| Coverage Policy Manual | |
| Policy #: | 2019005 |
| Category: | Pharmacy |
| Initiated: | July 2019 |
| Last Review: | April 2023 |
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| Pembrolizumab (e.g., KEYTRUDA®) | |
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| Description: |
The programmed death 1 protein (PD1) is an immune checkpoint receptor expressed by activated T cells. PD-1 binds to its ligands Pd1-L1 and PD1-L2 which are expressed on tumor cells, causing immunosuppression and preventing the immune system from rejecting the tumor.
PD-1 inhibition has been studied in clinical trials in metastatic melanoma, non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, head and neck cancer and urothelial cancer.
Regulatory Status
Pembrolizumab was originally approved under accelerated approval by the U.S. Food and Drug Administration on September 04, 2014 for the treatment of individuals with unresectable or metastatic melanoma and disease progression following ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor.
In October 2015, approval was received for the treatment of individuals with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA approved test and who have disease progression melanoma was revised to allow for unresectable or metastatic melanoma without the requirement of disease progression following ipilimumab and BRAF inhibitor treatment.
On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab for the treatment of individuals with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
On March 14, 2017, the U.S. Food and Drug Administration granted accelerated approval for pembrolizumab in the treatment of adult and pediatric individuals with refractory cHL, or who have relapsed after 3 or more prior lines of therapy. Products approved under the accelerated approval regulations, 21 CFR 601.41, require further adequate and well-controlled studies/clinical trials to verify and describeindividuals clinical benefit. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials (FDA, 2017).
On April 19, 2019, the Food and Drug Administration approved pembrolizumab plus axitinib for the first-line treatment of individuals with advanced renal cell carcinoma. 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.
On June 17, 2019, the Food and Drug Administration approved pembrolizumab as a first-line treatment for people with advanced head and neck cancer. The approval is for people with head and neck squamous cell carcinoma that has spread or that has come back and can’t be removed through surgery. Pembrolizumab can be used along with chemotherapy, or it can be used alone if the cancer cells have a certain level of the PD-L1 protein. Approval was based on KEYNOTE-048 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies.
On January 8, 2020, the Food and Drug Administration approved pembrolizumab for the treatment of individuals 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. (KEYNOTE-057, NCT02625961)
On June 16, 2020, the Food and Drug Administration approved pembrolizumab for treatment of adult and pediatric individuals with unresectable or metastatic tumor mutational burden-high (TMB-H) [>10 mutatina/megabase (mutMb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
On June 24, 2020, the Food and Drug Administration approved pembrolizumab for the treatment of individuals with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.
On June 29, 2020, the Food and Drug Administration approved pembrolizumab for the first-line treatment of individuals with unresectable or metastatic Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC).
On November 13, 2020, the Food and Drug Administration approved pembrolizumab in combination with chemotherapy, for the treatment of individuals with locally recurrent unresectable or metastatic triple negative breast cancer whose tumors express PD-L1 [Combined Positive Score (CPS) >10] as determined by an FDA approved test.
On March 1, 2021, Merck announced voluntarily withdrawal in the U.S. of Keytruda for the treatment of individuals with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. The withdrawal of this indication was done in consultation with the U.S. FDA after the confirmatory Phase 3 trial for this indication, met one of its dual primary endpoints of progression-free survival but did not reach statistical significance for the other primary endpoint of overall survival (OS). (Merck News Release, 2021).
On March 22, 2021, the Food and Drug Administration approved pembrolizumab for the treatment of individuals with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amendable to surgical resection or definitive chemoradiation, in combination with platinum and fluoropyrimidine-based chemotherapy. Additionally, the esophageal cancer section was updated with respect to the single agent indication for labeling consistency.
On November 17, 2021, the Food and Drug Administration approved pembrolizumab for adjuvant treatment of individuals with renal cell carcinoma at intermediate high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.
On December 2, 2021, the Food and Drug Administration approved pembrolizumab (e.g., Keytruda) for the adjuvant treatment of adult and pediatric (> 12 years of age) individuals with stage IIB or IIC melanoma following complete resection.
On March 21, 2022, the Food and Drug Administration approved pembrolizumab as monotherapy for the treatment of individuals with advanced endometrial carcinoma that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
On February 4, 2022, the Food and Drug Administration removed the approval of the third line gastrica cancer indication; i.e., “Keytruda , as a single agent, for the treatment of individuals with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS>1) as determined by an FDA-approved test, 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”.
On December 16, 2022, the U.S. Food and Drug Administration approved Pembrolizumab (e.g., Keytruda) for an alternative dosing regimen of 400 mg every six weeks for adult classical Hodgkin lymphoma and adult primary mediastinal large B cell lymphoma. These indications are approved under accelerated approval and continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.
On January 26, 2023, the FDA approved Pembrolizumab (e.g., Keytruda) as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult individuals with stage IB (T2a >4 cm), II, IIIA non-small cell lung cancer.
On April 3, 2023, the FDA approved Pembrolizumab (e.g., Keytruda) in combination with enfortumab vedotin for the treatment of adult individuals with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
Please see policy 2016005 for all other Anti-PD-1 (programmed death receptor-1) Therapy (Nivolumab) (Durvalumab) (Cemiplimab) and for Pembrolizumab coverage prior to July 2019.
Effective April 13, 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Pembrolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
OFF-LABEL INDICATIONS for Pembrolizumab (e.g., Keytruda)
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended dose of Pembrolizumab is:
Please refer to FDA guidelines for further prescribing information.
Pemetrexed is available for injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational.
Investigational services are specific exclusions in most member benefit certificates of coverage.
Effective January 18, 2023 to April 12, 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Pembrolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
For the treatment of TRIPLE-NEGATIVE BREAST CANCER (TNBC):
For the treatment of individuals with CERVICAL CANCER:
For the treatment of MICROSATELLITE INSTABILITY-HIGH or MISMATCH REPAIR DEFICIENT COLORECTAL CANCER (CRC) for the treatment of individuals with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) (FDA)
For the treatment of individuals with recurrent or metastatic CUTANEOUS SQUAMOUS CELL CARCINOMA (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. (FDA)
For the treatment of individuals with advanced ENDOMETRIAL CARCINOMA
For the treatment of ESOPHAGEAL or GASTROESOPHAGEAL JUNCTION:
For the treatment of GASTRIC CANCER:
For the treatment of HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC):
For the treatment of individuals with HEPATOCELLULAR CARCINOMA (HCC) who have previously been treated with sorafenib. (FDA)
For the treatment of CLASSICALHODGKIN LYMPHOMA (cHL):
For the treatment of ADULT CLASSICAL HODGKIN LYMPHOMA and ADULT PRIMART MEDIASTINAL LARGE B-CELL LYMPHOMA: Additional Dosing Regimen of 400 mg Every 6 Weeks:
For the treatment of B-CELL LYMPHOMA:
For the treatment of MELANOMA:
For the treatment of MERKEL CELL CARCINOMA:
For the treatment of individuals with metastatic NON-SMALL CELL LUNG CANCER (NSCLC):
For the treatment of RENAL CELL CARCINOMA (RCC):
For the treatment of adult and pediatric individuals with unresectable or metastatic, MICROSATELLITE INSTABILITY-HIGH CANCER (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment option (FDA)
For the treatment of adult and pediatric individuals 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. (FDA)
For the treatment of individuals with locally advanced or metastatic UROTHELIAL CARCINOMA:
OFF-LABEL INDICATIONS for Pembrolizumab (e.g., Keytruda)
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks.
HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
Urothelial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks.
MSI-H or dMMR Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
MSI-H or dMMR CRC: 200 mg every 3 weeks or 400 mg every 6 weeks.
Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
HCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
RCC: 200 mg every 3 weeks or 400 mg every 6 weeks as a single agent in the adjuvant setting or in the advanced setting with either
Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks with lenvatinib 20 mg orally once daily. Monotherapy: 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.
TMB-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
cSCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks.
Please refer to FDA guidelines for further prescribing information.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational.
Investigational services are specific exclusions in most member benefit certificates of coverage.
Effective July 1, 2022 to January 17, 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Pembrolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
For the treatment of TRIPLE-NEGATIVE BREAST CANCER (TNBC):
For the treatment of patients with CERVICAL CANCER:
For the treatment of MICROSATELLITE INSTABILITY-HIGH or MISMATCH REPAIR DEFICIENT COLORECTAL CANCER (CRC) for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) (FDA)
For the treatment of patients with recurrent or metastatic CUTANEOUS SQUAMOUS CELL CARCINOMA (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. (FDA)
For the treatment of patients with advanced ENDOMETRIAL CARCINOMA
For the treatment of ESOPHAGEAL or GASTROESOPHAGEAL JUNCTION:
For the treatment of GASTRIC CANCER:
For the treatment of HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC):
For the treatment of patients with HEPATOCELLULAR CARCINOMA (HCC) who have previously been treated with sorafenib. (FDA)
For the treatment of CLASSICALHODGKIN LYMPHOMA (cHL):
· for the treatment of adult patients with relapsed or refractory cHL. (FDA)
· for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. (FDA)
For the treatment of B-CELL LYMPHOMA:
Limitations of use: Pembrolizumab (e.g., KEYTRUDA) is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. (FDA)
For the treatment of MELANOMA:
For the treatment of MERKEL CELL CARCINOMA:
For the treatment of patients with metastatic NON-SMALL CELL LUNG CANCER (NSCLC):
For the treatment of RENAL CELL CARCINOMA (RCC):
For the treatment of adult and pediatric patients with unresectable or metastatic, MICROSATELLITE INSTABILITY-HIGH CANCER (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment option (FDA)
Limitations of use: The safety and effectiveness of Pembrolizumab (e.g., KEYTRUDA) in pediatric patients with TMB-H central nervous system cancers have not been established. (FDA)
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. (FDA)
Limitations of Use: The safety and effectiveness of Pembrolizumab (e.g., KEYTRUDA) in pediatric patients with TMB-H central nervous system cancers have not been established (FDA)
For the treatment of patients with locally advanced or metastatic UROTHELIAL CARCINOMA:
OFF-LABEL INDICATIONS for Pembrolizumab (e.g., Keytruda)
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks.
NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks.
HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
Urothelial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks.
MSI-H or dMMR Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
MSI-H or dMMR CRC: 200 mg every 3 weeks or 400 mg every 6 weeks.
Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
HCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
RCC: 200 mg every 3 weeks or 400 mg every 6 weeks as a single agent in the adjuvant setting or in the advanced setting with either
Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks with lenvatinib 20 mg orally once daily. Monotherapy: 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.
TMB-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
cSCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks.
Please refer to FDA guidelines for further prescribing information.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational.
Investigational services are specific exclusions in most member benefit certificates of coverage.
Effective May 4, 2022 to June 30, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Pembrolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
For the treatment of TRIPLE-NEGATIVE BREAST CANCER (TNBC):
For the treatment of patients with CERVICAL CANCER:
For the treatment of MICROSATELLITE INSTABILITY-HIGH or MISMATCH REPAIR DEFICIENT COLORECTAL CANCER (CRC) for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) (FDA)
For the treatment of patients with recurrent or metastatic CUTANEOUS SQUAMOUS CELL CARCINOMA (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. (FDA)
For the treatment of patients with advanced ENDOMETRIAL CARCINOMA
For the treatment of ESOPHAGEAL or GASTROESOPHAGEAL JUNCTION:
For the treatment of GASTRIC CANCER:
For the treatment of HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC):
For the treatment of patients with HEPATOCELLULAR CARCINOMA (HCC) who have previously been treated with sorafenib. (FDA)
For the treatment of CLASSICALHODGKIN LYMPHOMA (cHL):
· for the treatment of adult patients with relapsed or refractory cHL. (FDA)
· for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. (FDA)
For the treatment of B-CELL LYMPHOMA:
Limitations of use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. (FDA)
For the treatment of MELANOMA:
For the treatment of MERKEL CELL CARCINOMA:
For the treatment of patients with metastatic NON-SMALL CELL LUNG CANCER (NSCLC):
For the treatment of RENAL CELL CARCINOMA (RCC):
For the treatment of adult and pediatric patients with unresectable or metastatic, MICROSATELLITE INSTABILITY-HIGH CANCER (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment option (FDA)
Limitations of use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. (FDA)
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. (FDA)
Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established (FDA)
For the treatment of patients with locally advanced or metastatic UROTHELIAL CARCINOMA:
OFF-LABEL INDICATIONS for Pembrolizumab (e.g., Keytruda)
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks.
NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks.
HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
Urothelial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks.
MSI-H or dMMR Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
MSI-H or dMMR CRC: 200 mg every 3 weeks or 400 mg every 6 weeks.
Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks.
HCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
RCC: 200 mg every 3 weeks or 400 mg every 6 weeks as a single agent in the adjuvant setting or in the advanced setting with either
Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks with lenvatinib 20 mg orally once daily
TMB-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
cSCC: 200 mg every 3 weeks or 400 mg every 6 weeks.
TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks.
Please refer to FDA guidelines for further prescribing information.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational.
Investigational services are specific exclusions in most member benefit certificates of coverage.
For a hardcopy print of coverage effective May 4, 2022 and prior please email: codespecificinquiry@arkbluecross.com
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| Rationale: |
FDA accelerated approval of pembrolizumab was based on open-label, multicenter expansion cohort of phase I trial of adults aged 18-88 years with unresectable or metastatic melanoma with disease progression within 24 weeks of their last dose of ipilimumab, and if BRAF V600 mutation positive, prior treatment with BRAF inhibitor (Robert, 2014). The trial randomly assigned 173 participants to receive pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84) IV once every 3 weeks until disease progression or unacceptable toxicity, with median follow-up duration of 8 months. Additional inclusion criteria for the study included participants who had progressive, measurable, unresectable melanoma who previously received two or more doses of ipilimumab; with confirmed disease progression using immune-related response; adequate ECOG and organ function; and resolution of ipilimumab-related adverse events. Major study exclusion criteria were "previous treatment with a PD-1 or PD-L1 blocking agent, current systemic immunosuppressive therapy, and active infection or autoimmune disease." Participants were excluded from the study if there was evidence of central nervous system (CNS) progression within 8 weeks of previous treatment. The major efficacy endpoints that were confirmed included overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST v1.1) as assessed by a blinded independent review committee and duration of response (DOR). Both groups had an ORR of 26% with 21 of 81 participants in the 2 mg/kg group and 20 of 76 participants in the 10 mg/kg group (difference 0%, 95% confidence interval [CI], -14 to 13; p=0.96). Safety profiles were similar between groups with treatment well tolerated in this population. There were no drug-related deaths reported. Grade 3 or 4 adverse events occurred in 12% (n=20) of study participants; fatigue was the only drug-related grade 3 to 4 adverse event that occurred in more than 1 participant (n=5 [3%]). Drug-related serious adverse events were reported in 5% (n=8) of the population with 3% (n=6) discontinuing treatment as a result of a drug-related adverse event. Fatigue, pruritus, and rash were the most common drug-related adverse events of any grade reported. In summary Robert and colleagues conclude: “Our findings suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks could be an effective treatment option for patients with ipilimumab-refractory advanced melanoma, a population for whom there are few effective treatment options.”
In 2015, Robert and colleagues reported preliminary results from the KEYNOTE-006 trial, a phase III randomized, open-label, controlled study of 834 participants with histologically confirmed, unresectable stage III or IV melanoma with no more than one previous systemic therapy for advanced disease. The participants were randomly assigned in a 1:1:1 ratio to receive pembrolizumab 10mg/kg every 2 weeks or pembrolizumab 10 mg/kg every 3 weeks or 4 cycles of ipilimumab 3 mg/kg every 3 weeks. The study inclusion criteria included: Known BRAF V600 mutation status was required; previous BRAF inhibitor therapy was not required for patients with normal lactate dehydrogenase levels and no clinically significant tumor-related symptoms or evidence of rapidly progressive disease. Other key eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (on a 5-point scale, with higher scores indicating greater disability) and provision of a tumor sample adequate for assessing PD-L1 expression. Excluded from the study were patients who had received previous therapy with CTLA-4, PD-1, or PD-L1 inhibitors and those who had ocular melanoma, active brain metastases, or a history of serious autoimmune disease.
The estimated 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2% respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons).
The rate of Grade 3-5 adverse events was lower in the pembrolizumab group (13.3% and 10.1%) than in the ipilimumab group (19.9%). There were no drug-related deaths in the pembrolizumab group, one drug related death in the ipilimumab group, and common adverse events associated with the use of pembrolizumab were fatigue, diarrhea, rash and pruritus.
The author concluded that the "randomized study comparing two immune checkpoint inhibitors showed that pembrolizumab, as compared with ipilimumab, significantly prolonged progression-free and overall survival with fewer high-grade toxic events in patients with advanced melanoma."
The FDA expanded indication for use of pembrolizumab in individuals with metastatic NSCLC whose tumors express PD-L1 and have disease progression on or after platinum-containing chemotherapy is based on findings from the Phase I KEYNOTE-001 trial. The safety of pembrolizumab was studied in 550 participants with metastatic NSCLC. The most common side effects reported among study participants included dyspnea, cough, shortness of breath, fatigue, decreased appetite, and severe adverse events resulting from the immune system effect from pembrolizumab. The efficacy for pembrolizumab was demonstrated in a subgroup of 61 participants with pretreated PD-L1 positive advanced NSCLC as determined by the 22C3 pharmDx diagnostic test; the overall response rate for pembrolizumab (percentage of participants who experienced complete and partial shrinkage of their tumors) was 41% (n=25), with effect lasting between 2.1 and 9.1 months. Garon and colleagues (2015) reported findings from the KEYNOTE-1, authors conclude that "pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab".
September 2016 Update
On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
The approval was based on demonstration of a durable objective response rate in a subgroup of patients in an international, multicenter, non-randomized, open-label, multi-cohort study. The subgroup included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy.
As a condition of the accelerate approval, Merck is required to conduct a multicenter, randomized trial establishing the superiority of pembrolizumab over standard therapy to verify and describe the clinical benefit of pembrolizumab. Merck currently has an ongoing multicenter, randomized trial (NCT02252042) in patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy with a primary endpoint of overall survival.
2017 Update
The FDA granted accelerated approval to pembrolizumab for the treatment of classical Hodgkin lymphoma that has resisted treatment or relapsed after three or more prior lines of therapy. The decision was based on tumor response rate as well as durability of response in a study of 210 patients. The label states, “Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials" (FDA, 2017). The label includes the following information:
“The efficacy of KEYTRUDA was investigated in 210 patients with relapsed or refractory cHL, enrolled in a multicenter, non-randomized, open-label study. Patients with active, non-infectious pneumonitis, an allogeneic 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 were ineligible for the trial. Patients received KEYTRUDA at a dose of 200 mg every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients that did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, CRR, and duration of response) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria.
Among the 210 patients, the baseline characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; 49% had an ECOG performance status (PS) of 0 and 51% had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior auto-HSCT, 83% had received prior brentuximab and 36% of patients had prior radiation therapy” (FDA, 2017).
According to the information included in the FDA approved label, an overall response rate (ORR) of 69% was achieved with 22% of patients receiving complete remission and 47% achieving partial remission. There was an 11.1 month response duration (FDA, 2017).
2018 Update
A literature search conducted through November 2018 did not reveal any new literature that would prompt a change in the coverage statement.
February 2019 Update
A multicenter, phase 2, non-controlled study was conducted with pembrolizumab (anti–PD-1) for adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy. In this study, a total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. (Nghiem, Paul T et al., 2016) In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.) (Nghiem, Paul T et al., 2016).
June 2019 Update
In an open-label, phase 3 trial, 861 patients with previously untreated advanced clear-cell renal-cell carcinoma were randomly assigned to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.
After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab–axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab–axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab–axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab–axitinib group and in 70.6% in the sunitinib group.
Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.) (Rini,RB, Plimack, ER, Stus, V, et. al., 2019).
August 2019 Update
The efficacy of KEYTRUDA was investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease. A total of 628 patients were enrolled and randomized to KEYTRUDA (n=314) or investigator’s treatment of choice (n=314). Of these 628 patients, 167 (27%) had ESCC that expressed PD-L1 with a CPS ≥10.
The 628 patients were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks for up to 2 years or investigator’s choice of paclitaxel, docetaxel, or irinotecan. Randomization was stratified by histology (squamous cell carcinoma vs adenocarcinoma) and region (Asia vs rest of the world). The three co-primary endpoints were overall survival in the intent-to-treat population, the squamous cell carcinoma subgroup (n = 401), and the subgroup with a CPS ≥ 10 (n = 222). The boundary for statistical significance in the squamous cell carcinoma and intent-to-treat subgroups was P ≤ .0077; the boundary for the CPS ≥ 10 subgroup was P ≤ .0085. The median follow-up was approximately 7 months.
Although pembrolizumab was of significant benefit in patients with a PD-L1 CPS ≥ 10, it did not improve overall survival or progression-free survival in the overall intent-to-treat population. In the intent-to-treat analysis, median overall survival was 7.1 months in each arm (HR = 0.89, P = .0560). Survival rates were 32% with pembrolizumab and 24% with chemotherapy at 12 months, and 18% and 10%, respectively, at 24 months. In the squamous cell carcinoma subgroup, median overall survival was 8.2 months vs 7.1 months (HR = 0.78, P = .0095), respectively, with survival rates of 39% with pembrolizumab and 25% with chemotherapy at 12 months, and 23% vs 12%, respectively, at 24 months. These differences favoring pembrolizumab did not meet the study’s prespecified statistical boundary of P ≤ .0075.
At 12 months, progression-free survival rate was 21% vs 7% for pembrolizumab and chemotherapy, respectively, in the PD-L1 CPS ≥ 10 group; 15% vs 9% in the squamous cell carcinoma group; and 12% and 10% in the intent-to-treat group. Response rates with pembrolizumab were double or triple those achieved with chemotherapy for all 3 comparisons, though the median duration of response was only longer in the PD-L1 CPS ≥ 10 group (9.3 vs 7.7 months with chemotherapy).
December 2019 Update
The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-146 (NCT02501096), a single-arm, multicenter, open-label, multi-cohort trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily until unacceptable toxicity or disease progression as determined by the investigator. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) by independent radiologic review committee (IRC) using RECIST.
Administration of KEYTRUDA and lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA dosing was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 6 weeks until week 24, followed by every 9 weeks thereafter.
Among the 108 patients, 87% (n= 94) had tumors that were not MSI-H or dMMR, 10% (n=11) had tumors that were MSI-H or dMMR, and in 3% (n=3) the status was not known. Tumor MSI status was determined using a polymerase chain reaction (PCR) test. Tumor MMR status was determined using an immunohistochemistry (IHC) test. The baseline characteristics of the 94 patients with tumors that were not MSI-H or dMMR were: median age of 66 years, 62% age 65 or older; and 86% White, 6% Black, 4% Asian, and 3% other races; and ECOG PS of 0 (52%) or 1 (48%). All 94 of these patients received prior systemic therapy for endometrial carcinoma: 51% had one, 38% had two, and 11% had three or more prior systemic therapies.
Efficacy results of KEYTRUDA 200 mg every 3 weeks with lenvatinib were: Complete response rate was 10.6% and partial response rate was 27.7%. (Marker V, et.al., 2019)
February 2020 Update
The efficacy and safety of Keytruda in 148 patients with high-risk NMIBC, including 96 patients who had BCG-unresponsive CIS with or without papillary tumors was assessed in the KEYNOTE-057 trial. Patients received Keytruda 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. Of the 96 patients with high-risk BCG-unresponsive NMIBC with CIS, 41% experienced a complete response rate with a median duration of 16.2 months. That number was slightly higher (46%) when looking at patients who experienced a complete response rate that lasted at least 12 months.
Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. 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.(FDA, 2020)
June 2020 Update
In a multicohort, phase 1/2 study (Keynote 021) of pembrolizumab combination therapy in patients with advanced NSCLC, patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations were randomized to pembrolizumab 2 or 10 mg/kg Q3W plus carboplatin area under the serum concentration-time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m2 (cohort A, any histology), carboplatin AUC 6 mg/mL/min plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg (cohort B, non-squamous), or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m2 (cohort C, non-squamous) for 4 cycles followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C). Response was assessed by blinded independent central review.
Overall, 74 patients were randomized; median follow-up was 21.4, 16.4, and 17.4 months in cohorts A, B, and C, respectively. No dose-limiting toxicities occurred in any cohort at either pembrolizumab dose. Most frequent treatment-related adverse events (AEs) were alopecia, fatigue, and nausea. Treatment-related grade 3/4 AEs occurred in 40%, 42%, and 46% of patients in cohorts A, B, and C, respectively; AEs with possible immune etiology occurred in 24%, 50%, and 38% of patients, respectively. Objective response rates were 48%, 56%, and 75% in cohorts A, B, and C, respectively.
Pembrolizumab in combination with carboplatin-paclitaxel and with pemetrexed-carboplatin yielded encouraging antitumor activity and toxicity consistent with known toxicities of platinum-based chemotherapy or pembrolizumab monotherapy. (Gadgeel SM, Stevenson JP, Langer CJ, et al., 2018)
In a double-blind, phase 3 trial (KEYNOTE 189), 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease were randomly assigned (in a 2:1 ratio) to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy.
Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.
After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.
In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al., 2018)
2020 Update
The efficacy of Keytruda was investigated in a nonrandomized, open-label, multisite phase II study-planned retrospective analysis. Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced non-colorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST), as assessed by independent central radiologic review.
Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.
The study demonstrated the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy. (Marabelle A, Le DT, Ascierto PA, et al. 2020).
A phase II open-label study (KEYNOTE-164 (NCT02460198)) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC). It involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability.
A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A.
Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC. (Le DT, Kim TW, Van Cutsem E, et al. 2020).
The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC enrolled in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.
Patients received KEYTRUDA 200 mg intravenously every 3 weeks until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status.
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 ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Among the 105 patients treated, the study population characteristics were: median age of 72 years (range: 29 to 95), 71% age 65 or older; 76% male; 71% White, 25% race unknown; 34% ECOG PS of 0 and 66% ECOG PS of 1. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC, and 31% had both locally recurrent and metastatic cSCC. Eighty=even percent received one or more prior lines of therapy; 74% received prior radiation therapy. (FDA, 2020)
April 2021 Update
Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC.
Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS.
Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%.
Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. (Rudin CM, Awad MM, Navarro A, et. al., 2020)
Accelerated approval for KEYTRUDA was granted in June 2019 based on tumor response rate and durability of response data from KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1). Continued approval for this indication was contingent upon completion of the post-marketing requirement establishing superiority of KEYTRUDA as determined by overall survival (OS). As announced in Jan. 2020, KEYNOTE-604, the confirmatory Phase 3 trial for this indication, met one of its dual primary endpoints of progression-free survival but did not reach statistical significance for the other primary endpoint of OS.
Merck announced 3/1/2021 that it is voluntarily withdrawing the U.S. indication for Keytruda for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. The withdrawal of this indication was done in consultation with the U.S. FDA. (Merck, 2021).
The efficacy of Keytruda was investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively).
At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy.
Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events. (Kojima T, Shah MA, Muro K, et.al., 2020).
The efficacy of pembrolizumab was investigated in a randomized, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries. Patients with untreated locally recurrent inoperable or metastatic triple-negative breast cancer were randomly assigned 2:1 using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomization was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumor sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumor PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0·00411 at this interim analysis), then in patients with CPS of 1 or more (α=0·00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0·00111 at this interim analysis).
Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25.9 months (IQR 22·8-29·9) in the pembrolizumab-chemotherapy group and 26.3 months (22.7-29.7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9.7 months with pembrolizumab-chemotherapy and 5·6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0.65, 95% CI 0.49-0.86; one-sided p=0.0012 [primary objective met]). Median progression-free survival was 7.6 and 5.6 months (HR, 0.74, 0.61-0.90; one-sided p=0.0014 [not significant]) among patients with CPS of 1 or more and 7.5 and 5.6 months (HR, 0.82, 0.69-0.97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group.
Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer. (Cortes J, Cescon DW, Rugo HS, et.al., 2020)
December 2021 Update
In a double-blind, phase 3 trial, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, were randomly assigned, in a 1:1 ratio, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator’s assessment. Overall survival was a key secondary end point. Safety was a secondary end point.
A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P=0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred.
Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (KEYNOTE-564 ClinicalTrials.gov number, NCT03142334) (Choueiri TK, Tomczak P, Park SH, et.al., 2021)
2022 Update
The FDA approval of Keytruda as monotherapy for endometrial carcinoma was based on the results from a multicenter, non-randomized, open-label, muli-cohort Phase 2 KEYNOTE-158 trial. In 90 patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma in Cohorts D and K. MSI or MMR tumor status was determined using PCR or immunohistochemistry. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR). ORR was 46% for patients who received Keytruda, including a complete response rate of 12% and a partial response rate of 33%, at a medial follow-up of 15 months. Of the 41 patients with response , 68% had a response lasting 12 months or longer and 44% had a response lasting 24 months or longer (O'Malley, 2022).
The most common adverse reactions occurring were fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritis, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidsm. Immune-mediated side-effects included pneumonitis, colitis, hepatitis, and skin adverse reactions (O'Malley, 2022).
January 2023 Update
KEYNOTE-716 is a multicenter, double-blind, placebo-controlled, crossover or rechallenge, randomized, phase 3 trial done at 160 academic medical centers and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in pediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomization was done using an interactive response technology system and stratified by T category and pediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment.
Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhea (eight [2%] vs one [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported.
Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting. (Long GV, Luke JJ, Khattak MA, et.al., 2022)
April 2023 Update
In a randomized, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centers in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimization technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumor proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (i.e., all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population.
Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo.
Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression. (O'Brien M, Paz-Ares L, Marreaud S, 2022)
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