Keytruda was approved for the first line treatment of non-small cell lung cancer (NSCLC) based on the results of KEYNOTE-024, a randomized, open-label, phase 3, active-controlled trial in patients with metastatic NSCLC, whose tumors had high PD-L1 expression [tumor proportion score (TPS) of 50% or greater] and had not received prior systemic treatment for metastatic NSCLC. Based on an interim analysis demonstrating Keytruda was superior compared to chemotherapy for both the primary endpoint of progression free survival (PFS) and the secondary endpoint of overall survival (OS), the trial was stopped early in June 2016 to give patients still on chemotherapy the opportunity to receive Keytruda. Keytruda reduced the risk of progression or death by 50% compared to chemotherapy (HR, 0.50 [95% CI, 0.37, 0.68]; P<0.001). Additionally, Keytruda resulted in a 40% reduction in the risk of death compared to chemotherapy (HR, 0.60 [95% CI, 0.41, 0.89]; P=0.005).

Keytruda was approved for treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication was approved under accelerated approval. based on tumor response and durability of response. The approval is based KEYNOTE-087 trial with 210 patients, which demonstrated an overall response rate with Keytruda (200mg) every three weeks) of 69% (95% CI: 62, 75) with a complete remission rate of 22% and partial remission rate of 47%. The median follow-up time was 9.4 months. Among the 145 responding patients, the median duration of response was 11.1 months (range 0.0+ to 11.1 months).

Keytruda was approved as first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression when used in combination with pemetrexed and carboplatin. The approval was based on data from KEYNOTE-021, Cohort G1 in previously untreated patients with no EGFR or ALK genomic tumor aberrations and irrespective of PD-L1 expression. Treated patients demonstrated greater objective response rate (ORR) compared to patients treated with pemetrexed and carboplatin alone (55% [95% CI: 42, 68] compared to 29% [95% CI: 18.41], all responses were partial responses). Among the patients in the Keytruda treatment arm, 93% had a duration of response of six months or more (range 1.4+ to 13.0+ months) compared to 81% who received pemetrexed and carboplatin alone (range 1.4+ to 15.2+ months). In addition, findings demonstrated an improvement in PFS (HR 0.53 [95% CI, 0.31-0.91; p=0.0205]}, with a median PFS of 13.0 months (95% CI, 8.3-not estimable) for patients treated with Keytruda compared to 8.9 months (95% CI, 4.4-10.3) with pemetrexed and carboplatin alone.

Keytruda was approved for two indications for certain patients with locally advanced or metastatic urothelial carcinoma. The first-line approval was based on data open-label, single arm, KEYNOTE-052 trial of 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. The efficacy analysis showed an objective response rate (ORR) of 29 % [95% CI: 24,34], with complete response rate of 7% and a partial response rate of 22%. The median follow-up time was 7.8 months. The second-line approval was based on data from randomized, active-controlled KEYNOTE-045 trial of patients who have disease progression on or after platinum-containing chemotherapy. From this trial, patients treated with KEYTRUDA had 27% reduction in the risk of death compared to chemotherapy (HR, 0.73 [95% CI: 0.59, 0.91], p=0.004). The median overall survival was 10.3 months (95% CI: 8.0, 11.8) in the Keytruda arm, compared to 7.4 months (95% CI: 6.1, 8.3) in the chemotherapy arm. There was no statistically significant difference with respect to progression-free survival.

Keytruda was approved for use in patients with microsatellite instability-high cancer (MSI-H) or mismatch repair deficient (dMMR) solid tumors. The efficacy was evaluated in 149 patients identified in those were enrolled in one of five uncontrolled, open-label, multi-cohort, multi-center, single-arm trials. The majority of patients were identified using local laboratory- developed, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. The overall objective response rate was 39.6% (95% CI: 31.7, 47.9) and 78% of patients had response for greater than 6 months.

Keytruda was approved for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. The efficacy of Keytruda in gastric cancer was investigated in a multicenter, non-randomized, open-label multi-cohort trial (KEYNOTE-059) that enrolled patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least 2 prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet, and HER2/neu positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6 to 9 weeks. For the 143 patients, the ORR was achieved 19 patients (13.3%; 95% CI: 8.2, 20.0); 2 patients (1.4%) had a complete response and 17 patients (11.9%) had a partial response. Among the 19 responders, the duration of response ranged from 2.8 to 19.4 months.

On November 9, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. Approval was based on KEYNOTE 224 (NCT02702414), a single-arm, multicenter trial enrolling 104 patients with hepatocellular carcinoma. Patients were required to have disease progression on or after sorafenib or were intolerant to sorafenib, have measurable disease, and Child-Pugh Class A liver impairment. Twenty-one percent of the patients enrolled were HBV seropositive, 25% were HCV seropositive, and 9 patients (9%) were seropositive for both HBV and HCV. Patients with active autoimmune disease, more than one etiology of hepatitis, medical conditions requiring immunosuppression, or clinical evidence of ascites by physical exam were ineligible. Patients received pembrolizumab 200 mg as an intravenous infusion every three week until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The major efficacy outcome measure was confirmed overall response rate, as assessed by independent central review (ICR) according to RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The confirmed ICR-assessed overall response rate was 17% (95% CI: 11, 26), with one complete response and 17 partial responses. Response durations ranged from 3.1 to 16.7 months; 89% of responders had response durations of 6 months or longer and 56% had response durations of 12 months or longer. Adverse reactions occurring in patients with hepatocellular carcinoma were similar to those described in KEYTRUDA product labelling; however, there were increased incidences of grade 3 or 4 ascites (8%) and immune-mediated hepatitis (2.9%). Grade 3 and 4 laboratory abnormalities that occurred at a higher incidence than in other KEYTRUDA trials were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

On December 19, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Approval was based on Cancer Immunotherapy Trials Network protocol 9 (CITN-09), also known as KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients received pembrolizumab 2 mg/kg every 3 weeks. The major efficacy outcome measures were overall response rate (ORR) and response duration assessed by blinded independent central review per RECIST 1.1. The ORR was 56% (95% CI: 41, 70) with a complete response rate of 24%. The median response duration was not reached. Among the 28 patients with responses, 96% had response durations of greater than 6 months and 54% had response durations of greater than 12 months. The most common adverse reactions of pembrolizumab reported in at least 20% of patients who received pembrolizumab as a single agent were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

On April 19, 2019, the Food and Drug Administration approved pembrolizumab plus axitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC). Approval was based on KEYNOTE 426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status and were randomly allocated to receive either pembrolizumab 200 mg intravenously every 3 weeks in combination with axitinib 5 mg orally twice daily, or sunitinib 50 mg orally once daily for 4 weeks and then off treatment for 2 weeks. Treatment continued until confirmed disease progression or unacceptable toxicity. Pembrolizumab was received for maximum of 24 months. The main efficacy measures were overall survival (OS) and progression-free survival (PFS), assessed by blinded independent central review (RECIST 1.1.) The trial demonstrated a statistically significant improvement in OS in a pre-specified interim analysis for patients on the pembrolizumab plus axitinib arm (HR 0.53; 95% CI: 0.38, 0.74; p<0.0001). With deaths reported in 18% of patients, the median OS was not reached in either arm. The 12-month OS rate was 90% in the pembrolizumab plus axitinib arm and 78% for those treated with sunitinib. The trial also demonstrated a PFS improvement for patients receiving pembrolizumab plus axitinib (HR 0.69; 95% CI: 0.57, 0.84; p=0.0001). Median PFS was 15.1 and 11.1 months for those receiving pembrolizumab plus axitinib vs. sunitinib, respectively. Grade 3 or 4 hepatotoxicity occurred in 20% of patients. Hepatotoxicity resulted in permanent discontinuation of pembrolizumab or axitinib in 13% of patients. The most common adverse reactions in > 20% of patients who received pembrolizumab plus axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

[INFORMATIONAL NOTE: As per the FDA approved package insert, withhold pembrolizumab (Keytruda) for any of the following: grade 2 pneumonitis, grade 2 or 3 colitis, grade 3 or 4 endocrinopathies, grade 4 hematological toxicity in cHL patients, grade 2 nephritis, grade 3 severe skin reactions or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN, any other severe or Grade 3 treatment-related adverse reaction.

Resume pembrolizumab in patients whose adverse reactions recover to Grade 0-1.

Permanently discontinue pembrolizumab for any of the following:
· Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy, or hematological toxicity in patients with cHL)
· Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity
· Grade 3 or 4 nephritis
· Grade 4 severe skin reactions or confirmed SJS or TEN
· AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN

o For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week

On January 8, 2020, the Food and Drug Administration approved pembrolizumab (KEYTRUDA) for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Efficacy was investigated in KEYNOTE-057 (NCT, a multicenter, single-arm trial that enrolled 148 patients with high-risk NMIBC, 96 of whom had BCG-unresponsive CIS with or without papillary tumors. Patients received pembrolizumab 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response. The complete response rate in the 96 patients with high-risk BCG-unresponsive NMIBC with CIS was 41% (95% CI: 31, 51) and median response duration was 16.2 months (0.0+, 30.4+). Forty-six percent (46%) of responding patients experienced a complete response lasting at least 12 months. The most common adverse reactions (incidence ≥10%) in patients who received pembrolizumab in KEYNOTE-057 were fatigue, diarrhea, rash, pruritis, musculoskeletal pain, hematuria, cough, arthralgia, nausea, constipation, urinary tract infection, peripheral edema, hypothyroidism, and nasopharyngitis. The recommended pembrolizumab dose is 200 mg every 3 weeks.

On April 28, 2020, the Food and Drug Administration granted accelerated approval to a new dosing regimen of 400 mg every six weeks for pembrolizumab (KEYTRUDA) across all currently approved adult indications, in addition to the current 200 mg every three weeks dosing regimen. This new dosing regimen is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

The approval was based on pharmacokinetic modeling and exposure-response analyses that compared the predicted exposure of pembrolizumab 400 mg every six weeks to observed exposures of pembrolizumab in patients who received pembrolizumab at 2 mg/kg every three weeks, 200 mg every three weeks, and 10 mg/kg administered every two weeks. The pharmacokinetic modeling were supported by additional exposure-response analyses across the pembrolizumab development program and an interim analysis of pharmacokinetics and overall response rate (ORR) in a cohort of patients (Cohort B) enrolled in Study KEYNOTE-555 (NCT03665597). Cohort B of Study KEYNOTE-555 was an international, single-arm, multi-center study that enrolled 101 patients with advanced or metastatic melanoma who had not received prior PD-1, PD-L1, or CTLA-4 inhibitors (other than CTLA-4 inhibitors in the adjuvant setting). The ORR was 39% (95% CI: 24, 55) in the first 44 patients enrolled in KEYNOTE-555.

On June 16, 2020, the FDA granted accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Efficacy was investigated in a prospectively-planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in a multicenter, non-randomized, open-label trial, KEYNOTE-158 (NCT02628067). Patients received pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. The main efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) in patients who have received at least one dose of pembrolizumab as assessed by blinded independent central review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. A total of 102 patients (13%) had tumors identified as TMB-H, defined as TMB ≥10 mut/Mb. The ORR for these patients was 29% (95% CI: 21,39), with a 4% complete response rate and 25% partial response rate. The median DoR was not reached, with 57% of patients having response durations ≥12 months and 50% of patients having response durations ≥24 months. Adverse reactions occurring in patients with TMB‑H cancer enrolled in KEYNOTE-158 were similar to those occurring in patients with other solid tumors who received pembrolizumab as a single agent. The most common adverse reactions are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions. The prescribing information includes a “Limitation of Use” stating that the safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established. The recommended dosage regimen for TMB-H solid tumors is 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to a maximum of 200 mg) every 3 weeks for pediatric patients.

On June 24, 2020, the FDA approved pembrolizumab (Keytruda) for patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation. Efficacy was investigated in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The trial excluded patients who had previously received therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody and those with autoimmune disease or a medical condition that required immunosuppression. Patients received pembrolizumab 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks during the first year and every 9 weeks during the second year. The major efficacy outcome measures were objective response rate (ORR) and response duration as assessed by blinded independent central review according to RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR was 34% (95% CI: 24, 44) and median response duration was not reached (range: 2.7, 13.1+ months). Adverse reactions occurring in patients with cSCC enrolled in KEYNOTE-629 were similar to those occurring in patients who received pembrolizumab as a single agent in other clinical trials. The most common adverse reactions to pembrolizumab are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions. Efficacy and safety of pembrolizumab using a dosage of 400 mg every 6 weeks for cSCC was primarily based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma. The recommended pembrolizumab doses for cSCC are 200 mg every 3 weeks or 400 mg every 6 weeks.

On June 29, 2020, the FDA approved pembrolizumab (Keytruda) for the first-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. Approval was based on KEYNOTE‑177 (NCT02563002), a multicenter, international, open-label, active-controlled, randomized trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR colorectal cancer. Determination of MSI or MMR tumor status was made locally using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients were randomized (1:1) to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator’s choice of mFOLFOX6/FOLFIRI ± bevacizumab or cetuximab given intravenously every 2 weeks. Patients randomized to chemotherapy were offered pembrolizumab at the time of disease progression. The main efficacy outcome measures were progression-free survival (PFS) and overall survival (OS). Median PFS was 16.5 months (95% Confidence Interval [CI]: 5.4, 32.4) in the pembrolizumab arm and 8.2 months (95% CI: 6.1, 10.2) in the chemotherapy arm (HR 0.60, 95% CI 0.45, 0.80; two-sided p-value=0.0004). At the time of the PFS analysis, the OS data were not mature. The most common adverse reactions reported in ≥20% of patients receiving pembrolizumab as a single agent are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. The recommended pembrolizumab dose for MSI-H/dMMR colorectal cancer is 200 mg every 3 weeks or 400 mg every 6 weeks.

Policy:
[NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.

The requirements of the Horizon BCBSNJ Pembrolizumab (Keytruda) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).]

1. Prior to initiating therapy with pembrolizumab, ALL of the following must be documented:

• Member does not have active autoimmune disease or medical condition that requires immunosuppression
• Member does not have prior treatment with another anti-PD-1 agent (ex. nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab), unless otherwise specified
• The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist, urologist) or has consulted with a specialist in the area of the patient’s diagnosis

• Adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection; OR
• Treatment of unresectable or metastatic melanoma when ALL of the following criteria are met:
  • Member has an ECOG performance score of 0-1
  
  [INFORMATIONAL NOTE: In the Keynote-006 trial patients who had no previous anti-BRAF therapy with a BRAF V600 mutation and high lactate dehydrogenase levels and symptomatic or rapidly progressive disease were not enrolled. Targeted anti-BRAF agents have a rapid clinical benefit in this population. Of the patients enrolled, BRAF V600 status did not seem to affect the benefit of pembrolizumab over ipilimumab.]
• Treatment of metastatic Non-Small Cell Lung Cancer (NSCLC) when all of the following criteria are met:
  • Member has an ECOG performance score of 0-1; AND
  • One of the following:
    • Metastatic or Stage III (who are not candidates for surgical resection or definitive chemoradiation) non-small cell lung cancer (NSCLC) (nonsquamous and squamous) with high PD-L1 tumor expression (Tumor Proportion Score or TPS ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC; AND
      • Used as a single agent; OR
    • Metastatic non-small cell lung cancer (NSCLC) (nonsquamous and squamous) with tumor expression of PD-L1 (TPS > 1%) as determined by an FDA-approved test and the following:
      • The patient has disease progression on or after platinum-based chemotherapy; and
      • For the patient who has EGFR-mutation-positive or ALK-fusion oncogene-positive tumor, there is documentation of disease progression while on FDA-approved therapy for these mutations prior to receiving pembrolizumab (note: this does not apply if the patient’s tumor does not have these mutations); and
      • Used as a single agent; OR
    • Metastatic nonsquamous NSCLC in combination with pemetrexed and platinum therapy as first-line therapy with no EGFR or ALK genomic tumor aberrations; OR
    • Metastatic squamous NSCLC in combination with carboplatin and either paclitaxel or nab-paclitaxel as first-line therapy
• Treatment of metastatic Small Cell Lung Cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line to therapy
• Treatment of Head and Neck Squamous Cell Carcinoma (HNSCC) when ALL of the following criteria are met:
  • Member has an ECOG performance score of 0-1
  • Member does not have evidence of interstitial lung disease
  • Used as a single agent for one of the following:
    • Recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy; OR
    • First-line treatment of metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) >1] as determined by an FDA-approved test; OR
  • Used in combination with a platinum and fluorouracil for first-line treatment of metastatic or unresectable, recurrent HNSCC
• Treatment of adult and pediatric patients (2 years and older) with refractory classical Hodgkin Lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy
  • Member has an ECOG performance score of 0-1
  • Member has failed to achieve a response to, progressed after, or ineligible for autologous stem cell transplant and/or was treated with brentuximab vedotin
  • Member does not have prior allogeneic hematopoietic stem cell transplantation, known clinically active central nervous system involvement or known additional malignancy that is progressing or requires active treatment
• Treatment of locally advanced or metastatic urothelial carcinoma when ALL of the following criteria are met:
  • Used for one of the following
    • first-line therapy in patients who are not eligible for cisplatin-containing therapy and whose tumors express PD-L1 (CPS >10) as determined by an FDA-approved test; OR
    • first-line therapy in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status; OR
    • second-line therapy in patients who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
  • Member has an ECOG performance score of 0, 1, or 2
• Treatment of adult and pediatric patients (2 years or older) with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatched repair deficient
  • Member has solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options OR
  • Member has colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
  • Member has an ECOG performance score of 0 or 1
  • Tumor status has been confirmed by using polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR
  • Member is NOT a pediatric patient with MSI-H central nervous system cancers
• Treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma
  • Member has tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test (e.g. PD-L1 IHC 22C3 pharmDx (Dako))
  • Member has disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
  • Member does not have clinical evidence of ascites by physical exam.
  • Member has an ECOG performance score of 0 or 1
• Treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus
  • Member has tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test
  • Member has disease progression after one or more prior lines of systemic therapy
• Treatment of adult and pediatric patients (2 years or older) with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy (one of which must have been rituximab)
  · Member does not require urgent cytoreductive therapy
  · Member has an ECOG performance score of 0 or 1
  • Member does not have active non-infectious pneumonitis, allogenic HSCT within the past 5 years (or greater than 5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy.
• Treatment of patients with recurrent or metastatic cervical cancer
  · Member has disease progression on or after chemotherapy
  · Member’s tumors express PD-L1 (CPS≥1) as determined by an FDA-approved test (e.g. PD-L1 IHC 22C3 pharmDx (Dako))
  · Member has an ECOG performance score of 0 or 1
  · Member has received at least 1 prior line of therapy in the recurrent or metastatic setting
  [INFORMATIONAL NOTE: The efficacy of pembrolizumab was evaluated in patients enrolled in one of five uncontrolled, open-label, multi-cohort, single-arm trials, KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158. Patients evaluated for efficacy had colorectal cancer and other solid tumors which included endometrial cancer, biliary cancer, gastric cancer, pancreatic cancer, small intestinal cancer, breast cancer, prostate cancer, bladder cancer, esophageal cancer, sarcoma, thyroid cancer, retroperitoneal adenocarcinoma, small cell lung cancer, and renal cell cancer. The safety and effectiveness in pediatric patients with MSI-H central nervous system cancers have not been established.]
• Treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib
  • Member has been previously treated with sorafenib and has demonstrated disease progression or intolerance on or after treatment AND
  • Member has an ECOG performance score of 0 or 1 AND
  • Will be used as a single agent
• Treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC)
  • Presence of metastatic or advanced locoregional MCC determined to be not amenable to definitive surgery or radiation therapy AND
  • Member has an ECOG performance score of 0 or 1 AND
  • Will be used as a single agent
• Treatment in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC)
  • Will be administered in combination with axitinib AND
  • Member has a Karnofsky performance status (KPS) ≥ 70%
• Treatment in combination with lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
  • Will be administered in combination with lenvatinib AND
  • Member has an ECOG performance score of 0 or 1 AND
  • There is presence of disease progression following prior systemic therapy AND
  • Member is not a candidate for curative surgery or radiation
• Treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors
  • Member has an ECOG performance score of 0-2 AND
  • Member is ineligible for or has elected not to undergo cystectomy AND
  • Member has persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following as single induction course of BCG AND
  • Member has undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components) (residual CIS is acceptable) AND
  • Will be used as a single agent
• Treatment of adult and pediatric patients (2 years or older) with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options
  · If the request is for a pediatric member, member does not have a diagnosis of TMB-H central nervous system cancers
  · Member has not previously received an anti-PD-1 or other immune-modulating monoclonal antibody
  · Member has an ECOG performance score of 0 or 1
  · Member has histologically or cytologically-documented, advanced solid tumor
  · Member has had progression of tumor or intolerance to therapies known to provide clinical benefit
• Treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation
  · Member has an ECOG performance score of 0 or 1
  · Member has histologically-confirmed cSCC that is not amenable to surgical resection, local control with radiotherapy, or chemoradiotherapy
  · Member has not previously received an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent
• Treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) as first-line treatment
  · Member has an ECOG performance score of 0 or 1
  · Member has locally confirmed dMMR or MSI-H stage IV colorectal carcinoma
  · Member has not previously received prior systemic therapy for stage IV colorectal cancer (may have received prior adjuvant chemotherapy for colorectal cancer)
  · Member has not previously received prior therapy with an immune checkpoint inhibitor (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, etc.)
  

• Dosing should be calculated using actual body weight and not flat dosing (as applicable) based on the following:
  • Standard dose 200mg IV every 3 weeks for patients > 50 kg
  • Use 100 mg IV every 3 weeks for patients ≤ 50 kg
  • For Keytruda every 6 week dosing, patients weighing ≤ 82.5 kg use a dose recommendation of 300 mg IV every 6 weeks
Note: This information is not meant to replace clinical decision making when initiating or modifying medication therapy and should only be used as a guide. Patient-specific variables should be taken into account.

• Melanoma, Non-Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), Head and Neck Squamous Cell Carcinoma (HNSCC), Urothelial Carcinoma, Non-muscle invasive bladder cancer (NMIBC), Gastric Cancer, Esophageal Cancer, Cervical Cancer, Hepatocellular Carcinoma (HCC), Renal Cell Carcinoma (RCC), and Endometrial Carcinoma, Cutaneous Squamous Cell Carcinoma (cSCC), and MSI-H or dMMR colorectal cancer (CRC): 200 mg as an intravenous infusion over 30 minutes every 3 weeks or 400 mg as an intravenous infusion over 30 minutes every 6 weeks
• cHL, MSI-H, Primary Mediastinal Large B-Cell Lymphoma (PMBCL), and Metastatic Merkel Cell Carcinoma (MCC), and Tumor Mutational Burden-High (TMB-H) solid tumors: 200 mg every 3 weeks or 400 mg every 6 weeks in adults and 2 mg/kg (up to 200 mg) every 3 weeks in pediatric patients

[INFORMATIONAL NOTE: There is limited experience with pembrolizumab in pediatric patient. In a study, 40 pediatric patients (16 children ages 2 years to less than 12 years and 24 adolescent ages 12 years to 18 years) with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumors were administered 2mg/kg every 3 weeks. The concentrations of pembrolizumab in pediatric patients were comparable to those observed in adult patients at the same dose regimen and the safety profile was similar to that seen in adults. Efficacy of pediatric patients with cHL MSI-H, or PMBCL cancers is extrapolated from the results in the respective adult populations

The clinical trials in the FDA labeled package insert for various indications of Keytruda (melanoma, NSCLC, SCLC, HNSCC, and MSI-H cancer) studied weight based dosing while other indication clinical trials studied flat dosing (gastric cancer, cervical cancer, HCC, MCC, RCC). The weight based dosing of 2mg/kg IV every 3 weeks was compared with the flat dosing of 200mg IV every 3 weeks and doses were shown to provide similar distributions with no advantage to either dosing regimen approach with respect to controlling pharmacokinetic variability (for trials studied with flat dosing, pharmacokinetic studies can be extrapolated to have shown similar results with weight based dosing).

As per the FDA labeled package insert, dosing section: KEYTRUDA is indicated for use at an additional recommended dosage of 400 mg every 6 weeks for all approved adult indications. This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials]

• For the treatment of head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC), Esophageal Cancer, Merkel Cell Cancer (MCC), Classical Hodgkin Lymphoma (cHL), Urothelial Carcinoma, MSI-H Cancers, gastric/gastroesophageal junction cancer, primary mediastinal large B-cell lymphoma (PMBCL), hepatocellular Carcinoma (HCC), Renal Cell Carcinoma (RCC), Endometrial Carcinoma cervical cancer, non-muscle invasive bladder cancer (NMIBC), Cutaneous Squamous Cell Carcinoma (cSCC), Tumor Mutational Burden-High (TMB-H) solid tumors, MSI-H or dMMR colorectal cancer (CRC): pembrolizumab (Keytruda) can be continued for up to 24 months until unacceptable toxicity or disease progression, as defined above.
• For adjuvant treatment of melanoma: pembrolizumab (Keytruda) can be continued for up to 12 months until unacceptable toxicity or disease recurrence, as defined above.
  

6. Chow LQ, Burtness B, Weiss J, et al. LBA31 a phase Ib study of pembrolizumab (pembro; mk-3475) in patients with human papiilloma virus-positive and negative head and neck cancer. Ann Oncol (2014) 25 (5): 1-41

7. Garon EB, Gandhi L, Rizvi N, et al. LBA43 - Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non–small cell lung carcinoma (NSCLC). Ann Oncol (2014) 25 (5): 1-41

8. Ribas A, et al. Updated Clinical Efficacy of the Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) in 411 Patients With Melanoma. Society for Melanoma Research International Congress; Zurich,Switzerland. November 13-16, 2014.

9. Choueiri, et al. KEYNOTE-029; Phase I/II Study of Pembrolizumab in Combination with Pegylated Interferon Alfa-2b or Ipilimumab in Patients With Advanced Melanoma or Renal Cell Carcinoma. Abstract 1075Tip; Esmo Annual Meeting; Madrid, Spain. Sep 26-30, 2014.

10. Brahmer JR, Kim ES, Zhang J, et al. KEYNOTE-024: Phase III trial of pembrolizumab (MK-3475) vs platinum-based chemotherapy as first-line therapy for patients with metastatic non-small cell lung cancer (NSCLC) that expresses programmed cell death ligand 1 (PD-L1). J Clin Oncol 33, 2015 (suppl; abstr TPS8103).

11. Merck Sharp & Dohme Corp. Study of pembrolizumab (MK-3475) in participants with relapsed or refractory classical Hodgkin lymphoma (MK-3475-087/KEYNOTE-087). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2017 Apr 6]. Available from: https://clinicaltrials.gov/ct2/show/NCT02453594 NLM Identifier: NCT02453594.

12. Bellmunt J, de Wit R, Vaughn DR, et al, for the KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376 (11):1015-1026.

13. Balar AV, Castellano D, O'donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.

14. Paz‑Ares L., Luft A., Vicente D., et al. "Pembrolizumab Plus Chemotherapy For Squamous Non–Small-Cell Lung Cancer | NEJM". New England Journal Of Medicine, 2018, https://www.nejm.org/doi/full/10.1056/NEJMoa1810865. Accessed 1 Dec 2018.

15. Keytruda. Clinicaltrial.gov. Accessed on 12/1/18 . Available at: https://clinicaltrials.gov/ct2/show/NCT02775435

16. Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunotherapy of Cancer 2017;5:43.

17. Goldstein DA, Gordon N, Davidescu M, et al. A pharmacoeconomic analysis of personalized dosing vs fixed dosing of pembrolizumab in first-line PD-L1-positive non-small cell lung cancer. JNCI 109:1,2017.

18. Bach PB, Saltz LB. Raising the dose and raising the cost: the case of pembrolizumab in lung ancer. JNCI Natl Cancer Inst (2017) 109(11):djx125.

19. Clinicaltrials.gov. Phase 1b/2 Trial of Lenvatinib (E7080) Plus Pembrolizumab in Subjects With Selected Solid Tumors. NCT02501096. Available at: https://clinicaltrials.gov/ct2/show/NCT02501096. Accessed on October 30, 2019.

20. Study of Pembrolizumab (MK-3475) in Participants With High Risk Non-muscle Invasive Bladder Cancer (MK-3475-057/KEYNOTE-057). NCT02625961. Available at: https://clinicaltrials.gov/ct2/show/NCT02625961. Accessed January 10, 2020.

21. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. U.S Food & Drug Administration. January 8, 2020. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer.

22. FDA approves new dosing regimen for pembrolizumab. U.S. Food & Drug Administration. April 29, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-new-dosing-regimen-pembrolizumab.

23. FDA approved pembrolizumab for cutaneous squamous cell carcinoma. U.S. Food & Drug Administration. June 24, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-cutaneous-squamous-cell-carcinoma

24. FDA approved pembrolizumab for adults and children with TMB-H solid tumors.U.S. Food & Drug Administration. June 17, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors

25. ClinicalTrials.gov. Study of Pembrolizumab (MK-3475) in Adults With Recurrent/Metastatic Cutaneous Squamous Cell Carcinoma (cSCC) or Locally Advanced Unresectable cSCC (MK-3475-629/KEYNOTE-629). NCT03284424. Available at: https://clinicaltrials.gov/ct2/show/NCT03284424

26. ClinicalTrials.gov. Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158). NCT02628067. Available at: https://clinicaltrials.gov/ct2/show/NCT02628067

27. ClinicalTrials.gov. Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177). NCT02563002. Available at: https://clinicaltrials.gov/ct2/show/NCT02563002

28. Goldstein DA, Ratain MJ, Saltz LB. Weight-Based Dosing of Pembrolizumab Every 6 Weeks in the Time of COVID-19. JAMA Oncol. Published online May 27, 2020. doi:10.1001/jamaoncol.2020.249

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS

J9271