term fatigue included asthenia, malaise, and lethargy in some trials. Asthenia was reported in 11% or fewer (grade 3 or 4, 2% of less) patients who received single-agent pembrolizumab.[57889]

      Immune-mediated neurologic toxicity that was reported in less than 1% of patients who received pembrolizumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, and autoimmune neuropathy; cases may be severe or fatal. Pembrolizumab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Myositis occurred in 1% of patients receiving pembrolizumab monotherapy in 1 clinical trial and in 0.5% to 3.3% of patients receiving pembrolizumab in combination with enfortumab vedotin 2 other trials; autoimmune myositis with respiratory failure resulted in death in 1 patient who was treated with pembrolizumab monotherapy. Myelitis occurred in 0.5% of patients receiving pembrolizumab monotherapy in 1 clinical trial, and myasthenia gravis occurred in 2.5% of patients treated with pembrolizumab plus enfortumab vedotin. Peripheral neuropathy was reported in 10% or fewer (grade 3 or 4, 0.7%) patients who received pembrolizumab as a single-agent, 14% (grade 3 or 4, 1.1%) of patients treated with pembrolizumab in combination with only platinum-containing chemotherapy, and 31% to 67% (grade 3 or 4, 8% or less) of patients who received pembrolizumab in combination with other cytotoxic chemotherapy. The term peripheral neuropathy included sensory and motor peripheral neuropathy, hypoesthesia, paresthesias, dysesthesia, and polyneuropathy.[57889]

      Immune-mediated dermatologic/skin toxicity occurred in 1.4% (grade 3, 1%) of patients who received pembrolizumab in clinical trials (n = 2,799). Monitor patients for suspected severe skin reactions including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS); 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. In clinical trials, 40% of patients who experienced skin toxicity received systemic corticosteroids; skin toxicity resolved in 79% of patients. All patients who had pembrolizumab therapy held for skin toxicity resumed therapy after symptoms improvement; of these, 6% had a recurrence of skin toxicity. Rash was reported in 11% to 52% (grade 3 or 4, 5% or less) of patients who received pembrolizumab as a single-agent or in combination with chemotherapy, axitinib, or lenvatinib in clinical trials; the incidence was higher in patients treated with pembrolizumab in combination with enfortumab vedotin (68% to 71%; grade 3 or 4, 15% to 21%). The term rash included acneiform rash, butterfly rash, erythematous rash/erythema, eczema, asteatotic eczema, follicular rash/folliculitis, maculopapular rash, and pruritic rash, genital rash, pustular rash, atopic dermatitis, contact dermatitis, bullous rash, exfoliative dermatitis/rash, erythema multiforme, seborrheic dermatitis/seborrhea, psoriaform rash/dermatitis, palmar-plantar erythrodysesthesia (hand and foot syndrome), lichenoid keratosis, skin discoloration, perineal rash, eyelid rash, vesicular rash, injection site rash, morbilliform rash, rubelliform rash, vasculitic rash, viral rash, and urticaria in some trials. Vitiligo including skin hypopigmentation occurred in 13% of patients with melanoma who received single-agent pembrolizumab 10 mg/kg IV every 2 or 3 weeks in a randomized trial. Hand and foot syndrome was reported in 23% to 29% (grade 3 or 4, 2.9% to 5%) of patients who received pembrolizumab in combination with axitinib or lenvatinib in separate randomized clinical trials. DRESS resulting in death occurred in 1 patient with melanoma who was treated with pembrolizumab. Xerosis occurred in 17% to 21% (grade 3 or 4, 0.8% or less) of patients who received treatment with pembrolizumab in combination with enfortumab vedotin.[57889]

      Pruritus was reported in 11% to 41% (grade 3 or 4, 3.3% or less) of pembrolizumab-treated patients across clinical trials.[57889]

      Alopecia occurred in 31% to 61% (grade 3 or 4, 0.8% or less) of patients who received pembrolizumab in combination with cytotoxic chemotherapy.[57889]

      Musculoskeletal pain (19% to 41%; grade 3 or 4, 5% or less), arthralgia (18% or less; grade 3 or 4, 1.4% or less), back pain (12% or less; grade 3 or 4, 1.5% or less), myalgia (12% or less; grade 3 or 4, 1% or less), neck pain (6% or less; grade 3 or 4, 0.7% or less), and generalized pain (22% or less; grade 3 or 4, 2% or less) were reported in patients who received pembrolizumab monotherapy in clinical trials. Musculoskeletal disorders (53% to 58%; grade 3 or 4, 4% to 5%) and increased creatine kinase concentrations (19% to 24%; grade 3 or 4, 3.7% to 6%) occurred in patients treated with pembrolizumab plus lenvatinib. The terms musculoskeletal pain and/or musculoskeletal disorders included arthralgia, back pain, myalgia, myositis, bone pain/spinal pain, extremity pain, musculoskeletal chest pain/discomfort, neck pain, arthritis, breast pain, stiffness, and jaw pain. The term generalized pain including breast pain, cancer pain, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, skin pain, radicular pain, stoma site pain, and toothache/dental pain. Arthralgia (29% or less; grade 3 or 4, 1.7% or less) and myalgia (20% or less; grade 3 or 4, 0.5% or less) occurred in patients receiving pembrolizumab in combination with cytotoxic chemotherapy.[57889]

      Immune-mediated hematologic toxicity that was reported in less than 1% of patients who received pembrolizumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies includes hemolytic anemia and aplastic anemia. Pembrolizumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Anemia was reported in patients who received single-agent pembrolizumab (17% to 54%; grade 3 or 4, 24% or less), pembrolizumab in combination with platinum-containing chemotherapy (65% to 97%; grade 3 or 4, 15% to 35%), pembrolizumab plus enfortumab vedotin (53% to 69%; grade 3 or 4, 7% to 15%), pembrolizumab plus axitinib (29%; grade 3 or 4, 2.1%), and pembrolizumab plus lenvatinib (38% to 49%; grade 3 or 4, 3% to 8%) in clinical trials. The incidence of anemia (17%) in pediatric patients (n = 161; age range, 6 months to 17 years) with various cancers who received pembrolizumab 2 mg/kg IV every 3 weeks was at least 10% higher compared with adults.[57889]

      Lymphopenia was reported in 10% or 55% (grade 3 or 4, 25% or less) of patients who received single-agent pembrolizumab; 57% to 99% (grade 3 or 4, 15% to 96%) of patients who received pembrolizumab plus chemotherapy including enfortumab vedotin; 33% (grade 3 or 4, 11%) of patients who received pembrolizumab plus axitinib; and 50% to 54% (grade 3 or 4, 9% to 16%) of patients who received pembrolizumab plus lenvatinib in clinical trials. Neutropenia occurred in 30% or fewer (grade 3 or 4, 11% or less) patients who received single-agent pembrolizumab; 31% to 88% (grade 3 or 4, 4% to 62%) of patients who received pembrolizumab plus chemotherapy. Febrile neutropenia was reported in 1% to 15% of pembrolizumab-treated patients. Leukopenia occurred in 30% to 35% (grade 3 or 4, 1.3% to 9%) of patients who received pembrolizumab monotherapy (n = 53); 34% to 43% (grade 3 or 4, 1% to 3.5%) of patients who received pembrolizumab plus lenvatinib; and in 59% to 93% (grade 3 or 4, 7% to 46%) of patients treated with pembrolizumab in combination with cytotoxic chemotherapy in other clinical trials. The incidence of leukopenia (31%) and neutropenia (28%) in pediatric patients (age range, 6 months to 17 years) with various cancers who received pembrolizumab 2 mg/kg IV every 3 weeks was at least 10% higher compared with adults.[57889]

      Thrombocytopenia occurred in 34% or fewer (grade 3 or 4, 10% or less) patients who received single-agent pembrolizumab; 30% to 73% (grade 3 or 4, 5% to 19%) of patients who received pembrolizumab plus cytotoxic chemotherapy; 27% (grade 3 or 4, 1.4%) of patients who received pembrolizumab plus axitinib; and 39% to 50% (grade 3 or 4, 2% to 8%) of patients who received pembrolizumab plus lenvatinib in clinical trials. The incidence of thrombocytopenia (22%) in pediatric patients (age range, 6 months to 17 years) with various cancers who received pembrolizumab 2 mg/kg IV every 3 weeks was at least 10% higher compared with adults.[57889]

      Cases of infection, some fatal, have been reported in patients treated with pembrolizumab across clinical trials including urinary tract infections (11% to 32%; grade 3 or 4, 12% or less), pneumonia (8% to 19%; grade 3 or 4, 1% to 11%), upper respiratory infections (11% to 41%; grade 3 or 4, 2.6% or less), nasopharyngitis (10%), influenza-like illness (11%), herpes virus infection (9%), and sepsis (1% or more); additional infections have included autoimmune encephalitis, cellulitis, Clostridium difficile, cystitis, device-related infections, empyema, erysipelas, herpes virus infection, infected neoplasm, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, osteomyelitis, pelvic infection, pharyngotonsillitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, tooth abscess, uterine abscess, and vulvovaginal candidiasis.[57889]

      Hypophosphatemia occurred in 21% to 51% (grade 3 or 4, 15% or less) and hyponatremia in 10% to 60% (grade 3 or 4, 20% or less) of patients who received pembrolizumab as monotherapy or in combination with other drugs in clinical trials. Decreased bicarbonate/metabolic acidosis (22% or less; grade 3 or 4, 0.4% or less) occurred in ipilimumab-refractory melanoma patients who received single-agent pembrolizumab (n = 357) in a randomized trial.[57889]

      Hypocalcemia (15% to 49%; grade 3 or 4, 4.7% or less) and hypercalcemia (14% to 27%; grade 3 or 4, 0.7% to 4.6%) occurred in patients receiving pembrolizumab monotherapy or in combination with other anticancer therapy.[57889]

      Hypokalemia occurred in 42% or less (grade 3 or 4, 14% or less) of patients treated with pembrolizumab monotherapy or in combination with other drugs in clinical trials. Hyperkalemia was reported in 23% to 44% (grade 3 or 4, 1.4% to 9%) of pembrolizumab-treated patients in clinical trials.[57889]

      Hypomagnesemia was reported in 16% to 59% (grade 3 or 4, 6% or less) of patients treated with pembrolizumab monotherapy, in combination with cytotoxic chemotherapy, or in combination with lenvatinib in clinical trials. Hypermagnesemia occurred in 23% (grade 3 or 4, 2%) of patients with renal cell carcinoma who received pembrolizumab plus lenvatinib (n = 352) in a randomized trial.[57889]

      Immune-mediated cardiovascular toxicity that was reported in less than 1% of patients who received pembrolizumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include myocarditis, pericarditis, and vasculitis; cases may be severe or fatal. Pembrolizumab therapy may need to be to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Myocarditis was reported in 1.4% of patients with classical Hodgkin lymphoma who received pembrolizumab in clinical trials. Myocarditis has been reported in postmarketing surveillance of pembrolizumab. Death due to myocarditis occurred in patients with renal cell carcinoma who received pembrolizumab and axitinib (n = 1) or levatinib (n  = 1). Pericarditis occurred in 4% of patients with primary mediastinal large B-cell lymphoma who received pembrolizumab in a clinical trial (n = 53).[57889]

      Type 1 diabetes mellitus (which may 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. Type 1 diabetes mellitus occurred in 0.2% of patients who received pembrolizumab in clinical trials. All patients who developed diabetes required long-term insulin therapy. Hyperglycemia occurred in 36% to 74% (grade 3 or 4, 1.3% to 14%) of patients treated with pembrolizumab monotherapy or in combination with other anticancer therapy. Diabetic ketoacidosis occurred in 1% of patients with renal cell cancer who received adjuvant treatment with pembrolizumab monotherapy. Hypoglycemia was reported in 19% of patients with primary mediastinal large B-cell lymphoma and 13% (grade 3 or 4, 1.3%) of patients with cervical cancer who received single-agent pembrolizumab. Hypoglycemia also occurred in 44% (grade 3 or 4, 2%) of patients with renal cell carcinoma who received lenvatinib in combination with pembrolizumab (n = 352) in a randomized trial.[57889]

      Headache was reported in 15% or fewer (grade 3 or 4, 2% or less) patients who received single-agent pembrolizumab and in 11% to 30% (grade 3 or 4, 1% or less) of patients receiving pembrolizumab in combination with other anticancer drugs. The term headache included tension headache and migraine. The incidence of headache (25%) in pediatric patients (age range, 6 months to 17 years) with various cancers who received pembrolizumab was at least 10% higher compared with adults. Dizziness occurred in 5% (grade 3 or 4, 0.3%) of patients with HNSCC who received single-agent pembrolizumab and 10% (grade 3 or 4, 0.4%) of HNSCC patients who received pembrolizumab plus platinum-containing chemotherapy. Dizziness was reported in 23% of patients treated with pembrolizumab in combination with enfortumab vedotin.[57889]

      Primary or secondary adrenocortical insufficiency and immune-mediated hypophysitis have been reported with pembrolizumab therapy. 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. Adrenal insufficiency (0.8%; grade 3 or 4, 0.3%) and immune-mediated hypophysitis (0.6%; grade 3 or 4, 0.3%) occurred in patients who received pembrolizumab in clinical trials (n = 2,799). Of patients that developed adrenal insufficiency or hypophysitis, 77% and 94% received systemic corticosteroids, respectively; additionally, the majority of these patients remained on corticosteroids. Hypophysitis can present with acute symptoms associated with mass effect such as photophobia or visual field defects; hypophysitis may lead to hypopituitarism. Adrenal insufficiency was reported in 3% of patients with endometrial cancer treated with pembrolizumab plus lenvatinib in a nonrandomized study (n = 94).[57889]

      Antibody formation occurred in 27 patients (2.1%) who received pembrolizumab in clinical studies (n = 1,289). Of these, neutralizing antibodies were confirmed in 6 patients (0.5%).[57889]

      Cardiac arrhythmias including atrial fibrillation, sinus tachycardia, and supraventricular tachycardia (SVT) (11%; grade 3 or 4, 4%), pericardial effusion (2%), cardiac tamponade (2%), myocardial infarction (MI) (2%), and pericarditis (4%; grade 3 or 4, 2%) have been reported in patients with primary mediastinal large B-cell lymphoma who received pembrolizumab in a nonrandomized trial (n = 53). MI (3%) and angina pectoris (1%) occurred in patients with renal cell carcinoma who received pembrolizumab plus lenvatinib (n = 352) in a randomized trial; fatal cardiovascular events included arrhythmia (0.3%) and multiple organ dysfunction syndrome (0.3%). Additionally, pembrolizumab therapy was discontinued due to heart failure in 0.4% of patients with ipilimumab-naive, unresectable or metastatic melanoma treated with pembrolizumab 10 mg/kg every 2 or 3 weeks in a randomized, clinical trial (n = 555). Fatal respiratory/cardiac arrest has also occurred with pembrolizumab therapy. Fatal acute MI and cardiac arrest were each reported in 1 patient with cervical cancer who received pembrolizumab plus chemotherapy with or without bevacizumab (n = 307) in a randomized trial.[57889]

      Hypercholesterolemia (20%; grade 3 or 4, 0.7% to 1.2%) and hypertriglyceridemia (33% to 43%; grade 3 or 4, 2.6% or less) were reported in patients with advanced melanoma or non-small cell lung cancer (NSCLC) who received pembrolizumab at doses of either 2 mg/kg or 10 mg/kg (n = 1,594) in separate clinical trials. The incidence of hypercholesterolemia (53% to 64%; grade 3 or 4, 3.2% to 5%) and hypertriglyceridemia (70% to 80%; grade 3 or 4, 6% to 15%) were increased in patients treated with pembrolizumab plus lenvatinib in randomized trials.[57889]

      Fatal and serious adverse events occurred in patients who received an allogeneic hematopoietic stem-cell transplant (HSCT) prior to and after treatment with a PD-1/PD-L1 blocking antibody, such as pembrolizumab. Monitor patients closely for evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause); treat adverse events promptly. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.GVHD occurred in 1% or more of patients with classical Hodgkin lymphoma (n = 206) who received pembrolizumab in a clinical study; 1 patients died from GVHD after subsequent allogeneic SCT.[57889]

      Immune-mediated toxicity that was reported in less than 1% of patients who received pembrolizumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection; cases may be severe or fatal. Pembrolizumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.[57889]

      Bleeding was reported in 19% (grade 3 or 4, 5%) of patients with cervical cancer who received pembrolizumab monotherapy in a nonrandomized trial (n = 98). Fatal bleeding occurred in 3 patients with cervical cancer who received pembrolizumab plus chemotherapy with or without bevacizumab. Additionally, bleeding events occurred in 25% (grade 3 or 4, 2.6%) and 27% (grade 3 or 4, 5%) of patients with endometrial cancer and renal cell carcinoma (RCC), respectively, who received lenvatinib plus pembrolizumab in clinical trials. The term bleeding included epistaxis, hematuria, hemoptysis, metrorrhagia, rectal bleeding, uterine hemorrhage, and vaginal bleeding. The term bleeding events included blood blister, coital bleeding, disseminated intravascular coagulation (DIC), hemothorax, Mallory-Weiss syndrome, petechiae, retroperitoneal hemorrhage, contusion, ecchymosis, GI bleeding, hematemesis, hematochezia, subdural hematoma, hematoma, intracranial bleeding, injection site bleeding or bruising, melena, metrorrhagia, mouth bleeding, ocular hemorrhage, pulmonary hemorrhage, purpura, thrombotic thrombocytopenic purpura (TTP), rectal or anal bleeding, renal or urinary tract bleeding, ruptured aneurysm, stoma site hemorrhage, tumor bleeding, umbilical hemorrhage, and wound hemorrhage. Fatal aneurysm rupture (0.3%) and subarachnoid hemorrhage (0.3%) were reported in RCC patients who received lenvatinib plus pembrolizumab (n = 352) in a randomized trial. Prolonged bleeding time including increased INR (19% to 27%; grade 3 or 4, 2% or less) and activated partial thromboplastin time (14% to 22%; grade 3 or 4, 1.2% or less) occurred in patients treated with pembrolizumab monotherapy or in combination with axitinib in several clinical trials. Hematuria occurred in 12% to 19% (grade 3 or 4, 1.4% to 3%) of patients treated with pembrolizumab monotherapy in clinical trials; serious cases of hematuria were reported in 3.3% of patients with advanced urothelial cancer who received pembrolizumab in combination with enfortumab vedotin.[57889]

      Confusion occurred in at least 2% of patients with recurrent or metastatic head and neck cancer who received pembrolizumab in an open-label, single-arm clinical trial (n = 192). Additionally, confusion (4%) was among the commonly reported serious adverse reactions in patients with endometrial cancer treated with pembrolizumab plus lenvatinib in a nonrandomized, multicohort study.[57889]

      Dysphonia was reported in 22% to 30% (grade 3 or 4, 0.2% or less) of patients treated with pembrolizumab plus either axitinib or lenvatinib in separate clinical trials.[57889]

      Hypertension was reported in 48% (grade 3 or 4, 24%) of patients who received pembrolizumab plus axitinib, 56% to 67% (grade 3 or 4, 29% to 39%) of patients who received pembrolizumab plus lenvatinib, and 24% (grade 3 or 4, 9%) of patients who received pembrolizumab plus chemotherapy with or without bevacizumab in clinical trials. Fatal hypertensive crisis occurred in 1 patient (0.3%) who received pembrolizumab plus lenvatinib. The term hypertension included hypertensive crisis, labile hypertension, hypertensive encephalopathy, and hypertensive retinopathy.[57889]

      Insomnia occurred in 7% to 10% (grade 3 or 4, 0.7% or less) of patients with advanced head and neck cancer treated with pembrolizumab as monotherapy or in combination with platinum-based chemotherapy. In another clinical trial, 21% (grade 3 or 4, 0.5%) of patients with high-risk, early stage triple-negative breast cancer experienced insomnia during neoadjuvant treatment with pembrolizumab in combination with carboplatin/paclitaxel followed by doxorubicin/cyclophosphamide. Altered mental state was reported in 2.7% of patients with classical Hodgkin lymphoma who received pembrolizumab monotherapy in a randomized trial.[57889]

      Immune-mediated toxicity that was reported in less than 1% of patients who received pembrolizumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include pancreatitis and increases in serum amylase levels/hyperamylasemia and lipase levels; cases may be severe or fatal. Pembrolizumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. In pooled results from 2 trials (n = 105), grade 3 or 4 increased lipase level was reported in 17% of patients with advanced Merkel cell carcinoma who received pembrolizumab. Hyperamylasemia (25% to 59%; grade 3 or 4, 6% to 17%) and increased lipase level (36% to 61%; grade 3 or 4, 14% to 34%) occurred in patients who received pembrolizumab plus lenvatinib in a randomized trial. An increase in lipase from baseline was also reported in 59% (grade 3 or 4, 32%) of patients who received treatment with pembrolizumab in combination with enfortumab vedotin.[57889]

      Fatal reversible posterior leukoencephalopathy syndrome (RPLS) was reported in a nonrandomized, multicohort study of patients with endometrial cancer treated with pembrolizumab plus lenvatinib.[57889]

      Fatal intestinal/GI perforation was reported in patients with endometrial cancer treated with pembrolizumab plus lenvatinib and in patients with cervical cancer who received pembrolizumab plus chemotherapy with or without bevacizumab.[57889]

      Muscle weakness was responsible for discontinuation of therapy in 2% of patients with endometrial cancer treated with pembrolizumab plus lenvatinib in a nonrandomized, multicohort study.[57889]

      Syncope was responsible for interruption of therapy in 2% of patients with endometrial cancer treated with pembrolizumab plus lenvatinib in a nonrandomized, multicohort study.[57889]

      Pulmonary embolism occurred in 2% of patients with high-risk non-muscle invasive bladder cancer in a multicenter, noncomparative trial. A fatal event involving a cerebrovascular accident and femur fracture with perioperative pulmonary embolus occurred in 1 patient with cervical cancer who received pembrolizumab plus chemotherapy with or without bevacizumab (n = 307) in a randomized trial.[57889]

      Tumor flare was reported in 1.4% of patients with classical Hodgkin lymphoma who received pembrolizumab monotherapy (n = 148) in a randomized trial.[57889]

      Immune-mediated ocular toxicity that was reported in less than 1% of patients who received pembrolizumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include uveitis, iritis, and other ocular inflammation toxicity; some cases may be associated with retinal detachment. Pembrolizumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Patients may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss. Visual impairment including vision loss/blindness may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a diagnosis of Vogt-Koyanagi-Harada syndrome. Uveitis was reported in 1.4% or less of patients with classical Hodgkin lymphoma who received pembrolizumab in clinical trials. Xerophthalmia (24% to 25%) and blurred vision (6%) were reported in patients treated with pembrolizumab in combination with enfortumab vedotin.[57889]

      Immune-mediated arthritis occurred in 1.5% of patients who received pembrolizumab therapy. Other immune-mediated musculoskeletal toxicity that was reported in less than 1% of patients who received pembrolizumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure) and polymyalgia rheumatica; cases may be severe or fatal. Pembrolizumab therapy may need to be to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Myositis was reported in 0.5% of patients with classical Hodgkin lymphoma who received pembrolizumab in a clinical trial (n = 210). Autoimmune myositis with respiratory failure resulted in death in 1 patient with melanoma who was treated with pembrolizumab. Arthritis was reported in 2% of patients with primary mediastinal B-cell lymphoma who received pembrolizumab in a clinical trial (n = 53).[57889]

      Proteinuria (including hemoglobinuria and nephrotic syndrome) occurred in 29% (grade 3 or 4, 6%) and 30% (grade 3 or 4, 8%) of patients with endometrial cancer and renal cell cancer, respectively, who received lenvatinib plus pembrolizumab in randomized clinical trials.[57889]

      An injection site reaction/extravasation occurred in 0.8% to 2% of patients who received treatment with pembrolizumab in combination with enfortumab vedotin.[57889]

      Revision Date: 02/02/2024, 02:28:51 PM

      References

      57889 - Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2024 Jan.

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • adrenal insufficiency
      • allogeneic stem cell transplant
      • anemia
      • autoimmune disease
      • breast-feeding
      • children
      • colitis
      • contraception requirements
      • Crohn's disease
      • diabetic ketoacidosis
      • geriatric
      • Guillain-Barre syndrome
      • hepatitis
      • hepatotoxicity
      • hyperglycemia
      • hyperthyroidism
      • hypophysitis
      • hypopituitarism
      • hypothyroidism
      • immune-mediated reactions
      • infants
      • inflammatory bowel disease
      • infusion-related reactions
      • multiple myeloma
      • myasthenia gravis
      • neurological disease
      • neutropenia
      • organ transplant
      • pneumonitis
      • pregnancy
      • pregnancy testing
      • radiation therapy
      • renal failure
      • renal impairment
      • reproductive risk
      • serious rash
      • systemic lupus erythematosus (SLE)
      • thrombocytopenia
      • treatment outside of a clinical trial
      • type 1 diabetes mellitus
      • ulcerative colitis
      • viral infection

      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.[57889]

      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.[57889]

      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]

      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]

      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]

      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.[57889]

      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.[57889]

      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).[57889]

      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.[57889]

      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.[57889]

      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.[57889]

      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.[57889]

      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.[57889] 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.[62286]

      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.[57889]

      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.[57889]

      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) or mismatch repair deficient (dMMR) 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, abdominal pain, headache, leukopenia, lymphopenia, neutropenia, thrombocytopenia, and anemia in pediatric patients (range, 6 months to 17 years; n = 173) 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]

      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%).[57889]

      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.[57889] 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.[66947] [66948] [66949]

      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 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.[57889]

      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. Maternal IgG is known to be present in human milk.[57889] Pembrolizumab is a large protein molecule (molecular weight of 149,000 Daltons). It is unknown if pembrolizumab is present in human milk, the amount of drug in milk is likely to be very low. Pembrolizumab may be partially destroyed in the gastrointestinal tract resulting in minimal absorption.[66941] The effects of local gastrointestinal exposure and limited systemic exposure to pembrolizumab in the breastfed child are unknown.[57889]

      Revision Date: 04/13/2023, 01:38:23 PM

      References

      57889 - Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2024 Jan.62286 - US Food and Drug Administration (FDA). MedWatch FDA Drug Safety Communication: Keytruda (pembrolizumab) in Patients with Multiple Myeloma: FDA Statement - Two Clinical Trials on Hold. Retrieved August 31, 2017. Available on the World Wide Web at: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm574347.htm66941 - National Institutes of Health (NIH). Pembrolizumab monograph. LactMed: Drug and Lactation Database. Revised April 2021. Available at https://www.ncbi.nlm.nih.gov/books/NBK500739/. Accessed August 26, 2021.66947 - Johnson DB, Sullivan RJ, and Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer 2017;123(11):1904-1911.66948 - Meggyes M, Miko E, Szigeti B, et al. The importance of the PD-1/PD-L1 pathway at the maternal-fetal interface. BMC Pregnancy Childbirth 2019;19(1):74.66949 - Wang SC, Li YH, Piao HL, Hong XW, et al. PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy. Cell Death Dis 2015;6(5):e1738.

      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] Combination treatment of a PD-1 blocking antibody and lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and reduced tumor growth in syngeneic mouse tumor models compared to either treatment alone.[57889]

      Revision Date: 10/30/2023, 04:04:50 PM

      References

      57889 - Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2024 Jan.57904 - Robert C, Soria JC, and Eggermont AM. Drug of the year: programmed death-1 receptor/programmed death-1 ligand-1 receptor monoclonal antibodies. Eur J Cancer 2013;49(14):2968-2971.

      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%).[57889]

      Route-Specific Pharmacokinetics

      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.[57889] 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.[57890] 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 with solid tumors (i.e., melanoma, non-small cell lung cancer) 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 a time-dependent pharmacokinetic (PK) model that evaluated PK parameters across indications, the clearance of pembrolizumab is reduced in patients with Hodgkin lymphoma (HL) or primary mediastinal B-cell lymphoma (PMBCL) tumor types; however, the minor increase in pembrolizumab exposure is not considered clinically significant.[65362] Although there does not appear to be any clinically significant differences in efficacy and safety with pembrolizumab dosages of 200 mg every 3 weeks compared with 400 mg every 6 weeks in patients with solid tumors, the exposure-response relationships for efficacy or safety are not fully known at the pembrolizumab 400 mg every 6 weeks dosage in patients with classical HL or PMBCL.[57889]

      Special Populations

      Hepatic Impairment

      Mild to moderate hepatic impairment (total bilirubin less than 3 times the upper limit of normal (ULN) and any AST) had no clinically significant impact on pembrolizumab clearance. Pembrolizumab has not been studied sufficiently in patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST).[57889]

      Renal Impairment

      Renal impairment (eGFR 15 mL/min/1.73 m2 or higher) had no clinically significant impact on pembrolizumab clearance in a population pharmacokinetic analysis.[57889]

      Pediatrics

      Following weight-based dosing at 2 mg/kg IV every 3 weeks, pembrolizumab concentrations in pediatric patients (age range, 10 months to 17 years) were comparable to pembrolizumab concentrations in adults who received the same dosage.[57889]

      Geriatric

      Age (range, 15 to 94 years) had no clinically significant impact on pembrolizumab clearance in a population pharmacokinetic analysis.[57889]

      Gender Differences

      Gender had no clinically significant impact on pembrolizumab clearance in a population pharmacokinetic analysis.[57889]

      Ethnic Differences

      Race had no clinically significant impact on pembrolizumab clearance in a population pharmacokinetic analysis.[57889]

      Other

      Tumor Burden

      Tumor burden had no clinically significant impact on pembrolizumab clearance in a population pharmacokinetic analysis.[57889]

      Revision Date: 02/05/2024, 06:03:00 PM

      References

      57889 - Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2024 Jan.57890 - Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014;384(9948):1109-1117.65362 - Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer 2020;131:68-75.

      Pregnancy/Breast-feeding

      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.[57889] 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.[66947] [66948] [66949]

      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. Maternal IgG is known to be present in human milk.[57889] Pembrolizumab is a large protein molecule (molecular weight of 149,000 Daltons). It is unknown if pembrolizumab is present in human milk, the amount of drug in milk is likely to be very low. Pembrolizumab may be partially destroyed in the gastrointestinal tract resulting in minimal absorption.[66941] The effects of local gastrointestinal exposure and limited systemic exposure to pembrolizumab in the breastfed child are unknown.[57889]

      Revision Date: 02/06/2023, 02:40:15 PM

      References

      57889 - Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2024 Jan.66941 - National Institutes of Health (NIH). Pembrolizumab monograph. LactMed: Drug and Lactation Database. Revised April 2021. Available at https://www.ncbi.nlm.nih.gov/books/NBK500739/. Accessed August 26, 2021.66947 - Johnson DB, Sullivan RJ, and Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer 2017;123(11):1904-1911.66948 - Meggyes M, Miko E, Szigeti B, et al. The importance of the PD-1/PD-L1 pathway at the maternal-fetal interface. BMC Pregnancy Childbirth 2019;19(1):74.66949 - Wang SC, Li YH, Piao HL, Hong XW, et al. PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy. Cell Death Dis 2015;6(5):e1738.

      Interactions

      Level 3 (Moderate)

      • Tuberculin Purified Protein Derivative, PPD
      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. [43298] [43299]
      Revision Date: 09/29/2023, 01:50:00 AM

      References

      43298 - Aplisol (tuberculin purified protein derivative, diluted) package insert. Chestnut Ridge, NY: Par Pharmaceuticals; 2016 Mar.43299 - Tubersol (tuberculin purified protein derivative, mantoux) package insert. Swiftwater, PA: Sanofi Pasteur, Inc.; 2020 Nov.

      Monitoring Parameters

      • blood glucose
      • LFTs
      • pregnancy testing
      • serum creatinine/BUN
      • thyroid function tests (TFTs)

      US Drug Names

      • Keytruda
      ;