Medical Policy

Policy Num:       02.001.059
Policy Name:     KEYTRUDA® (pembrolizumab)

Policy ID:          [02.001.059 ] [Ac / L / M+ / P+]  [ 0.00.00 ]

Last Review:       October 24, 2024
Next Review:       October 20, 2025
 

Related Policies:

5.21.50

KEYTRUDA^®  (pembrolizumab)

SUMMARY

Pembrolizumab is a highly selective anti-PD-1 humanized monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to block PD-1 ligands (PD-L1 and PD-L2) from binding. Blocking the PD-1 pathway inhibits the negative immune regulation caused by PD-1 receptor signaling (Hamid 2013). Anti-PD-1 antibodies (including pembrolizumab) reverse T-cell suppression and induce antitumor responses (Robert 2014).

OBJECTIVE

The objective of this evidence review is to evaluate the medical use of Keytruda as it improves the net health outcome of the patient by adequate selection, individual diagnosis

and dosing of this antineoplastic agent.

POLICY STATEMENTS

Keytruda may be considered medically necessary in patients with:

Labeled Indications:

Biliary Tract Cancer (BTC):

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

Melanoma:

Adjuvant treatment of melanoma with lymph node(s) involvement following complete resection

Treatment of unresectable or metastatic melanoma

Non-small cell lung cancer:

First-line, single-agent treatment of non-small cell lung cancer (NSCLC) in patients with stage III NSCLC (who are not candidates for surgical resection or definitive chemoradiation) or in patients with metastatic NSCLC, and with tumors with PD-L1 expression (tumor proportion score [TPS] ≥1%), as determined by an approved test, and with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations

First-line treatment (in combination with pemetrexed and platinum chemotherapy) of metastatic nonsquamous NSCLC in patients with no EGFR or ALK genomic tumor aberrations

First-line treatment (in combination with carboplatin and either paclitaxel or paclitaxel [protein bound]) of metastatic squamous NSCLC

Single-agent treatment of metastatic NSCLC in patients with tumors with PD-L1 expression (TPS ≥1%), as determined by an approved test, and with disease progression on or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving pembrolizumab.

For the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. 

As a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

Off-label dosing (in patients with metastatic non-small cell lung cancer (NSCLC) with disease progression following platinum-containing chemotherapy): 2 mg/kg once every 3 weeks for 24 months or until disease progression or unacceptable toxicity (Herbst 2016).

Head and neck cancer, squamous cell (recurrent or metastatic):

First-line treatment (in combination with platinum and fluorouracil) of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC)

First-line, single-agent treatment of metastatic or unresectable recurrent HNSCC in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test

Single-agent treatment of recurrent or metastatic HNSCC in patients with disease progression on or after platinum-containing chemotherapy

Hodgkin lymphoma, classical (relapsed or refractory):

Treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma or patients who have relapsed after 2 or more prior lines of therapy

For the treatment of adult patients with relapsed or refractory cHL.

Primary mediastinal large B-cell lymphoma (relapsed or refractory): Treatment of primary mediastinal large B-cell lymphoma (PMBCL) in adult and pediatric patients with refractory disease or who have relapsed after 2 or more prior lines of therapy

Limitation of use: Not recommended for treatment of PMBCL in patients who require urgent cytoreductive therapy

Urothelial carcinoma (locally advanced or metastatic):

Treatment of locally advanced or metastatic urothelial cancer in patients who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10) as determined by an approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status

Treatment of locally advanced or metastatic urothelial cancer in patients with disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy

As a single agent 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.

In combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer.

Microsatellite instability-high cancer (unresectable or metastatic):

Solid tumors: Treatment of unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors in adult and pediatric patients that have progressed following prior treatment and have no satisfactory alternate treatment options.

Limitation of use: Safety and efficacy in pediatric patients with MSI-H central nervous system cancers have not been established.

Colorectal cancer: Treatment of unresectable or metastatic, MSI-H or mismatch repair deficient colorectal cancer in adult and pediatric patients that have progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Gastric cancer /  (recurrent locally advanced or metastatic): 

In combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

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

Esophageal cancer (recurrent locally advanced or metastatic): Treatment of recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus in patients whose tumors express PD-L1 (CPS ≥10) as determined by an approved test, with disease progression after one or more prior lines of systemic therapy.  Pembrolizumab (Keytruda, Merck Sharp & Dohme Corp.) in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal (GEJ) (tumors with epicenter 1 to 5 centimeters above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation.

Cervical cancer (recurrent or metastatic): 

Treatment of recurrent or metastatic cervical cancer in patients whose tumors express PD-L1 (combined positive score [CPS] ≥1), as determined by an approved test, and with disease progression on or after chemotherapy.

In combination with chemoradiotherapy, for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer.

In combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

Hepatocellular carcinoma (advanced):  For the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD1/PD-L1-containing regimen.

Treatment of hepatocellular carcinoma in patients who have been previously treated with sorafenib

Merkel cell carcinoma (recurrent or metastatic): Treatment of recurrent locally advanced or metastatic Merkel cell carcinoma in adult and pediatric patients

Renal cell carcinoma (advanced):  In combination with axitinib, for the first-line treatment of adult patients with advanced RCC. 

In combination with axitinib, for the first-line treatment of adult patients with advanced RCC.

In combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC.

For the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. 

Endometrial carcinoma (advanced): Treatment of advanced endometrial carcinoma (in combination with lenvatinib) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) in patients who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

In combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.

As a single agent, for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. 

Cutaneous squamous cell carcinoma (recurrent or metastatic): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months. FDA 6/24/2020

Tumor mutational burden-high cancer (unresectable or metastatic): IV: 200 mg once every 3 weeks or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months. FDA 6/18/2020

Triple-Negative Breast Cancer (TNBC)

For the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

In combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA approved test. 

On Nov. 13, 2020, the U.S. Food and Drug Administration (FDA) approved the immunotherapy Keytruda (chemical name: pembrolizumab) in combination with chemotherapy to treat unresectable locally advanced or metastatic triple-negative, PD-L1-positive breast cancer.

Pembrolizumab (Keytruda) is recommended by the NCCN Drugs and Biologics Compendium^® for off-label use for the following indication:

• Chondrosarcoma - as a single agent for unresectable or metastatic, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), and tumor mutational burden-high (TMB-H) conventional chondrosarcoma, dedifferentiated chondrosarcoma, and mesenchymal chondrosarcoma that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Chordoma - as a single agent for unresectable or metastatic, tumor mutational burden-high (TMB-H) disease that has progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Classic Hodgkin lymphoma - as single agent, palliative therapy for disease that has relapsed or progressed after autologous hematopoietic stem cell transplant with or without brentuximab vedotin, for relapsed/refractory disease and transplant ineligible based on comorbidity or failure of second-line chemotherapy, or post-allogeneic transplant in individuals older than age 60
• CNS - Brain metastases (limited) - as a single agent for limited brain metastases in patients with melanoma or PD-L1-positive non-small cell lung cancer as initial treatment in select patients, as treatment for recurrent brain metastases, or as treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options
• CNS - Brain metastases (extensive) - as a single agent for extensive brain metastases in patients with melanoma or PD-L1-positive non-small cell lung cancer as primary treatment in select patients or as treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options
• High-grade undifferentiated pleomorphic sarcoma of the bone - as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Mesenchymal chondrosarcoma - as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Pancreatic cancer - single agent, first-line therapy for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) metastatic disease in patients with poor performance status
• Pancreatic cancer - as a single agent, subsequent-line therapy for microsatellite instability-high or mismatch repair deficient tumors) for locally advanced or metastatic disease for patients with disease progression
• Pancreatic cancer - as a single agent for microsatellite instability-high or mismatch repair deficient tumors for local recurrence in the pancreatic operative bed after resection, metastatic disease with or without local recurrence if 6 or more months from completion of primary therapy, or metastatic disease with or without local recurrence if less than 6 months from completion of primary therapy
• Penile cancer (squamous cell) - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Poorly differentiated/large or small cell neuroendocrine and adrenal tumors - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors when disease progressed following prior treatment and when there is no satisfactory alternative treatment options
• Poorly differentiated/large or small cell neuroendocrine and adrenal tumors - as a single agent in children for mutational burden-high (≥ 10 mutations/megabase), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Renal cell cancer (clear cell histology) - as first-line therapy in combination with axitinib for advance disease
• Renal cell cancer (clear cell histology) - as subsequent therapy in combination with axitinib for relapse or stage IV disease
• Uterine Sarcoma - as single agent, second-line therapy for tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] in patients with high-grade endometrial stroma sarcoma, undifferentiated uterine sarcoma, and uterine leiomyosarcoma in patients whose disease progressed following prior treatment and in whom no satisfactory alternative treatment options exist

• Recommendations for pembrolizumab (Keytruda) are designated as Limited Evidence for the following FDA-approved indications:

• Adrenal gland tumors - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Anal carcinoma - as a single agent in children and adults for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Breast cancer (inflammatory) - as a single agent in pediatric patients for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] tumors that have progressed following prior treatment when there are no satisfactory alternative treatment options
• Breast cancer (invasive) - as a single agent for tumor mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options in adult and pediatric patients
• Breast cancer (invasive) - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), metastatic or recurrent disease in patients age < 18 that progressed on or after chemotherapy when there are no satisfactory alternative treatment options available
• Cervical cancer - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), metastatic or recurrent disease in adults and children that progressed on or after chemotherapy when there are no satisfactory alternative treatment options available
• Cervical cancer - as a single agent for tumor-mutational burden-high (TMB-H) metastatic or recurrent disease in adults and children that progressed on or after chemotherapy when there are no satisfactory alternative treatment options available
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer - as a single agent for unresectable or metastatic, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] tumors in patients whose disease progressed following prior treatment and for whom no satisfactory treatment options exist 
• Extrahepatic cholangiocarcinoma - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in pediatric patients with no satisfactory alternative treatment options
• Gallbladder cancer - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in pediatric patients with no satisfactory alternative treatment options
• Gastric cancer - as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Gastric cancer - as first-line treatment in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for patients with locally advanced unresectable or metastatic HER2-positive adenocarcinoma
• Gestational trophoblastic neoplasia - as a single agent for unresectable or metastatic disease that is either deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] in patients whose disease has progressed following prior treatment and for whom no satisfactory alternative treatment options exist
• Head and neck cancer - as a single agent for unresectable or metastatic disease that is either deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] in patients whose disease has progressed following prior treatment and for whom no satisfactory alternative treatment options exist
• Hepatocellular carcinoma - as a single agent for patients previously treated with sorafenib
• Hepatocellular carcinoma - as a single agent for unresectable or metastatic, deficient mismatch repair/microsatellite instability-high tumors or mutational burden-high tumors in patients whose disease progressed following prior treatment and for whom no satisfactory treatment options exist
• Intrahepatic cholangiocarcinoma - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in pediatric patients with no satisfactory alternative treatment options
• Malignant peritoneal mesothelioma - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Malignant pleural mesothelioma - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Mesenchymal chondrosarcoma - as a single agent in individuals < age 18 with unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Ovarian cancer- as a single agent in adults and children with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Poorly differentiated/large or small cell neuroendocrine and adrenal tumors - as a single agent in children for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Poorly differentiated/large or small cell neuroendocrine and adrenal tumors - as a single agent in children for mutational burden-high (≥ 10 mutations/megabase), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Primary mediastinal large B-cell lymphoma - as a single agent in pediatric patients with refractory disease or disease that relapsed after 2 or more prior lines of therapy when urgent cytoreductive therapy is not required
• Prostate cancer (adenocarcinoma) - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Renal cell cancer - single agent therapy for patients with unresectable or metastatic, deficient mismatch repair/microsatellite instability-high or tumor mutational burden-high disease who progressed following prior treatment and in whom no satisfactory alternative treatment options exist
• Testicular cancer - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment patients with no satisfactory alternative treatment options
• Thymomas and thymic carcinomas - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Urothelial (transitional cell) carcinoma - as first-line, single agent therapy for locally advanced or metastatic disease
• Urothelial (transitional cell) carcinoma - as single agent therapy for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] tumors that progressed following prior treatment when there are no satisfactory alternative treatment options
• Vulvar cancer - as a single agent in adults and children with metastatic or unresectable, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors or tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] that have progressed following prior treatment in patients with no satisfactory alternative treatment options

• Pembrolizumab (Keytruda) is recommended by the NCCN Drugs and Biologics Compendium^® for off-label use for the following indications:

• Adrenal gland tumors - as a single agent or in combination with mitotane for metastatic adrenocorticoid tumors
• Ampullary adenocarcinoma - first-line or subsequent single agent therapy for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or mutational burden-high (TMB-H) disease
• Anal carcinoma - as single agent, second-line or subsequent therapy for metastatic disease and for locally recurrent, progressive disease prior to abdominoperineal resection
• Appendiceal adenocarcinoma - as initial systemic therapy for advanced or metastatic disease as a single agent in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors
• Breast cancer (inflammatory) - in combination with albumin-bound paclitaxel, paclitaxel, or gemcitabine with carboplatin as first-line therapy or second and subsequent line therapy (if PD-L1 inhibitor not previously used) for PD-L1 positive, HER2-negative, hormone receptor-negative disease in patients who have had no response to preoperative systemic therapy, or for recurrent or unresectable (local or regional) disease or stage IV (M1) disease
• Breast cancer (inflammatory) - as a single agent in patients who have had no response to preoperative systemic therapy or for recurrent or unresectable (local or regional) or stage IV (M1) disease that is mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) (≥10 mut/Mb) that has progressed following prior treatment when there are no satisfactory alternative treatment options
• Breast cancer (invasive) - single agent therapy after neoadjuvant therapy for triple negative breast cancer
• Breast cancer (invasive) - first-line or subsequent therapy in combination with albumin-bound paclitaxel, paclitaxel, or gemcitabine with carboplatin for stage IV or recurrent unresectable (local or regional), PD-L1-positive, HER2-negative, hormone receptor-negative disease
• Breast cancer (invasive) - as single agent therapy for unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors when disease progressed following prior treatment and when there are no satisfactory alternative treatment options
• Cervical cancer - as single agent, second-line therapy for tumors that expresses PD-L1 (combined positive score ≥ 1) and progressed on or after chemotherapy for squamous cell, adenocarcinoma, or adenosquamous disease with local/regional recurrence or that is stage IVB or has distant metastases
• Cervical cancer - as a single agent, second-line therapy for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), squamous cell, adenocarcinoma, or adenosquamous disease with local/regional recurrence or that is stage IVB or has distant metastases
• Cervical cancer - as a single agent, second-line therapy for tumor mutational burden-high (TMB-H), squamous cell, adenocarcinoma, or adenosquamous disease with local/regional recurrence or that is stage IVB or has distant metastases
• Chondrosarcoma - as a single agent for unresectable or metastatic, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), and tumor mutational burden-high (TMB-H) conventional chondrosarcoma, dedifferentiated chondrosarcoma, and mesenchymal chondrosarcoma that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Chordoma - as a single agent for unresectable or metastatic, tumor mutational burden-high (TMB-H) disease that has progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) - additional therapy as a single agent or in combination with ibrutinib for clonally related or unknown clonal status Richter's transformation to diffuse large B-cell lymphoma in patients with del(17p)/TP53 mutations who are chemotherapy refractory and unable to receive chemoimmunotherapy
• Classic Hodgkin lymphoma - as single agent, palliative therapy for disease that has progressed after high-dose therapy and autologous stem cell rescue (HDT/ASCR) with or without brentuximab vedotin, or for post-allogeneic transplant in individuals older than age 60
• Classic Hodgkin lymphoma - as a single agent for progressive disease after HDT/ASCR with or without brentuximab vedotin in patients with refractory disease who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy, or for post-allogeneic transplant in individuals age > 18 and < age 60
• CNS - Brain metastases (limited) - as a single agent in patients with BRAF non-specific melanoma or PD-L1 positive non-small cell lung cancer as initial treatment in select patients or for recurrent or relapsed disease
• CNS - Brain metastases (extensive) - as a single agent in patients with BRAF non-specific melanoma or PD-L1 positive non-small cell lung cancer as primary treatment in select patients or for recurrent disease
• Colon cancer - as single agent, primary treatment for locally unresectable or medically inoperable disease in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors
• Colon cancer - adjuvant therapy as a single agent for dMMR/MSI-H tumors following resection and/or local therapy for resectable metachronous metastases in patients who received previous chemotherapy, for unresectable metachronous metastases that converted to resectable disease after primary treatment, or following synchronized or staged resection and/or local therapy for synchronous liver and/or lung metastases that converted from unresectable to resectable disease after primary treatment
• Colon cancer - neoadjuvant treatment as a single agent in patients with dMMR/MSI-H tumors for resectable synchronous liver and/or lung metastases or as primary treatment for clinical T4b disease
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer - as a single agent palliative, second-line or subsequent therapy in patients who are not candidates for surgery for unresectable locally advanced, recurrent, or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) or tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] tumors
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer - palliative second line therapy for esophageal squamous cell carcinoma with PD-L1 combined positive score of ≥10 in patients who are not candidates for surgery for unresectable locally advanced, recurrent, or metastatic disease if there is no prior tumor progression while on therapy with a checkpoint inhibitor
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – first-line palliative therapy for patients with HER2- positive adenocarcinoma who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease in combination with fluorouracil, cisplatin or oxaliplatin, and trastuzumab or capecitabine, cisplatin or oxaliplatin, and trastuzumab if no prior tumor progression while on therapy with a checkpoint inhibitor
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – first-line palliative therapy in combination with oxaliplatin and fluorouracil or capecitabine for patients with HER2-negative disease who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease with PD-L1 combined positive score [CPS] ≥ 10 or PD-L1 CPS < 10 adenocarcinoma or squamous cell carcinoma, if no prior tumor progression while on therapy with a checkpoint inhibitor
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – first-line palliative therapy in combination with cisplatin and fluorouracil or capecitabine for patients with HER2-negative disease who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease with PD-L1 combined positive score [CPS] ≥ 10 or PD-L1 CPS < 10 adenocarcinoma or squamous cell carcinoma, if no prior tumor progression while on therapy with a checkpoint inhibitor
• Ewing sarcoma - as a single agent in patients with unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden high (TMB-H) tumors that have progressed following prior treatment in adults who have no satisfactory alternative treatment options
• Extrahepatic cholangiocarcinoma - as primary treatment as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors
• Extrahepatic cholangiocarcinoma - as subsequent single agent treatment in patients not previously treated with a checkpoint inhibitor who have disease progression on or after systemic treatment for unresectable or metastatic disease that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) or tumor mutational burden high (TMB-H)
• Extrahepatic cholangiocarcinoma - as subsequent treatment in combination with lenvatinib in patients not previously treated with a checkpoint inhibitor for disease progression on or after systemic treatment for unresectable or metastatic disease
• Extranodal NK/T-cell lymphoma, nasal type - as a single therapy for relapsed or refractory disease following additional therapy with an alternate asparaginase-based combination chemotherapy regimen, not previously used and when a clinical trial is not available
• Gallbladder cancer - as primary treatment as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors
• Gallbladder cancer – as subsequent single agent treatment in patients not previously treated with a checkpoint inhibitor who have disease progression on or after systemic treatment for unresectable or metastatic disease that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) or tumor mutational burden high (TMB-H)
• Gallbladder cancer – as subsequent treatment in combination with lenvatinib in patients not previously treated with a checkpoint inhibitor for disease progression on or after systemic treatment for unresectable or metastatic disease
• Gastric cancer - as single agent, second-line or subsequent therapy in patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors or tumor mutational burden (TMB) high (≥ 10 mutations/megabase) tumors as palliative therapy for locoregional disease
• Gastric cancer - as first-line therapy in combination with cisplatin, trastuzumab, and fluorouracil or capecitabine, or oxaliplatin, trastuzumab, and fluorouracil or capecitabine as palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease with HER2-positive adenocarcinoma
• Gastric cancer - as primary treatment in combination with cisplatin, trastuzumab, and fluorouracil or capecitabine, or oxaliplatin, trastuzumab, and fluorouracil or capecitabine for medically fit patients with surgically unresectable locoregional HER2-positive adenocarcinoma
• Gestational trophoblastic neoplasia - as a single agent for recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen when the disease is multiagent chemotherapy resistant
• Gestational trophoblastic neoplasia - as a single agent for methotrexate-resistant high-risk disease
• Head and neck cancer (supraglottic larynx, glottic larynx, subglottis, oropharynx, hypopharynx, ethmoid sinus, maxillary sinus, oral cavity including mucosal lip) – as first-line, single agent therapy in tumors with PD-L1 combined positive score ≥ 1 for T4b, N0-3, M0 disease, newly diagnosed; unresectable nodal disease with no metastases, newly diagnosed; non-metastatic disease and unfit for surgery, newly diagnosed; unresectable second primary with prior radiation; unresectable persistent disease without prior radiation therapy (RT); or unresectable persistent disease with prior RT or as subsequent line therapy in tumors with PD-L1 combined positive score ≥ 1 for unresectable locoregional recurrence or persistent disease without prior radiation therapy (RT); unresectable locoregional recurrence, second primary, or persistent disease with prior radiation therapy (RT); metastatic (M1) disease at initial presentation; or recurrent/persistent disease with distant metastases
• Head and neck cancer (supraglottic larynx, glottic larynx, subglottis, oropharynx, hypopharynx, ethmoid sinus, maxillary sinus, oral cavity including mucosal lip) – as first-line single agent therapy for microsatellite instability-high (MSI-H) tumors and T4b, N0-3, M0 disease, newly diagnosed; newly diagnosed unresectable nodal disease with no metastases; patients unfit for surgery, newly diagnosed non-metastatic; unresectable locoregional recurrence or persistent disease without prior radiation (RT); metastatic (M1) disease at initial presentation; recurrent/persistent disease with distant metastases; or unresectable locoregional recurrence, secondary primary, or persistent disease with prior RT or as subsequent-line therapy for unresectable locoregional recurrence or persistent disease without prior radiation therapy (RT); unresectable locoregional recurrence, second primary, or persistent disease with prior RT; metastatic (M1) disease at initial presentation; or recurrent/persistent disease with distant metastases
• Head and neck cancer (supraglottic larynx, glottic larynx, subglottis, oropharynx, hypopharynx, ethmoid sinus, maxillary sinus, oral cavity including mucosal lip) – in combination with cetuximab, paclitaxel and carboplatin, paclitaxel and cisplatin, docetaxel and carboplatin, docetaxel and cisplatin, fluorouracil and carboplatin, or fluorouracil and cisplatin as first-line or subsequent-line systemic therapy for unresectable locoregional recurrence or persistent disease with prior radiation therapy (RT); unresectable second primary with prior RT; metastatic (M1) disease at initial presentation; recurrent/persistent disease with distant metastases; or resectable locoregional recurrence or persistent disease without prior RT
• Head and neck cancer (nasopharynx) – first-line or subsequent line systemic therapy in combination with cisplatin and gemcitabine for T1-4, N0-3, M1 disease; unresectable locoregional recurrence, second primary, or persistent disease with prior radiation therapy (RT); or recurrent/persistent disease with distant metastases
• Head and neck cancer (nasopharynx) – as subsequent systemic therapy in combination with cisplatin and gemcitabine for unresectable locoregional recurrence, second primary, or persistent disease with prior radiation therapy (RT) or recurrent/persistent disease with distant metastases
• Head and neck cancer (occult primary) – as first-line single agent therapy for non-nasopharyngeal unresectable nodal disease with no metastases, newly diagnosed; non-metastatic disease and unfit for surgery, newly diagnosed; unresectable second primary with prior radiation; unresectable persistent disease without prior radiation therapy (RT); or unresectable persistent disease with prior RT
• Head and neck cancer (occult primary) – as first-line single agent therapy for microsatellite instability-high (MSI-H) tumors and newly diagnosed unresectable nodal disease with no metastases; patients unfit for surgery, newly diagnosed non-metastatic; unresectable locoregional recurrence or persistent disease without prior radiation (RT); metastatic (M1) disease at initial presentation; recurrent/persistent disease with distant metastases; or unresectable locoregional recurrence, secondary primary, or persistent disease with prior RT
• Head and neck cancer (occult primary) – as single agent, subsequent-line therapy for tumors with PD-L1 combined positive score ≥ 1 in patients who have not been treated with pembrolizumab for unresectable locoregional recurrence or persistent disease without prior radiation therapy (RT); unresectable locoregional recurrence, second primary, or persistent disease with prior radiation therapy (RT); metastatic (M1) disease at initial presentation; or recurrent/persistent disease with distant metastases
• Head and neck cancer (occult primary) – as single agent, subsequent-line therapy for microsatellite instability-high (MSI-H) tumors and unresectable locoregional recurrence or persitent isease without prior radiation therapy (RT); unresectable locoregional recurrence, second primary, or persistent disease with prior RT; metastatic (M1) disease at initial presentation; or recurrent/persistent disease with distant metastases
• Head and neck cancer (salivary gland tumor) – as single agent for Tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] recurrent disease with distant metastases; unresectable locoregional recurrence with prior radiation therapy (RT); or unresectable second primary with prior RT 
• Hepatocellular carcinoma - as first-line, single agent therapy in patients who have unresectable disease and are not a transplant candidate; have liver-confined disease, inoperable by performance status, comorbidity or with minimal or uncertain extrahepatic disease; or have metastatic disease or extensive liver tumor burden
• Hepatocellular carcinoma - as subsequent, single agent therapy in patients with Child-Pugh class A only who have not been previously treated with a checkpoint inhibitor, who may or may not have microsatellite instability high (MSI-H) tumors, and have progressive disease that is unresectable in non-candidates for transplant; confined to the liver and inoperable by performance status or comorbidity or with minimal or uncertain extrahepatic disease; or metastatic disease or extensive liver tumor burden
• High-grade undifferentiated pleomorphic sarcoma of the bone - as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Intrahepatic cholangiocarcinoma - as primary treatment as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors
• Intrahepatic cholangiocarcinoma – as subsequent single agent treatment in patients not previously treated with a checkpoint inhibitor who have disease progression on or after systemic treatment for unresectable or metastatic disease that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) or tumor mutational burden high (TMB-H)
• Intrahepatic cholangiocarcinoma – as subsequent treatment in combination with lenvatinib in patients not previously treated with a checkpoint inhibitor for disease progression on or after systemic treatment for unresectable or metastatic disease
• Melanoma (cutaneous) - as single agent, reinduction therapy for metastatic or unresectable disease
• Melanoma (cutaneous) - as a single agent, adjuvant therapy for resected stage III sentinel lymph node-positive disease during nodal basin ultrasound surveillance or after completion lymph node dissection; stage III disease with clinically positive node(s) following wide excision of primary tumor and therapeutic lymph node dissection; stage III disease with clinical satellite/in-transit metastases if no evidence of disease after complete excision to clear margins; stage III disease with clinical satellite/in-transit metastases if no evidence of disease after initial local or regional therapy; local satellite/in-transit recurrence if no evidence of disease after complete excision to clear margins; local satellite/in-transit recurrence if no evidence of disease after initial local or regional therapy; or following therapeutic lymph node dissection and/or complete resection of nodal recurrence or complete resection of distant metastatic disease
• Melanoma (cutaneous) - as single agent, initial therapy for limited resectable stage III disease with clinical satellite/in-transit metastases or limited resectable local satellite/in-transit recurrence
• Melanoma (cutaneous) - as single agent, reinduction therapy for metastatic or unresectable disease when prior checkpoint inhibitor immunotherapy resulted in disease control with subsequent disease progression or relapse more than 3 months after treatment was discontinued and when there is no residual toxicity
• Mycosis fungoides (MF) Sezary syndrome (SS) - in combination with systemic therapy, as primary systemic treatment for generalized cutaneous or extracutaneous lesions with large cell transformation (LCT)
• Mycosis fungoides (MF) Sezary syndrome (SS) - systemic therapy as a single agent as subsequent treatment for LCT that is refractory to multiple previous therapies and has limited cutaneous lesions or generalized cutaneous or extracutaneous lesions
• Mycosis fungoides (MF) Sezary syndrome (SS) - systemic therapy in combination with skin-directed therapy as subsequent treatment for limited cutaneous lesions with LCT that is refractory to multiple previous therapies, or for relapsed or persistent generalized cutaneous or extracutaneous lesions with LCT
• Mycosis fungoides (MF) Sezary syndrome (SS) - systemic therapy in combination with skin-directed therapy as subsequent treatment for stage IA MF that is refractory to multiple previous therapies
• Mycosis fungoides (MF) Sezary syndrome (SS) - systemic therapy in combination with skin-directed therapy as primary treatment for stage IB-IIA MF; in combination with skin-directed therapy as subsequent treatment for relapsed stage IB-IIA MF with a lower skin disease burden; or for stage IB-IIA MF with a higher skin disease burden that is relapsed or persistent with T1-T2 disease
• Mycosis fungoides (MF) Sezary syndrome (SS) - systemic therapy as a single agent as subsequent treatment for stage IIB MF with limited or generalized tumor lesions that is refractory to multiple previous therapies; or in combination with skin-directed therapy for relapsed stage IIB MF with T1-2 limited or generalized tumor lesions; or for stage IIB MF with generalized tumor lesions that is refractory to multiple previous therapies
• Mycosis fungoides (MF) Sezary syndrome (SS) - systemic therapy as a single agent as subsequent treatment for stage III MF that is refractory to multiple previous therapies; in combination with skin-directed therapy as primary treatment for stage III MF; or as subsequent treatment for stage III MF that is relapsed or persistent or refractory to multiple previous therapies
• Mycosis fungoides (MF) Sezary syndrome (SS) - systemic therapy as a single agent as subsequent treatment for stage IVA2 non-Sezary or IVB visceral disease (solid organ) that is refractory to multiple previous therapies
• Mycosis fungoides (MF) Sezary syndrome (SS) - systemic therapy in combination with skin directed therapy as primary treatment for stage IVA1 or IVA2 SS; as a single agent as subsequent treatment for stage IVA1 or IVA2 that is refractory to multiple previous therapies; or in combination with skin-directed therapy as subsequent treatment for relapsed or persistent stage IVA1 or IVA2 SS
• Non-small cell lung cancer - in combination with carboplatin and paclitaxel or albumin-bound paclitaxel or cisplatin and paclitaxel or albumin-bound paclitaxel as first-line or subsequent therapy for metastatic disease or locoregional recurrence
• Non-small cell lung cancer - as first-line, single agent therapy for locoregional recurrence when the tumor is PD-L1 expression-positive (≥ 1%) and negative for actionable molecular markers
• Non-small cell lung cancer - as single agent or in combination with pemetrexed and platinum chemotherapy, carboplatin and paclitaxel or albumin-bound paclitaxel for metastatic disease or locoregional recurrence or symptomatic local disease as first-line or initial therapy
• Non-small cell lung cancer - as a single agent or in combination with pemetrexed for continuation maintenance therapy
• Non-small cell lung cancer - as a single agent subsequent therapy for stage IV metastatic or locoregional recurrence or symptomatic local disease following progression
• Osteosarcoma - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or tumor mutational burden-high (TMB-H) metastatic or unresectable tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
• Ovarian cancer (epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer; mucinous carcinoma; carcinosarcoma; clear cell carcinoma) - as a single agent for persistent or recurrent deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) disease as immediate treatment for serially rising CA-125 in patients who previously received chemotherapy; progression on primary, maintenance, or recurrence therapy; stable or persistent disease (if not on maintenance therapy); complete remission and relapse less than 6 months after completing chemotherapy; radiographic and/or clinical relapse and previous complete remission and relapse after 6 or more months after completing prior chemotherapy
• Pancreatic cancer - single agent, first-line therapy for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) metastatic disease in patients with poor performance status
• Pancreatic cancer - as a single agent, subsequent-line therapy for microsatellite instability-high or mismatch repair deficient tumors) for locally advanced or metastatic disease for patients with disease progression
• Pancreatic cancer - as a single agent for microsatellite instability-high or mismatch repair deficient tumors for local recurrence in the pancreatic operative bed after resection, metastatic disease with or without local recurrence if 6 or more months from completion of primary therapy, or metastatic disease with or without local recurrence if less than 6 months from completion of primary therapy
• Pediatric diffuse high-grade glioma - as single agent, adjuvant treatment for patients with hypermutant tumors excluding diffuse midline glioma, H3 K26-altered or pontine location
• Pediatric diffuse high-grade glioma - as single agent treatment for recurrent or progressive disease in hypermutant tumors excluding oligodendroglioma, IDH-mutant and 1p/19q co-deleted or astrocytoma IDH-mutant
• Penile cancer (squamous cell) - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Penile cancer - as a single agent for unresectable or metastatic, TMB-H tumors that progressed on previously approved lines of therapy
• Poorly differentiated/large or small cell neuroendocrine and adrenal tumors - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors when disease progressed following prior treatment and when there is no satisfactory alternative treatment options
• Poorly differentiated/large or small cell neuroendocrine and adrenal tumors - as a single agent in children for mutational burden-high (≥ 10 mutations/megabase), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options
• Prostate cancer (adenocarcinoma) - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), castration-resistant distant metastatic (M1) disease that has progressed through at least one line of systemic therapy in patients who have not previously received pembrolizumab
• Primary cutaneous CD30+ T-cell lymphoproliferative disorders - as a single agent for relapsed or refractory primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions and cutaneous ALCL with regional nodes (excludes systemic ALCL)
• Primary mediastinal large B-cell lymphoma - as a single agent, second-line or subsequent therapy for relapsed or refractory disease
• Rectal cancer - as primary treatment for stage 0-III disease as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), T3, N Any; T1-2, N1-2; T4, N Any or locally unresectable or medically inoperable tumors when resection is contraindicated following neoadjuvant therapy or total neoadjuvant therapy
• Rectal cancer - as adjuvant treatment as a single agent in patients with dMMR/MSI-H tumors following resection and/or local therapy for resectable metachronous metastases or for unresectable metachronous metastases that converted to resectable disease after primary treatment
• Rectal cancer - as neoadjuvant treatment as a single agent in patients with dMMR/MSI-H tumors for resectable synchronous liver only and/or lung only metastases or for resectable synchronous liver only and/or lung only metastases and previously treated with neoadjuvant radiation with or without concurrent chemotherapy
• Renal cell cancer (clear cell histology) - as first-line therapy in combination with axitinib for advance disease
• Renal cell cancer (clear cell histology) - as subsequent therapy in combination with axitinib for relapse or stage IV disease
• Small bowel adenocarcinoma - initial therapy as a single agent for advanced metastatic, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) disease
• Small bowel adenocarcinoma - subsequent therapy as a single agent for advanced metastatic, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) disease
• Small cell lung cancer - as a single agent for disease relapse following complete or partial response or stable disease with primary treatment or for primary progressive disease
• Soft tissue sarcoma - as a single agent for alveolar soft part sarcoma or undifferentiated metastatic pleomorphic sarcoma
• Testicular cancer - as single agent, third-line therapy in patients with microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) or tumor mutational burden-high (TMB-H) disease
• Thymomas and thymic carcinomas - as single agent, second-line therapy for thymic carcinomas that are unresectable after first-line therapy for potentially resectable locally advanced disease, solitary metastasis, ipsilateral pleural metastasis or for extrathoracic metastatic disease
• Thyroid carcinoma - as aggressive first-line single agent therapy for stage IVC (metastatic) disease
• Urothelial (transitional cell) carcinoma (bladder) - as first-line, single agent therapy in patients not eligible for any platinum-containing therapy or not eligible for cisplatin-containing chemotherapy and tumor expresses PD-L1 for stage II (cT2, N0) disease; stage IIIA (cT3, N0; cT4a, N0; cT1-T4a, N1) disease; stage IIIA (cT3, N0; cT4a, N0; cT1-4a, N1) disease and non-cystectomy candidate; stage IIIB (cT1-T4a, N2,3) disease as downstaging systemic therapy; stage IIIB (cT1-T4a, N2,3) disease; stage IVA (cT4b, any N, M0; any T, any N, M1a) disease; stage IVB (any T, any N, M1b) disease; metastatic or local recurrence post cystectomy; and muscle invasive local recurrence or persistent disease in preserved bladder
• Urothelial (transitional cell) carcinoma (bladder) - as single agent, second-line, post-platinum therapy for stage IIIB (cT1-T4a, N2,3) disease; stage IVA (cT4b, any N, M0) disease; stage IVA (any T, any N, M1a) disease; stage IVB (any T, any N, M1b) disease; metastatic or local recurrence post cystectomy; and muscle invasive local recurrence or persistent disease in a preserved bladder
• Urothelial (transitional cell) carcinoma [upper genitourinary (renal pelvis and ureter) or prostate)] - as first-line, single agent therapy in patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and tumor expresses PD-L1
• Urothelial (transitional cell) carcinoma (primary carcinoma of the urethra) - as first-line, single agent therapy in patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and tumor expresses PD-L1 with clinical stage T3-4, cN1-2 disease; cN1-2 palpable inguinal lymph nodes; or recurrent disease
• Urothelial (transitional cell) carcinoma [upper genitourinary (renal pelvis and ureter) or prostate)] - as second-line, single agent, post-platinum therapy for metastatic disease or third-line or subsequent therapy for metastatic disease
• Urothelial (transitional cell) carcinoma (primary carcinoma of urethra) - as second-line, single agent, post-platinum therapy for recurrent or metastatic disease or third-line or subsequent therapy for recurrent or metastatic disease
• Uveal melanoma - as a single agent for distant metastatic disease
• Vulvar cancer - as single agent, second-line therapy for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) locally advanced, metastatic, or recurrent disease
• Vulvar cancer - as single agent, second-line therapy for disease that progressed on or after chemotherapy when PD-L1 expression ≥ 1

Keytruda is considered investigational in patients with all other indications.

POLICY GUIDELINES

There are several Off-Label indications that may be considered medically necessary by NCCN compendia:

Malignant Pleural Mesothelioma  relapsed/refractory, PD-L1+ 

• Used as subsequent therapy as a singel agent

Central Nervous System Cancer

Brain Metastases as a single agent therapy in brain metastases in melanoma or PD-L1 positive non-small cell lung cancer 

• used for newly diagnosed or recurrent disease as a single agent for brain metastasis: AND
• Pembrolizumab is active against the primary melanoma or NSCLC tumor

T-Cell Lymphoma/Extranodal NK

• Patient has relapsed or refractory nasal type disease; AND
• Disease progressed following additional treatment with asparaginase-basd chemotherapy, clinical trials or other best supportive care

Anal Carcinoma

• Patient has metastatic squamous cell disease; AND
• Used as a single agent for second-line therapy

    Breast cancer, triple negative, early stage (off-label use): IV:

Neoadjuvant therapy: 200 mg once every 3 weeks (in combination with paclitaxel and carboplatin) for 4 cycles (first neoadjuvant treatment), followed by 200 mg once every 3 weeks (in combination with cyclophosphamide and either doxorubicin or epirubicin) for 4 cycles (second neoadjuvant treatment). Patients underwent definitive surgery 3 to 6 weeks after the last cycle of the neoadjuvant phase (Schmid 2020).

Adjuvant therapy: 200 mg once every 3 weeks (in combination with radiation therapy) for up to 9 cycles (Schmid 2020).

      Poorly Differentiated Neuroendocrine Carcinoma/Large or Small Cell Carcinoma

 - poorly Differentiated (High Grade)/Large or Small Cell - for persons with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors that have progressed following prior treatment with no satisfactory alternative treatment options.

     Epithelial Ovarian/Fallopian Tube/Primary Peritoneal Cancer 

- as a single agent for recurrent or persistent microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors

     Gestational Trophoblastic Neoplasia 

- as a single agent in persons with recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen; or methotrexate-resistant high-risk disease.

BENEFIT APPLICATION

BlueCard/National Account Issues -  N/A

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

A DOSAGE AND ADMINISTRATION -----------------------

 Melanoma: 200 mg every 3 weeks, or 400 mg every 6weeks; continue until disease progression, unacceptable toxicity, or put to 12 months in a patient without disease recurence.

 NSCLC: 

stage III or metastatic, single-agent therapy: IV: 200 mg once every 3 weeks (Mok 2019; Reck 2016) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

metastatic, nonsquamous, combination therapy: IV: 200 mg once every 3 weeks (in combination with pemetrexed and either cisplatin or carboplatin) for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks (with or without optional indefinite pemetrexed maintenance therapy) until disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles or 24 months (Gandhi 2018; Langer 2016). Pembrolizumab 400 mg once every 6 week

metastatic, squamous, combination therapy: IV: 200 mg once every 3 weeks (in combination with carboplatin and either paclitaxel or paclitaxel [protein bound]) for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks until radiographic disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles (Paz-Ares 2018). Pembrolizumab 400 mg once every 6 weeks has been approved as an additional dosing option.

 SCLC: 200 mg every 3 weeks (Small Cell Lung Ca)   (Chung 2020) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

 HNSCC: 200 mg every 3 weeks. (Head and Neck Sq Cell Ca)  Burtness 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (initially in combination with 6 cycles of fluorouracil and either carboplatin or cisplatin).

 cHL or PMBCL: 200 mg every 3 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (Classical Hodgkin lymphoma)

 Urothelial Carcinoma: 200 mg every 3 weeks. 

 MSI-H Cancer: 200 mg every 3 weeks for adults or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months and 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.

 Gastric Cancer: 200 mg every 3 weeks  (Fuchs 2018) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months. . 

 Esophageal Cancer: 200 mg every 3 weeks  (Shah 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without  disease progression) for up to 24 months.

Pembrolizumab (Keytruda, Merck Sharp & Dohme Corp.) in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal (GEJ) (tumors with epicenter 1 to 5 centimeters above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation.

 Cervical Cancer: 200 mg every 3 weeks (Chung 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months. . 

 HCC: 200 mg every 3 weeks. (Hepatocellular Carcinoma)   (Zhu 2018) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

 MCC: 200 mg every 3 weeks for adults or 400 mg once every 6 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months. ; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (Merkel Cell Ca)

 RCC: 200 mg every 3 weeks (Rini 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (in combination with axitinib 5 mg orally twice daily. (Renal Cell Ca)

 Endometrial Carcinoma: 200 mg every 3 weeks  (Makker 2019) or 400 mg once every 6 weeks; continue until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (in combination with lenvatinib 20 mg orally once daily.

   Triple-Negative Breast Cancer (TNBC) • in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA approved test.

Malignant pleural mesothelioma, relapsed/refractory, PD-L1+ (off-label use): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Alley 2017; Metaxas 2018).

Breast cancer, triple negative, early stage (off-label use): IV:

Neoadjuvant therapy: 200 mg once every 3 weeks (in combination with paclitaxel and carboplatin) for 4 cycles (first neoadjuvant treatment), followed by 200 mg once every 3 weeks (in combination with cyclophosphamide and either doxorubicin or epirubicin) for 4 cycles (second neoadjuvant treatment). Patients underwent definitive surgery 3 to 6 weeks after the last cycle of the neoadjuvant phase (Schmid 2020).

Adjuvant therapy: 200 mg once every 3 weeks (in combination with   radiation therapy) for up to 9 cycles (Schmid 2020).

Administer KEYTRUDA as an intravenous infusion over 30 minutes

B. The decision to treat a patient with Keytruda® must be based on the following criteria:

         1. It must be prescribed by a hematologist or oncologist.    

         2. Patient 18 years of age or older (there are pediatric indications)
         

         3. Information required:
             

a) Present condition status, primary tumor, extenet of disease, age and weight of the patient
             

b) Evidence of having received chemotherapy and what type, if prescribed and not used as first line treatment
           

c) Presents evidence of having obtained a positive result to the PD-L1 protein expression (determined by the approved test by the FDA) if done.

C. Admission of the patient to the hospital for the sole and sole purpose of administer Keytruda® requires individual pre-authorization for the treatment in essence of service. The

     request must include the following documentation:
       

         1. Insured's contract number.
       

         2. It must be prescribed by a hematologist or oncologist.
     

         3. Diagnostic code ICD-10.
       

         4. Documentation of medical necessity
           

            a) Evidence of  metastasis if present

        5 Dosing of medication requested

 Dosing: Adult

     Cervical cancer (recurrent or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Chung 2019).

     Endometrial carcinoma (advanced): IV: 200 mg once every 3 weeks (in combination with lenvatinib) until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Makker 2019).

     Esophageal cancer (recurrent locally advanced or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Shah 2019). Pembrolizumab (Keytruda, Merck Sharp & Dohme Corp.) in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal (GEJ) (tumors with epicenter 1 to 5 centimeters above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation.

     Gastric cancer (recurrent locally advanced or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Fuchs 2018).

     Head and neck cancer, squamous cell, (unresectable/recurrent or metastatic), single-agent therapy: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

     Head and neck cancer, squamous cell, (unresectable/recurrent or metastatic), combination therapy: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (initially in combination with 6 cycles of fluorouracil and either carboplatin or cisplatin) (Rischin 2019).

     Hepatocellular carcinoma (advanced): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Zhu 2018).

     Hodgkin lymphoma, classical (relapsed or refractory): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

     Melanoma (adjuvant treatment ): IV: 200 mg once every 3 weeks until disease recurrence, unacceptable toxicity, or for up to 12 months in patients without disease recurrence (Eggermont 2018).

     Melanoma (unresectable or metastatic): IV: 200 mg once every 3 weeks until disease progression or unacceptable toxicity.

Off-label dosing: 2 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Ribas 2015).

     Merkel cell carcinoma, recurrent or metastatic: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Off-label dosing: 2 mg/kg once every 3 weeks for up to 2 years or until complete response, or until disease progression or unacceptable toxicity (Nghiem 2016).

     Microsatellite instability-high cancer (unresectable or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

     Non-small cell lung cancer (stage III or metastatic), single-agent therapy: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Mok 2019; Reck 2016).

Off-label dosing (in patients with metastatic NSCLC with disease progression following platinum-containing chemotherapy): 2 mg/kg once every 3 weeks for 24 months or until disease progression or unacceptable toxicity (Herbst 2016).

     Non-small cell lung cancer (metastatic, nonsquamous), combination therapy: IV: 200 mg once every 3 weeks (in combination with pemetrexed and either cisplatin or carboplatin) for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks (with or without optional indefinite pemetrexed maintenance therapy) until disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles or 24 months (Gandhi 2018; Langer 2016).

     Non-small cell lung cancer (metastatic, squamous), combination therapy: IV: 200 mg once every 3 weeks (in combination with carboplatin and either paclitaxel or paclitaxel [protein bound]) for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks until radiographic disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles (Paz-Ares 2018).

     Primary mediastinal large B-cell lymphoma (relapsed or refractory): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Zinzani 2017).

     Renal cell carcinoma (advanced): IV: 200 mg once every 3 weeks (in combination with axitinib) until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Rini 2019).

     Small cell lung cancer (metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

     Urothelial carcinoma (locally advanced or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Bellmunt 2017).

     Dosing: Pediatric    

     Note: FDA approval through an accelerated process; well-controlled trials in pediatric patients are scant and dosing based on adult efficacy and safety trials and pediatric pharmacokinetic and safety data.

      Hodgkin lymphoma, classical (relapsed or refractory): Children ≥2 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months

      Merkel cell carcinoma (recurrent locally advanced or metastatic): Children ≥2 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months

      Microsatellite instability-high cancer (MSI-H) (unresectable or metastatic); non-CNS solid tumors that have progressed following prior treatment without satisfactory alternative treatment options: Children ≥2 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months

      Primary mediastinal large B-cell lymphoma (PMBCL) (relapsed or refractory): Children ≥2 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months

      Dosing adjustment for toxicity : Children ≥2 years and Adolescents: In general, no dosage reductions of pembrolizumab are recommended and depending of severity of identified toxicity, pembrolizumab therapy is either withheld or discontinued to manage toxicities.

D.   If a patient, with the diagnosis approved for payment by this policy, is admitted to the hospital, and as part of the treatment requires the use of Keytruda®, Triple-S will cover

    the treatment after the requirements are met previously exposed.

E. Triple-S pays only the dose every 3 weeks of the medication.

F. Triple-S will not consider for payment the use of Keytruda® under the following Circumstances
   

    a. The patient has hypersensitivity to the product or any of its components.
   

    b. Patient does not meet any of the above criteria

regulatory status

FDA-approved indication: Keytruda is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of:

Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks.
NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks.
SCLC: 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 Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics.
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.  On March 22, 2021, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck Sharp & Dohme Corp.) in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal (GEJ) (tumors with epicenter 1 to 5 centimeters above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation.
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 with axitinib 5 mg orally twice daily.
Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks with lenvatinib 20 mg orally once daily for tumors that are not MSI-H or dMMR                                TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks.  

Administer pembrolizumab as an intravenous infusion over 30 minutes.Pembrolizumab is available as a carton containing one 50 mg single-dose vial, a carton containing one 100 mg/4 mL (25 mg/mL) single-dose vial or as a carton containing two 100 mg/4 mL (25 mg/mL) single-dose vials. 

RATIONALE

Keytruda is a monoclonal antibody indicated for the treatment of patients with advanced or unresectable melanoma, metastatic non-small cell lung cancer (NSCLC), metastatic nonsquamous non-small cell lung cancer (NSCLC), recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), refractory classical Hodgkin lymphoma (cHL) who are no longer responding to other drugs, refractory primary mediastinal large B-cell lymphoma (PMBCL), locally advanced or metastatic urothelial carcinoma, recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, microsatellite instability-high or mismatch repair deficient solid tumors that have progressed following prior treatments, and recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, hepatocellular carcinoma, merkel cell carcinoma, renal cell carcinoma and endometrial carcinoma . 

Clinically significant immune-mediated adverse reactions may occur with Keytruda therapy including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism. Based on the severity of the adverse reaction, Keytruda should be withheld or discontinued and corticosteroids administered. Keytruda may cause fetal harm when administered to a pregnant woman.

Safety and effectiveness of Keytruda have been established in pediatric patients (1-4). Prior authorization is required to ensure the safe, clinically appropriate and cost-effective use of Keytruda while maintaining optimal therapeutic outcomes.

Population Reference No. 1 

Melanoma

• KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

  KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Ipilimumab-Naive Melanoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-006 (NCT01866319), a randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive KEYTRUDA at a dose of 10 mg/kg intravenously every 2 weeks or 10 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review [BICR] using Response Evaluation Criteria in Solid Tumors [RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ]). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DoR).

The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 66% had no prior systemic therapy for metastatic disease; 69% ECOG PS of 0; 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay; 65% had M1c stage disease; 68% with normal LDH; 36% with reported BRAF mutationpositive melanoma; and 9% with a history of brain metastases. Among patients with BRAF mutationpositive melanoma, 139 (46%) were previously treated with a BRAF inhibitor.

The study demonstrated statistically significant improvements in OS and PFS for patients randomized to KEYTRUDA as compared to ipilimumab. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every 3 weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to KEYTRUDA 10 mg/kg every 2 weeks with an objective response, response durations ranged from 1.4+ to 8.2 months.

Adjuvant Treatment of Resected Stage IIB or IIC Melanoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-716 (NCT03553836), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected stage IIB or IIC melanoma. Patients were randomized to KEYTRUDA 200 mg or the pediatric (≥12 years old) dose of KEYTRUDA 2 mg/kg intravenously (up to a maximum of 200 mg) every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by AJCC 8th edition T Stage (>2.0-4.0 mm with ulceration vs. >4.0 mm without ulceration vs. >4.0 mm with ulceration). Patients must not have been previously treated for melanoma beyond complete surgical resection for their melanoma prior to study entry. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) (defined as the time between the date of randomization and the date of first recurrence [local, in-transit or regional lymph nodes or distant recurrence] or death, whichever occurred first). New primary melanomas were excluded from the definition of RFS. Patients underwent imaging every six months for one year from randomization, every 6 months from years 2 to 4, and then once in year 5 from randomization or until recurrence, whichever came first.

The study population characteristics were: median age of 61 years (range: 16 to 87), 39% age 65 or older; 60% male; 98% White; and 93% ECOG PS of 0 and 7% ECOG PS of 1. Sixty-four percent had stage IIB and 35% had stage IIC.  The trial demonstrated a statistically significant improvement in RFS for patients randomized to the KEYTRUDA arm compared with placebo.

Adjuvant Treatment of Stage III Resected Melanoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-054 (NCT02362594), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB, or IIIC melanoma. Patients were randomized to KEYTRUDA 200 mg intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated). Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. New primary melanomas were excluded from the definition of RFS. Patients underwent imaging every 12 weeks after the first dose of KEYTRUDA for the first two years, then every 6 months from year 3 to 5, and then annually.

The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; and 84% had PD-L1 positive melanoma with TPS ≥1% according to an IUO assay.  The trial demonstrated a statistically significant improvement in RFS for patients randomized to the KEYTRUDA arm compared with placebo.

Population Reference No. 2 

Non-small cell lung cancer:

First-line, single-agent treatment of non-small cell lung cancer (NSCLC) in patients with stage III NSCLC (who are not candidates for surgical resection or definitive chemoradiation) or in patients with metastatic NSCLC, and with tumors with PD-L1 expression (tumor proportion score [TPS] ≥1%), as determined by an approved test, and with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

First-line treatment (in combination with pemetrexed and platinum chemotherapy) of metastatic nonsquamous NSCLC in patients with no EGFR or ALK genomic tumor aberrations.

First-line treatment (in combination with carboplatin and either paclitaxel or paclitaxel [protein bound]) of metastatic squamous NSCLC.

Single-agent treatment of metastatic NSCLC in patients with tumors with PD-L1 expression (TPS ≥1%), as determined by an approved test, and with disease progression on or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving pembrolizumab.

The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, activecontrolled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms:

KEYTRUDA 200 mg, pemetrexed 500 mg/m2 , and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.

Placebo, pemetrexed 500 mg/m2 , and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks.

Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Patients randomized to placebo and chemotherapy were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS 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. Additional 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. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG PS of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy.

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy

The efficacy of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407 (NCT02775435), a randomized, multicenter, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PDL1 status (TPS <1% [negative] vs. TPS ≥1%), choice of paclitaxel or paclitaxel protein-bound, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

KEYTRUDA 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.  Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks.

Treatment with KEYTRUDA and chemotherapy or placebo and chemotherapy continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients randomized to the placebo and chemotherapy arm were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. An additional efficacy outcome measure was 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.

The study population characteristics were: median age of 65 years (range: 29 to 88), 55% age 65 or older; 81% male; 77% White; 71% ECOG PS of 1; and 8% with a history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel. The trial demonstrated a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy.

First-line treatment of metastatic NSCLC as a single agent

KEYNOTE-042

The efficacy of KEYTRUDA was investigated in KEYNOTE-042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or patients with metastatic NSCLC. Only patients whose tumors expressed PD-L1 (TPS ≥1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG PS (0 vs. 1), histology (squamous vs. nonsquamous), geographic region (East Asia vs. non-East Asia), and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%). Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of either of the following platinum-containing chemotherapy regimens:

Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;

 Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies.

Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECISTdefined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with KEYTRUDA could be reinitiated at the time of subsequent disease  progression and administered for up to 12 months. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. Additional efficacy outcome measures were PFS and ORR in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC 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.

The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Sixty-nine percent had ECOG PS of 1; 39% with squamous and 61% with nonsquamous histology; 87% had M1 disease and 13% had Stage IIIA (2%) or Stage IIIB (11%) and who were not candidates for surgical resection or definitive chemoradiation per investigator assessment; and 5% with treated brain metastases at baseline. Forty-seven percent of patients had TPS ≥50% NSCLC and 53% had TPS 1 to 49% NSCLC.

KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

Population Reference No. 3 

Malignant Pleural Mesothelioma

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM).

Interventions of interest are:
Therapy  in combination with pemetrexed and platinum chemotherapy

Comparators of interest are:
Medical treatment without Keytruda

Relevant outcomes include:

Overall survival
Morbid events
Treatment related mortality
Treatment related morbidity

Population Reference No. 4

Head and Neck Squamous Cell Cancer (HNSCC)

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC) whose tumors express programmed death ligand 1 (PD⁠-⁠L1) [combined positive score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated 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.

First-line treatment of metastatic or unresectable, recurrent HNSCC

The efficacy of KEYTRUDA was investigated in 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. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor PD-L1 expression (TPS ≥50% or <50%) according to the PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC (positive or negative), and ECOG PS (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms:

KEYTRUDA 200 mg intravenously every 3 weeks

 KEYTRUDA 200 mg intravenously every 3 weeks, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2 /day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU)

 Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2 /day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU)

Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at Week 9 and then every 6 weeks for the first year, followed by every 9 weeks through 24 months. A retrospective re-classification of patients’ tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization.

The main efficacy outcome measures were OS and PFS 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)

sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1, and the overall population. The study population characteristics were: median age of 61 years (range: 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian and 2.4% Black; 61% had ECOG PS of 1; and 79% were former/current smokers. Twenty-two percent of patients’ tumors were HPV-positive, 23% had PD-L1 TPS ≥50%, and 95% had Stage IV disease (Stage IVA 19%, Stage IVB 6%, and Stage IVC 70%). Eighty-five percent of patients’ tumors had PD-L1 expression of CPS ≥1 and 43% had CPS ≥20. The trial demonstrated a statistically significant improvement in OS for patients randomized to KEYTRUDA in combination with chemotherapy compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis in the overall population.

Previously treated recurrent or metastatic HNSCC

The efficacy of KEYTRUDA was investigated in KEYNOTE-012 (NCT01848834), a multicenter, nonrandomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS ≥2 were ineligible.

Patients received KEYTRUDA 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum

The study population characteristics were median age of 60 years, 32% age 65 or older; 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of 0 and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2.

The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median DoR had not been reached (range: 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and DoR were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status

Population Reference No. 5

Classical Hodgkin Lymphoma (cHL)

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory classical Hodgkin lymphoma (cHL), or cHL that has relapsed after 2 or more lines of therapy.

KEYNOTE-204 The efficacy of KEYTRUDA was investigated in KEYNOTE-204 (NCT02684292), a randomized, openlabel, active controlled trial conducted in 304 patients with relapsed or refractory cHL. The trial enrolled adults with relapsed or refractory disease after at least one multi-agent chemotherapy regimen. Patients were randomized (1:1) to receive:

KEYTRUDA 200 mg intravenously every 3 weeks or

 Brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks

Treatment was continued until unacceptable toxicity, disease progression, or a maximum of 35 cycles (up to approximately 2 years). Disease assessment was performed every 12 weeks. Randomization was stratified by prior autologous HSCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse <12 months after completion vs. relapse ≥12 months after completion). The main efficacy measure was PFS as assessed by BICR using 2007 revised International Working Group criteria.

The study population characteristics were: median age of 35 years (range: 18 to 84); 57% male; 77% White, 9% Asian, 3.9% Black. The median number of prior therapies was 2 (range: 1 to 10) in the KEYTRUDA arm and 3 (range: 1 to 11) in the BV arm, with 18% in both arms having 1 prior line. Fortytwo percent of patients were refractory to the last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior BV, and 39% had prior radiation therapy.

KEYNOTE-087 The efficacy of KEYTRUDA was investigated in KEYNOTE-087 (NCT02453594), a multicenter, nonrandomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients with active, noninfectious pneumonitis, an allogeneic HSCT within the past 5 years (or >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 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, Complete Response Rate, and DoR) were assessed by BICR according to the 2007 revised International Working Group (IWG) criteria.

The study population characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; and 49% ECOG PS of 0 and 51% 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 autologous HSCT, 83% had received prior brentuximab vedotin and 36% of patients had prior radiation therapy.

Population Reference No. 6

Primary Mediastinal Large B-Cell Lymphoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-170 (NCT02576990), a multicenter, openlabel, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients were not eligible if they had active non-infectious pneumonitis, allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by BICR according to the 2007 revised IWG criteria. The efficacy outcome measures were ORR and DoR.

The study population characteristics were: median age of 33 years (range: 20 to 61 years); 43% male; 92% White; and 43% ECOG PS of 0 and 57% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy.  For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range 2.1 to 8.5 months).  The median follow-up time for 370 patients treated with KEYTRUDA was 11.4 months (range 0.1 to 63.8 months).

Population Reference No. 7

Population Reference No. 8

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

For the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options

Population Reference No. 9

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) as determined by an FDA-approved test. 

The efficacy of KEYTRUDA was investigated in patients with MSI-H or mismatch repair deficient (dMMR), solid tumors enrolled in one of five uncontrolled, open-label, multi-cohort, multi-center, single-arm trials. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible across the five trials. Patients received either KEYTRUDA 200 mg every 3 weeks or KEYTRUDA 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. A maximum of 24 months of treatment with KEYTRUDA was administered. For the purpose of assessment of anti-tumor activity across these 5 trials, the major efficacy outcome measures were ORR 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, and DoR.

A total of 149 patients with MSI-H or dMMR cancers were identified across the five trials. Among these 149 patients, the baseline characteristics were: median age of 55 years, 36% age 65 or older; 56% male; 77% White, 19% Asian, and 2% Black; and 36% ECOG PS of 0 and 64% ECOG PS of 1. Ninety-eight percent of patients had metastatic disease and 2% had locally advanced, unresectable disease. The median number of prior therapies for metastatic or unresectable disease was two. Eighty-four percent of patients with metastatic CRC and 53% of patients with other solid tumors received two or more prior lines of therapy. The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Fourteen of the 149 patients were retrospectively identified as MSI-H by testing tumor samples from a total of 415 patients using a central laboratory developed PCR test. Forty-seven patients had dMMR cancer identified by IHC, 60 had MSI-H identified by PCR, and 42 were identified using both tests.

Population Reference No. 10

Gastric Cancer

• in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic
HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test

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

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

The efficacy of KEYTRUDA in combination with trastuzumab plus fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that was designed to enroll 692 patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms.

KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2 /day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle.

 Placebo, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2 /day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX).

All study medications, except oral capecitabine, were administered as an intravenous infusion for every 3 week cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. In an interim efficacy analysis, major outcome measures assessed were ORR and DoR by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

At the time of the interim analysis, ORR and DoR were assessed in the first 264 patients randomized. Among the 264 patients, the population characteristics were: median age of 62 years (range: 19 to 84), 41% age 65 or older; 82% male; 63% White, 31% Asian, and 0.8% Black; 47% ECOG PS of 0 and 53% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (stage IV) and 3% had locally advanced unresectable disease. Eighty-seven percent had tumors that expressed PD-L1 with a CPS ≥1. Ninety-one percent (n=240) had tumors that were not MSI-H, 1% (n=2) had tumors that were MSI-H, and in 8% (n=22) the status was not known. Eighty-seven percent of patients received CAPOX. A statistically significant improvement in ORR was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy.

Previously Treated Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-059 (NCT02335411), a multicenter, nonrandomized, open-label multi-cohort trial that enrolled 259 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. HER2/neu positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6 to 9 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.

Among the 259 patients, 55% (n = 143) had tumors that expressed PD-L1 with a CPS ≥1 and microsatellite stable (MSS) tumor status or undetermined MSI or MMR status. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. The baseline characteristics of these 143 patients were: median age of 64 years, 47% age 65 or older; 77% male; 82% White and 11% Asian; and 43% ECOG PS of 0 and 57% ECOG PS of 1. Eighty-five percent had M1 disease and 7% had M0 disease. Fifty-one percent had two and 49% had three or more prior lines of therapy in the recurrent or metastatic setting.

For the 143 patients, the ORR was 13.3% (95% CI: 8.2, 20.0); 1.4% had a complete response and 11.9% had a partial response. Among the 19 responding patients, the DoR ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of 6 months or longer and 5 patients (26%) having responses of 12 months or longer.

Among the 259 patients enrolled in KEYNOTE-059, 7 (3%) had tumors that were determined to be MSI-H. An objective response was observed in 4 patients, including 1 complete response. The DoR ranged from 5.3+ to 14.1+ months.

Population Reference No. 11

Esophageal Cancer

 for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is
not amenable to surgical resection or definitive chemoradiation either:

o in combination with platinum- and fluoropyrimidine-based
chemotherapy, or

o as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined
by an FDA-approved test.

First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal/Gastroesophageal Junction Cancer

KEYNOTE-590 The efficacy of KEYTRUDA was investigated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients with active autoimmune disease, a medical condition that required immunosuppression, or who received prior systemic therapy in the locally advanced or metastatic setting were ineligible. Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and ECOG performance status (0 vs. 1).

Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

KEYTRUDA 200 mg on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.

 Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.

Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with KEYTRUDA for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, CPS ≥10, and in all patients. Additional efficacy outcome measures were ORR and DoR, according to modified RECIST v1.1, as assessed by the investigator.

The study population characteristics were: median age of 63 years (range: 27 to 94), 43% age 65 or older; 83% male; 37% White, 53% Asian, and 1% Black; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. Ninety-one percent had M1 disease and 9% had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27% had adenocarcinoma. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with chemotherapy, compared to chemotherapy. Table 70 and Figure 15 summarize the efficacy results for KEYNOTE-590 in all patients.

In a pre-specified formal test of OS in patients with PD-L1 CPS ≥ 10 (n=383), the median was 13.5 months (95% CI: 11.1, 15.6) for the KEYTRUDA arm and 9.4 months (95% CI: 8.0, 10.7) for the placebo arm, with a HR of 0.62 (95% CI: 0.49, 0.78; p-Value < 0.0001). In an exploratory analysis, in patients with PD-L1 CPS < 10 (n=347), the median OS was 10.5 months (95% CI: 9.7, 13.5) for the KEYTRUDA arm and 10.6 months (95% CI: 8.8, 12.0) for the placebo arm, with a HR of 0.86 (95% CI: 0.68, 1.10).

Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer

KEYNOTE-181 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. Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy. All patients were required to have tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible.

Patients were randomized (1:1) to receive either KEYTRUDA 200 mg every 3 weeks or investigator’s choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every 4-week cycle, docetaxel 75 mg/m2 every 3 weeks, or irinotecan 180 mg/m2 every 2 weeks. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs. esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs. ex-Asia). Treatment with KEYTRUDA or chemotherapy continued  until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue beyond the first RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measure was OS evaluated in the following co-primary populations: patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. Additional efficacy outcome measures were PFS, ORR, and DoR, according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.

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. Of these 167 patients, 85 patients were randomized to KEYTRUDA and 82 patients to investigator’s treatment of choice [paclitaxel (n=50), docetaxel (n=19), or irinotecan (n=13)]. The baseline characteristics of these 167 patients were: median age of 65 years (range: 33 to 80), 51% age 65 or older; 84% male; 32% White and 68% Asian; 38% had an ECOG PS of 0 and 62% had an ECOG PS of 1. Ninety percent had M1 disease and 10% had M0 disease. Prior to enrollment, 99% of patients had received platinum-based treatment and 84% had also received treatment with a fluoropyrimidine. Thirtythree percent of patients received prior treatment with a taxane. The observed OS hazard ratio was 0.77 (95% CI: 0.63, 0.96) in patients with ESCC, 0.70 (95% CI: 0.52, 0.94) in patients with tumors expressing PD-L1 CPS ≥10, and 0.89 (95% CI: 0.75, 1.05) in all randomized patients. On further examination in patients whose ESCC tumors expressed PD-L1 (CPS ≥10), an improvement in OS was observed among patients randomized to KEYTRUDA as compared with chemotherapy. Table 71 and Figure 16 summarize the key efficacy measures for KEYNOTE-181 for patients with ESCC CPS ≥10.

KEYNOTE-180 The efficacy of KEYTRUDA was investigated in KEYNOTE-180 (NCT02559687), a multicenter, nonrandomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181.

The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.

Among the 121 patients enrolled, 29% (n=35) had ESCC that expressed PD-L1 CPS ≥10. The baseline characteristics of these 35 patients were: median age of 65 years (range: 47 to 81), 51% age 65 or older; 71% male; 26% White and 69% Asian; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. One hundred percent had M1 disease.

The ORR in the 35 patients with ESCC expressing PD-L1 was 20% (95% CI: 8, 37). Among the 7 responding patients, the DoR ranged from 4.2 to 25.1+ months, with 5 patients (71%) having responses of 6 months or longer and 3 patients (57%) having responses of 12 months or longer.

Population Reference No. 12

Cervical Cancer

Persistent, Recurrent, or Metastatic Cervical Cancer The efficacy of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826 (NCT03635567), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 617 patients with persistent, recurrent, or first-line  metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent. Patients were enrolled regardless of tumor PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab, and PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥10). Patients were randomized (1:1) to one of the two treatment groups:

Treatment Group 1: KEYTRUDA 200 mg plus chemotherapy with or without bevacizumab

 Treatment Group 2: Placebo plus chemotherapy with or without bevacizumab

The investigator selected one of the following four treatment regimens prior to randomization:

1. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2

2. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 + bevacizumab 15 mg/kg

3. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min 4. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min + bevacizumab 15 mg/kg

All study medications were administered as an intravenous infusion. All study treatments were administered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 of each 3-week treatment cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed every 9 weeks for the first year, followed by every 12 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, according to RECIST v1.1, as assessed by investigator.

Of the 617 enrolled patients, 548 patients (89%) had tumors expressing PD-L1 with a CPS ≥1. Among these 548 enrolled patients with tumors expressing PD-L1, 273 patients were randomized to KEYTRUDA in combination with chemotherapy with or without bevacizumab, and 275 patients were randomized to placebo in combination with chemotherapy with or without bevacizumab. Sixty-three percent of the 548 patients received bevacizumab as part of study treatment. The baseline characteristics of the 548 patients were: median age of 51 years (range: 22 to 82), 16% age 65 or older; 59% White, 18% Asian, 6% American Indian or Alaska Native, and 1% Black; 37% Hispanic or Latino; 56% ECOG performance status 0 and 43% ECOG performance status 1. Seventy-five percent had squamous cell carcinoma, 21% adenocarcinoma, and 5% adenosquamous histology, and 32% of patients had metastatic disease at diagnosis. At study entry, 21% of patients had metastatic disease only and 79% had persistent or recurrent disease with or without distant metastases, of whom 39% had received prior chemoradiation only and 17% had received prior chemoradiation plus surgery.

Previously Treated Recurrent or Metastatic Cervical Cancer

The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort 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 unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.

Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the IHC 22C3 pharmDx kit. The baseline characteristics of these 77 patients were: median age of  45 years (range: 27 to 75); 81% White, 14% Asian, and 3% Black; 32% ECOG PS of 0 and 68% ECOG PS of 1; 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 95% had M1 disease and 5% had recurrent disease; and 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting.

Population Reference No. 13

Hepatocellular Carcinoma (HCC)

• for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD1/PD-L1-containing regimen

Population Reference No. 14

Advanced Hepatocellular Carcinoma (HCC)

• for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD1/PD-L1-containing regimen

The efficacy of KEYTRUDA was investigated in KEYNOTE-224 (NCT02702414), a single-arm, multicenter trial in 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib; had measurable disease; and Child-Pugh class A liver impairment. Patients with active autoimmune disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of ascites by physical exam were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity, investigatorassessed confirmed disease progression (based on repeat scan at least 4 weeks from the initial scan showing progression), or completion of 24 months of KEYTRUDA. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.

The study population characteristics were: median age of 68 years, 67% age 65 or older; 83% male; 81% White and 14% Asian; and 61% ECOG PS of 0 and 39% ECOG PS of 1. Child-Pugh class and score were A5 for 72%, A6 for 22%, B7 for 5%, and B8 for 1% of patients. Twenty-one percent of the patients were HBV seropositive and 25% HCV seropositive. There were 9 patients (9%) who were seropositive for both HBV and HCV. For these 9 patients, all of the HBV cases and three of the HCV cases were inactive. Sixty-four percent (64%) of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both. Thirty-eight percent (38%) of patients had alpha-fetoprotein (AFP) levels ≥400 mcg/L. All patients received prior sorafenib; of whom 20% were unable to tolerate sorafenib. No patient received more than one prior systemic therapy (sorafenib).

Population Reference No. 15

Biliary Tract Cancer (BTC)

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

Population Reference No. 16

Merkel Cell Carcinoma (MCC)

The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603), a multicenter, nonrandomized, 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 with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1.

The study population characteristics were: median age of 71 years (range: 46 to 91), 80% age 65 or older; 68% male; 90% White; and 48% ECOG PS of 0 and 52% ECOG PS of 1. Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy.

Population Reference No. 17

Renal Cell Carcinoma (RCC)

• in combination with axitinib, for the first-line treatment of adult patients with advanced RCC.

• in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC.

• for the adjuvant treatment of patients with RCC at
intermediate-high or high risk of recurrence following
nephrectomy, or following nephrectomy and resection of
metastatic lesions.

The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603), a multicenter, nonrandomized, 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 with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1.

The study population characteristics were: median age of 71 years (range: 46 to 91), 80% age 65 or older; 68% male; 90% White; and 48% ECOG PS of 0 and 52% ECOG PS of 1. Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy.

First-line treatment with axitinib

KEYNOTE-426

The efficacy of KEYTRUDA in combination with axitinib was investigated in 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. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database.

Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus “Rest of the World”).

Patients were randomized (1:1) to one of the following treatment arms:

KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.

 Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.

Treatment with KEYTRUDA and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter.

The study population characteristics were: median age of 62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate and 13% poor.

The main efficacy outcome measures were OS and PFS 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. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. Table 76 and Figure 18 summarize the efficacy results for KEYNOTE-426. The median follow-up time was 12.8 months (range 0.1 to 22.0 months). Consistent results were observed across pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression status.

First-line treatment with lenvatinib

KEYNOTE-581

The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-581 (NCT02811861), a multicenter, open-label, randomized trial conducted in 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region (North America versus Western Europe versus “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable versus intermediate versus poor risk).

Patients were randomized (1:1:1) to one of the following treatment arms:

KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with lenvatinib 20 mg orally once daily.

 Lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily.

 Sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks.

Treatment continued until unacceptable toxicity or disease progression. Administration of KEYTRUDA with 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 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 8 weeks.

The study population characteristics were: median age of 62 years (range: 29 to 88 years), 42% age 65 or older; 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by MSKCC risk categories was 27% favorable, 64% intermediate, and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).

The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to RECIST v1.1, and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC. KEYTRUDA in combination with lenvatinib demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib.

Adjuvant Treatment of RCC (KEYNOTE-564)

The efficacy of KEYTRUDA was investigated as adjuvant therapy for RCC in KEYNOTE-564 (NCT03142334), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease (NED). The intermediate-high risk category included: pT2 with Grade 4 or sarcomatoid features; pT3, any Grade without nodal involvement (N0) or distant metastases (M0). The high risk category included: pT4, any Grade N0 and M0; any pT, any Grade with nodal involvement and M0. The M1 NED category included patients with metastatic disease who had undergone complete resection of primary and metastatic lesions. Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins ≥4 weeks prior to the time of screening. Patients were excluded from the trial if they had received prior systemic therapy for advanced RCC. Patients with active autoimmune disease or a medical condition that required immunosuppression were also ineligible. Patients were randomized to KEYTRUDA 200 mg administered intravenously every 3 weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. Randomization was stratified by metastasis status (M0, M1 NED); M0 group was further stratified by ECOG PS (0,1) and geographic region (US, non-US).

The study population characteristics were: median age of 60 years (range: 25 to 84), 33% age 65 or older; 71% male; 75% White, 14% Asian, 9% Unknown, 1% Black or African American, 1% American Indian or Alaska Native, 1% Multiracial; 13% Hispanic or Latino, 78% Not Hispanic or Latino, 8% Unknown; and 85% ECOG PS of 0 and 15% ECOG PS of 1. Ninety-four percent of patients enrolled had N0 disease; 11% had sarcomatoid features; 86% were intermediate-high risk; 8% were high risk; and 6%  were M1 NED. Ninety-two percent of patients had a radical nephrectomy, and 8% had a partial nephrectomy.

The major efficacy outcome measure was investigator-assessed disease-free survival (DFS), defined as time to recurrence, metastasis, or death. An additional outcome measure was OS. A statistically significant improvement in DFS was demonstrated at the pre-specified interim analysis in patients randomized to the KEYTRUDA arm compared with placebo. At the time of the DFS analysis, OS data were not mature, with 5% deaths in the overall population.

Population Reference No. 18

Endometrial Carcinoma

• in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.

• in combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDAapproved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

• as a single agent, for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. 
 

The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775 (NCT03517449), a multicenter, open-label, randomized, active-controlled trial that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinumbased chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients with endometrial carcinoma that were not MSI-H or dMMR were stratified by ECOG performance status, geographic region, and history of pelvic radiation. Patients were randomized (1:1) to one of the following treatment arms:

KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily.

 Investigator’s choice, consisting of either doxorubicin 60 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 given weekly, 3 weeks on/1 week off.

Treatment with KEYTRUDA and lenvatinib continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for KEYTRUDA, a maximum of 24 months. Treatment was  permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit, and the treatment was tolerated. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were OS and PFS 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. Additional efficacy outcome measures included ORR and DoR, as assessed by BICR.

Among the 697 not dMMR patients, 346 patients were randomized to KEYTRUDA in combination with lenvatinib, and 351 patients were randomized to investigator’s choice of doxorubicin (n=254) or paclitaxel (n=97). The not dMMR population characteristics were: median age of 65 years (range: 30 to 86), 52% age 65 or older; 62% White, 22% Asian, and 3% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1. The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear cell carcinoma (7%), mixed (4%), and other (3%). All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy.

Population Reference No. 19

TMB-H Cancers

• 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

• Limitations of Use: The safety and effectiveness of
KEYTRUDA in pediatric patients with TMB-H central nervous
system cancers have not been established

The efficacy of KEYTRUDA was investigated in a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with high tumor mutation burden (TMB-H) who were enrolled in a multicenter, non-randomized, open-label trial, KEYNOTE-158 (NCT02628067). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Assessment of tumor status was performed every 9 weeks for the first 12 months and every 12 weeks thereafter.

The statistical analysis plan pre-specified ≥10 and ≥13 mutations per megabase using the FoundationOne CDx assay as cutpoints to assess TMB. Testing of TMB was blinded with respect to clinical outcomes. The major efficacy outcome measures were ORR and DoR in patients who received at least one dose of KEYTRUDA 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.

In KEYNOTE-158, 1050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB ≥10 mutations per megabase. Among the 102 patients with TMB-H advanced solid tumors, the study population characteristics were: median age of 61 years (range: 27 to 80), 34% age 65 or older;  34% male; 81% White; and 41% ECOG PS of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy.

In an exploratory analysis in 32 patients enrolled in KEYNOTE-158 whose cancer had TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was 13% (95% CI: 4%, 29%), including two complete responses and two partial responses.

Population Reference No. 20

Cutaneous Squamous Cell Carcinoma (cSCC)

• for the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation

The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC or locally advanced 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 with recurrent or metastatic cSCC 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-seven percent received one or more prior lines of therapy; 74% received prior radiation therapy.

Among the 54 patients with locally advanced cSCC treated, the study population characteristics were: median age of 76 years (range: 35 to 95), 80% age 65 or older; 72% male; 83% White, 13% race unknown; 41% ECOG PS of 0 and 59% ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63% received prior radiation therapy

Population Reference No. 21

TNBC or High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)

Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC The efficacy of KEYTRUDA in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522 (NCT03036488), a randomized (2:1), multicenter, double-blind, placebo-controlled trial conducted in 1174 patients with newly diagnosed previously untreated high-risk early-stage TNBC (tumor size >1 cm but ≤2 cm in diameter with nodal involvement or tumor size >2 cm in diameter regardless of nodal involvement).

Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by nodal status (positive vs. negative), tumor size (T1/T2 vs. T3/T4), and choice of carboplatin (dosed every 3 weeks vs. weekly). Patients were randomized (2:1) to one of the following two treatment arms; all study medications were administered intravenously:

 Arm 1:

 Four cycles of preoperative KEYTRUDA 200 mg every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with: o Carboplatin

 AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen -or-

 AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen

Paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen

 Followed by four additional cycles of preoperative KEYTRUDA 200 mg every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with: o Doxorubicin 60 mg/m2 -or- epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen -ando Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen

 Following surgery, nine cycles of KEYTRUDA 200 mg every 3 weeks were administered

Arm 2:

 Four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with: o Carboplatin

 AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen -or-

 AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen -ando Paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen

Followed by four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with: o Doxorubicin 60 mg/m2 -or- epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen -ando Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen

 Following surgery, nine cycles of placebo every 3 weeks were administered.

The main efficacy outcomes were pathological complete response (pCR) rate and event-free survival (EFS). pCR was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause. An additional efficacy outcome was overall survival (OS).

The study population characteristics were: median age of 49 years (range: 22 to 80), 11% age 65 or older; 99.9% female; 64% White, 20% Asian, 4.5% Black, and 1.8% American Indian or Alaska Native; 87% ECOG PS of 0 and 13% ECOG PS of 1; 56% were pre-menopausal status and 44% were post-menopausal status; 7% were primary Tumor 1 (T1), 68% T2, 19% T3, and 7% T4; 49% were nodal involvement 0 (N0), 40% N1, 11% N2, and 0.2% N3; 75% of patients were overall stage II and 25% were stage III.

Locally Recurrent Unresectable or Metastatic TNBC

The efficacy of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355 (NCT02819518), a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting.

Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by chemotherapy treatment (paclitaxel or paclitaxel protein-bound vs. gemcitabine and carboplatin), tumor PD-L1 expression (CPS ≥1 vs. CPS <1) according to the PD-L1 IHC 22C3 pharmDx kit, and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no). Patients were randomized (2:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

KEYTRUDA 200 mg on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days.

Placebo on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days.

Assessment of tumor status was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeks thereafter. The main efficacy outcome measure was PFS 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 tested in the subgroup of patients with CPS ≥10. Additional efficacy outcome measures were OS as well as ORR and DoR as assessed by BICR.

The study population characteristics for patients were: median age of 53 years (range: 22 to 85), 21% age 65 or older; 100% female; 68% White, 21% Asian, and 4% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1; and 68% were post-menopausal status. Seventy-five percent of patients had tumor PD-L1 expression CPS ≥1 and 38% had tumor PD-L1 expression CPS ≥10.

Population Reference No. 22

Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks

• for use at an additional recommended dosage of 400 mg every 6 weeks for Classical Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma in adults 

1 This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
2 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

Population Reference No. 23

Adrenal gland tumors

• Adrenal gland tumors - as a single agent or in combination with mitotane for metastatic adrenocorticoid tumors

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 24

Anal carcinoma  

• Anal carcinoma - as single agent, second-line or subsequent therapy for metastatic disease and for locally recurrent, progressive disease prior to abdominoperineal resection

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 25

Cervical cancer

• Cervical cancer - as single agent, second-line therapy for recurrent or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors that progressed on or after chemotherapy in tumors that expresses PD-L1 (combined positive score ≥ 

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 26

Chondrosarcoma

• Chondrosarcoma - as a single agent for unresectable or metastatic, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), and tumor mutational burden-high (TMB-H) conventional chondrosarcoma, dedifferentiated chondrosarcoma, and mesenchymal chondrosarcoma that have progressed following prior treatment in patients who have no satisfactory alternative treatment options

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 27

Chordoma

• Chordoma - as a single agent for unresectable or metastatic, tumor mutational burden-high (TMB-H) disease that has progressed following prior treatment in patients who have no satisfactory alternative treatment options

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 28

CNS - Brain metastases

• CNS - Brain metastases (limited) - as a single agent for limited brain metastases in patients with melanoma or PD-L1-positive non-small cell lung cancer as initial treatment in select patients, as treatment for recurrent brain metastases, or as treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options
• CNS - Brain metastases (extensive) - as a single agent for extensive brain metastases in patients with melanoma or PD-L1-positive non-small cell lung cancer as primary treatment in select patients or as treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 29

High-grade undifferentiated pleomorphic sarcoma of the bone

• High-grade undifferentiated pleomorphic sarcoma of the bone - as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 30

Mesenchymal chondrosarcoma

• Mesenchymal chondrosarcoma - as a single agent for unresectable or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 31

Pancreatic cancer

• Pancreatic cancer - single agent, first-line therapy for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) metastatic disease in patients with poor performance status
• Pancreatic cancer - as a single agent, subsequent-line therapy for microsatellite instability-high or mismatch repair deficient tumors) for locally advanced or metastatic disease for patients with disease progression
• Pancreatic cancer - as a single agent for microsatellite instability-high or mismatch repair deficient tumors for local recurrence in the pancreatic operative bed after resection, metastatic disease with or without local recurrence if 6 or more months from completion of primary therapy, or metastatic disease with or without local recurrence if less than 6 months from completion of primary therapy

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 32

Penile cancer (squamous cell) 

• Penile cancer (squamous cell) - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 33

Poorly differentiated/large or small cell neuroendocrine and adrenal tumors

• Poorly differentiated/large or small cell neuroendocrine and adrenal tumors - as a single agent for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors when disease progressed following prior treatment and when there is no satisfactory alternative treatment options
• Poorly differentiated/large or small cell neuroendocrine and adrenal tumors - as a single agent in children for mutational burden-high (≥ 10 mutations/megabase), metastatic or unresectable tumors that have progressed following prior treatment in patients with no satisfactory alternative treatment options

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 34

Uterine Sarcoma

• Uterine Sarcoma - as single agent, second-line therapy for tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] in patients with high-grade endometrial stroma sarcoma, undifferentiated uterine sarcoma, and uterine leiomyosarcoma in patients whose disease progressed following prior treatment and in whom no satisfactory alternative treatment options exist.

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 

Population Reference No. 35

 Mycosis fungoides/Sézary syndrome, relapsed / refractory

• Mycosis fungoides (MF) Sezary syndrome (SS) - as a single agent or skin-directed therapy for stage IA-IIA relapsed or persistent MF with B1 blood involvement
• Mycosis fungoides (MF) Sezary syndrome (SS) - as a single agent or skin-directed therapy for stage IIB MF with limited tumor lesions that is refractory to multiple previous therapies; as a single agent for stage IIB MF with generalized tumor lesions that is refractory to multiple previous therapies or disease progression; or as a single agent or skin-directed therapy for stage IIB relapsed or persistent MF with generalized tumor lesions
• Mycosis fungoides (MF) Sezary syndrome (SS) - as a single agent for stage III MF that is refractory to multiple previous therapies or as a single agent or with skin-directed therapy for relapsed or persistent disease 
• Mycosis fungoides (MF) Sezary syndrome (SS) – as a single agent or with radiation therapy for local control for relapsed or persistent stage IV non-Sezary or visceral disease (solid organ) 
• Mycosis fungoides (MF) Sezary syndrome (SS) – as a single agent, primary treatment for stage IV SS or as a single agent for relapsed or persistent stage IV SS

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use 
 

Population Reference No. 36

Kaposi Sarcoma

• Useful in certain circumstances as single agent therapy for subsequent systemic therapy for endemic or classic Kaposi Sarcoma* for relapsed/refractory advanced cutaneous, oral, visceral, or nodal disease that has progressed on or not responded to first-line systemic therapy, and progressed on alternate first-line systemic therapy
• *immune checkpoint inhibitors should not be used in patients with multicentric Castleman disease (MCD) or KSHV–associated inflammatory cytokine syndrome (KICS) due to risk of flare of these conditions

Recommended by the NCCN Drugs and Biologics Compendium® for off-label use 

Population Reference No. 37

Thymomas and Thymic Carcinomas 

• Consider as a preferred single agent for those who cannot tolerate first-line combination regimens for thymic carcinoma as preoperative systemic therapy for surgically resectable disease if R0 resection is considered uncertain
• Consider for postoperative treatment as a preferred single agent for those who cannot tolerate first-line combination regimens for thymic carcinoma after R1 or R2 resection
• Consider as preferred first-line therapy for recurrent, advanced, or metastatic disease (for thymic carcinomas only) as a single agent for those who cannot tolerate first-line combination regimens for
  • potentially resectable locally advanced disease
  • potentially resectable solitary metastasis or ipsilateral pleural metastasis
  • consideration following surgery for solitary metastasis or ipsilateral pleural metastasis
  • medically inoperable/unresectable solitary metastasis or ipsilateral pleural metastasis
  • extrathoracic metastatic disease
• Preferred second-line therapy (for thymic carcinomas only) as a single agent for
  • unresectable locally advanced disease
  • solitary metastasis or ipsilateral pleural metastasis
  • extrathoracic metastatic disease

Population Reference No. 38

Testicular Cancer

• Used as single-agent third-line therapy in patients with microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) or tumor mutational burden-high (TMB-H) tumors (useful in certain circumstances)
  • for seminoma
  • after prior high-dose chemotherapy for nonseminoma
  • for late relapse of nonseminoma (recurrence >2 years after completion of second-line chemotherapy)

Population Reference No. 39

Pediatric Central Nervous System Cancers - Pediatric Diffuse High-Grade Gliomas

• Adjuvant treatment for hypermutant tumor pediatric diffuse high-grade glioma*
  • following standard brain radiation therapy (RT) with or without concurrent temozolomide in patients ≥3 years old (useful in certain circumstances)
  • in patients <3 years old
• *Except diffuse midline glioma, H3 K27-altered or pontine location
• Preferred treatment for recurrent or progressive disease for hypermutant tumor pediatric diffuse high-grade glioma*
  
  *Except oligodendroglioma, IDH-mutant and 1p/19q co-deleted or astrocytoma IDH-mutant (see NCCN Guidelines for Central Nervous System Cancers in Adults) Preferred treatment for recurrent or progressive disease for hypermutant tumor pediatric diffuse high-grade glioma*
  
  *Except oligodendroglioma, IDH-mutant and 1p/19q co-deleted or astrocytoma IDH-mutant (see NCCN Guidelines for Central Nervous System Cancers in Adults)

Population Reference No. 40

Vulvar Cancer

• Second-line or subsequent therapy for advanced or recurrent/metastatic disease as a single agent (useful in certain circumstances) for
  • tumor mutational burden-high (TMB-H) (≥10 mutations/megabase [mut/Mb]) tumors, as determined by an FDA-approved assay or a validated test performed in a CLIA-certified laboratory, that have progressed following prior treatment and who have no satisfactory alternative treatment options
  • disease progression on or after chemotherapy in patients whose tumors express PD-L1 (Combined Positive Score ≥1) as determined by an FDA-approved assay or a validated test performed in a CLIA-certified laboratory
  • microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors

Population Reference No. 41

Prostate Cancer

• Useful in certain circumstances as a single-agent* for castration-resistant distant metastatic (M1) disease if

  • received no prior docetaxel and no prior novel hormone therapy (for microsatellite instability-high (MSI-H)/ mismatch repair deficient (dMMR))
  • progression on prior docetaxel and no prior novel hormone therapy (for MSI-H/dMMR)
  • progression on prior novel hormone therapy and no prior docetaxel (for MSI-H/dMMR)
  • progression on prior docetaxel and a novel hormone therapy (for MSI-H/dMMR, or tumor mutational burden (TMB) ≥10 mutations/megabase)

*Continue androgen deprivation therapy (ADT) to maintain castrate levels of serum testosterone (<50 ng/dL)

Population Reference No. 42

Melanoma: Uveal 

• Single agent therapy for metastatic or unresectable diseas

Population Reference No. 43

Head and Neck Cancers - Cancer of the Nasopharynx- Very Advanced Head and Neck Cancer-Salivary Gland Tumors

• First-line systemic therapy in combination with cisplatin and gemcitabine (preferred) for T1-4, N0-3, M1
  • oligometastatic disease and PS 0-2
  • widely metastatic disease and good PS (0-2)
• If not previously used, may be considered as subsequent-line systemic therapy in combination with cisplatin and gemcitabine for T1-4, N0-3, M1
  • oligometastatic disease and performance status (PS) 0-2
  • widely metastatic disease and good PS (0-2)
• Subsequent-line single agent systemic therapy if previously treated, PD-L1–positive, recurrent or metastatic disease, or for tumor mutational burden-high (TMB-H) tumors (≥ 10 mut/Mb) for T1-4, N0-3, M1
  • oligometastatic disease and performance status (PS) 0-2
  • widely metastatic disease and good PS (0-2)
• Systemic therapy as a single agent for non-nasopharyngeal cancer tumors that express PD-L1 with CPS ≥1 as a
  • first-line option (preferred) for performance status (PS) 3 for newly diagnosed T4b, N0-3, M0 disease, newly diagnosed unresectable nodal disease with no metastases, newly diagnosed non-metastatic disease for patients who are unfit for surgery
  • first-line (preferred) or alternate subsequent-line* option for PS 0-3 for metastatic (M1) disease at initial presentation
  • first-line (preferred) or subsequent-line* option for PS 3 and unresectable locoregional recurrence without prior radiation therapy (RT) or unresectable persistent disease without prior RT
  • first-line (preferred) or alternate subsequent-line* option for PS 0-3 and unresectable locoregional recurrence with prior RT, unresectable second primary with prior RT, unresectable persistent disease with prior RT, or recurrent/persistent disease with distant metastases
• *if not previously used, may be considered in subsequent-lines
• Useful in certain circumstances as a systemic therapy option as a single agent for non-nasopharyngeal cancer in patients with microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR), or tumor mutational burden high TMB-H (≥10 mut/Mb) tumors as a
• first-line option for performance status (PS) 3 for newly diagnosed T4b, N0-3, M0 disease, newly diagnosed unresectable nodal disease with no metastases, newly diagnosed non-metastatic disease for patients who are unfit for surgery

  • first-line or alternate subsequent-line option for PS 0-3 for metastatic (M1) disease at initial presentation

  • first-line or subsequent-line option for PS 3 and unresectable locoregional recurrence without prior radiation therapy (RT) or unresectable persistent disease without prior RT

  • first-line or alternate subsequent-line option for PS 0-3 and unresectable locoregional recurrence with prior RT, unresectable second primary with prior RT, unresectable persistent disease with prior RT, or recurrent/persistent disease with distant metastases

• Systemic therapy as a first-line or subsequent-line option in patients with non-nasopharyngeal cancer and performance status (PS) 0-1 for

  • metastatic (M1) disease at initial presentation
  • recurrent/persistent disease with distant metastases
  • unresectable locoregional recurrence with prior radiation therapy (RT)
  • unresectable second primary with prior RT
  • unresectable persistent disease with prior RT
• Given in combination with
  • fluorouracil and carboplatin (preferred first-line)*
  • fluorouracil and cisplatin (preferred first-line)*
  • docetaxel and carboplatin
  • docetaxel and cisplatin
  • paclitaxel and carboplatin
  • paclitaxel and cisplatin
  • cetuximab (useful in certain circumstances)
• *if not previously used, may be considered in subsequent-lines

Used as combination systemic therapy in non-nasopharyngeal cancer for resectable locoregional recurrence or persistent disease without prior radiation therapy (RT) given with

• fluorouracil and carboplatin (preferred first-line)*
• fluorouracil and cisplatin (preferred first-line)*
• docetaxel and carboplatin
• docetaxel and cisplatin
• paclitaxel and carboplatin
• paclitaxel and cisplatin
• cetuximab (useful in certain circumstances)

*if not previously used, may be considered in subsequent-lines

Systemic therapy as a preferred alternate single agent subsequent-line option, if immunotherapy not previously used, for non-nasopharyngeal cancer if disease progression on or after platinum therapy in patients with

• performance status (PS) 0-3 and persistent or progressive metastatic disease (M1) at initial presentation following first-line therapy
• PS 3 and unresectable locoregional recurrence without prior radiation therapy (RT) or unresectable persistent disease without prior RT
• PS 0-3 and unresectable locoregional recurrence with prior RT, unresectable second primary with prior RT, unresectable persistent disease with prior RT, or recurrent/persistent disease with distant metastases

Systemic therapy as a first-line or subsequent-line* option in patients with nasopharyngeal cancer and performance status (PS) 0-1 for: unresectable locoregional recurrence with prior radiation therapy (RT), unresectable second primary with prior RT, unresectable persistent disease with prior RT, or recurrent/persistent disease with distant metastases in combination with

• cisplatin and gemcitabine (preferred first-line)

*if not previously used, may be considered in subsequent-lines

Systemic therapy as an alternate single agent subsequent-line option in patients with tumor mutational burden-high (TMB-H [≥10 mut/Mb]) (useful in certain circumstances) or previously treated, PD-L1-positive nasopharyngeal cancer and performance status (PS) of 0-3 for

• unresectable locoregional recurrence with prior radiation therapy (RT), unresectable second primary with prior RT, unresectable persistent disease with prior RT, or recurrent/persistent disease with distant metastases

Useful in certain circumstances as single-agent systemic therapy for microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR), or tumor mutational burden high (TMB-H [≥10 mut/Mb]) recurrent disease with

• distant metastases in patients with a performance status (PS) of 0-3
• unresectable locoregional recurrence or second primary with prior radiation therapy

Population Reference No. 44

T-Cell Lymphomas - Extranodal NK/T-Cell Lymphomas

• Preferred for relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used, if a clinical trial is unavailable

SUPPLEMENTAL INFORMATION

N/A

Practice Guidelines and Position Statements

Review criteria used by Triple-S to determine whether chemotherapy ± supportive agent(s) are medically necessary for anticancer treatment include the following:

• New drugs or regimens (combinations of drugs) approved by the United States Food and Drug Administration (FDA), i.e., that are used on-label
• Drugs and biologics may be used off-label, i.e., without FDA approval. They are considered medically accepted or necessary if supported by any of the following 5 compendia that Medicare uses to determine a “medically accepted indication” for off-label drugs and biologics in anticancer chemotherapeutic treatment and are not listed as unsupported, not indicated, or not recommended within any one of the compendia below.
  • o NCCN Drugs & Biologics Compendium®
    • Category 1-2A recommendations are considered medically accepted uses
    • Category 2B recommendations will be considered if identified as medically accepted if listed in at least one of the 5 Medicare-recognized compendia or supported by peer-reviewed scientific literature eligible for coverage as outlined below. Meeting abstracts and case reports are generally excluded from consideration
    • Category 3 listings are considered not medically accepted uses
  • Clinical Pharmacology
    • Medically accepted uses are identified by narrative text that is supportive
    • Not medically accepted uses are identified by narrative text that is “not supportive”
  • American Hospital Formulary Service Drug Information (AHFS DI)
    • Medically accepted uses are identified by narrative text that is supportive
    • Not medically accepted uses are identified by narrative text that is “not supportive”
  • Thompson Micromedex DrugDex®
    • Class I, IIA, or IIb recommendations are considered medically accepted uses
    • Class III listings are considered not medically accepted uses
  • Wolters Kluwer Lexi-Drugs®
    • Medically accepted uses are identified by an indication listed as “Use: Off-Label” and rated as “Evidence Level A”
    • Not medically accepted uses are those indications listed as “Use: Unsupported”
• Off-label use of drugs and biologics may also be considered medically accepted if supported as safe and effective according to peer-reviewed articles eligible for coverage from one of the following journals; this is in accordance with the medical literature used by local Medicare contractors to determine medically-accepted indications for drugs and biologics used in anticancer treatment:

o American Journal of Medicine;

o Annals of Internal Medicine;

o Annals of Oncology;

o Annals of Surgical Oncology;

o Biology of Blood and Marrow Transplantation;

o Blood; o Bone Marrow Transplantation;

o British Journal of Cancer;

o British Journal of Hematology;

o British Medical Journal;

o Cancer;

o Clinical Cancer Research;

o Drugs;

o European Journal of Cancer (formerly the European Journal of Cancer and Clinical Oncology);

o Gynecologic Oncology;

o International Journal of Radiation, Oncology, Biology, and Physics;

o The Journal of the American Medical Association;

o Journal of Clinical Oncology;

o Journal of the National Cancer Institute;

o Journal of the National Comprehensive Cancer Network (NCCN);

o Journal of Urology;

o Lancet;

o Lancet Oncology;

o Leukemia;

o The New England Journal of Medicine; or

o Radiation Oncology

o Pediatric Hematology and Oncology

o Pediatric Blood and Cancer

o Journal of Adolescent and Young Adult Oncology

• . Coverage determination may also be directed by CMS National Coverage Determinations (NCDs) or state-specific Local Coverage Determinations (LCDs), state-specific Medicaid drug utilization requirements and/or health plan-specific drug coverage policies, where applicable.
• Unique cases that do not fit NCCN Categories 1-3:
  • Non-standard protocols may be approved based on unique clinical circumstances, especially for rare diseases that may lack guideline-based treatment recommendations
  • Non-standard protocols are entered into the database, as needed

National Comprehensive Cancer Network (NCCN) Recommendations

The National Comprehensive Cancer Network Drugs & Biologics Compendium (NCCN,  2019) recommends the use of pembrolizumab for the following indications:

• Anal Carcinoma

  Preferred second-line or subsequent therapy as a single agent for metastatic disease [2A]

• B-Cell Lymphomas

  Diffuse Large B-Cell Lymphoma

  Used to treat relapsed or refractory primary mediastinal large B-cell lymphoma  [2A]

• Bladder Cancer

  Upper GU Tract Tumors

  Therapy for metastatic disease as a single agent for [1 for subsequent systemic therapy post-platinum; 2A for other]

  • first-line systemic therapy (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression
  • subsequent systemic therapy post-platinum (preferred regimen)
     

  Urothelial Carcinoma of the Prostate

  Therapy for metastatic disease as a single agent for [1 for subsequent systemic therapy post-platinum; 2A for other]

  • first-line systemic therapy (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression
  • subsequent systemic therapy post-platinum (preferred regimen)
     

  Primary Carcinoma of the Urethra

  • Primary treatment as a single agent for clinical stage T3-4, cN1-2 disease or cN1-2 palpable inguinal lymph nodes as first-line systemic therapy (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression [2A]. Chemotherapy regimen based on histology. See Non-Urothelial and Urothelial with Variant Histology (BL-D) if appropriate.
  • Used as a single agent for recurrent or metastatic disease as [2B for recurrence of clinical stage T3-4 disease or palpable inguinal lymph nodes; 2A for all others; 1 for subsequent systemic therapy post-platinum]
     
    • first-line systemic therapy (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression
    • subsequent systemic therapy post-platinum (preferred)
       

  Chemotherapy regimen based on histology. See Non-Urothelial and Urothelial with Variant Histology (BL-D) if appropriate.

  Bladder Cancer

  • Used as first-line systemic therapy as a single agent (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression for [2A]
     
    • stage II (cT2, N0) disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent chemoradiotherapy
    • stage IIIA (cT3, N0; cT4a, N0; cT1-T4a, N1) disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent chemoradiotherapy
    • stage IIIB (cT1-T4a, N2,3) disease as downstaging systemic therapy
    • stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with concurrent chemoradiotherapy
    • stage IVA (cT4b, any N, M0; any T, any N, M1a) disease
    • stage IVB (any T, any N, M1b) disease
    • metastatic or local recurrence post cystectomy
       
  • Used as subsequent systemic therapy post-platinum as a single agent (preferred) for [1]
     
    • stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy
    • stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy
    • stage IVB (any T, any N, M1b) diseasemetastatic or local recurrence post cystectomy 
       
  • Used for the treatment of select patients with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer with Tis with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy [2A]

• Bone Cancer

  Osteosarcoma

  Single-agent therapy for patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options [2A]

  Ewing Sarcoma

  Single-agent therapy for patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options [2A]

• Central Nervous System Cancers

  Extensive Brain Metastases

  Single-agent treatment for recurrent brain metastases in patients with melanoma or PD-L1-positive non-small cell lung cancer and stable systemic disease or reasonable systemic treatment options [2A]

  Limited Brain Metastases

  Single-agent treatment for brain metastases in patients with melanoma or PD-L1-positive non-small cell lung cancer  [2A]

  • for newly diagnosed brain metastases in select patients (eg, patients with small asymptomatic brain metastases) and stable systemic disease or reasonable systemic treatment options
  • for recurrent brain metastases
     

• Cervical Cancer

  Preferred second-line therapy as a single agent for recurrent or metastatic disease if [2A]

  • instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors
  • disease progression on or after chemotherapy in patients whose tumors express PD-L1 (combined positive score [CPS ≥1]) as determined by an FDA-approved test
     

• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

  Used as a single agent or in combination with ibrutinib for treatment of histologic (Richter's) transformation to diffuse large B-cell lymphoma (clonally related or unknown clonal status) for patients with del(17p)/TP53 mutation or who are chemotherapy refractory and unable to receive chemoimmunotherapy [2B]

• Colon Cancer

  • Initial therapy as a single agent for patients with unresectable advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) who are not appropriate for intensive therapy [2A]
  • Primary treatment as a single agent for unresectable metachronous metastases (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months [2A]
  • Subsequent therapy as a single agent (if nivolumab or pembrolizumab not previously given) for unresectable advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy [2A]
     

• Cutaneous Melanoma

  • Preferred second-line or subsequent therapy as a single agent for metastatic or unresectable disease after disease progression or maximum clinical benefit from BRAF targeted therapy [2A]

    • if anti PD-1 therapy checkpoint inhibitor immunotherapy was not previously used
    • may be considered as re-induction therapy if prior checkpoint inhibitor immunotherapy resulted in disease control (complete response, partial response, or stable disease) and no residual toxicity, and disease progression/relapse occurred >3 months after treatment discontinuation
       

  • Preferred adjuvant treatment as a single agent  [1 for resected AJCC 7th edition stage IIIA disease with SLN metastases >1 mm, or for AJCC 7th edition stage IIIB/C disease during active nodal basin ultrasound surveillance or after CLND, or for stage III disease following wide excision of primary tumor and a complete therapeutic lymph node dissection, or following CLND and/or complete resection of nodal recurrence ; 2A for all others]

    • for resected stage III sentinel lymph node (SLN) positive disease during active nodal basin ultrasound surveillance or after complete lymph node dissection (CLND)
    • for stage III disease with clinically positive node(s) following wide excision of primary tumor and a complete therapeutic lymph node dissection
    • for stage III disease with clinical or microscopic satellite/in-transit metastases if no evidence of disease post-surgery
    • for local satellite/in-transit recurrence if no evidence of disease post-surgery
    • following CLND and/or complete resection of nodal recurrence
    • following complete resection of distant metastatic disease
       

  • Preferred first-line therapy as a single agent for metastatic or unresectable disease [1].

• Esophageal and Esophagogastric Junction Cancers

  Esophageal Cancer

•  for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

• o in combination with platinum- and fluoropyrimidine-based chemotherapy, or

• o as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test

• Palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and Karnofsky performance score ≥60% or ECOG performance score ≤2 as [2B for second-line therapy for esophageal SCC, esophageal adenocarcinoma and EGJ adenocarcinoma with PD-L1 expression by CPS of levels ≥10 ; 2A for all others]

  • preferred second-line or subsequent therapy as a single agent for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors
  • second-line therapy for esophageal squamous cell carcinoma (SCC), esophageal adenocarcinoma and EGJ adenocarcinoma with PD-L1 expression by CPS of levels ≥10
  • third-line or subsequent therapy as a single agent for esophageal and EGJ adenocarcinoma with PD-L1 expression levels by CPS of ≥1
     

• Gastric Cancer

  Palliative therapy for locoregional disease in patients who are not surgical candidates, recurrent, or metastatic disease and Karnofsky performance score ≥60% or ECOG performance score ≤2 as [2A]

  • preferred second-line or subsequent therapy as a single agent for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors
  • third-line or subsequent therapy as a single agent for gastric adenocarcinoma with PD-L1 expression levels by CPS of ≥1
     

• Gestational Trophoblastic Neoplasia

  Single-agent therapy for [2A]

  • recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen
  • methotrexate-resistant high-risk disease
     

• Head and Neck Cancers

  Very Advanced Head and Neck Cancer

  • Systemic therapy as a single agent first-line therapy option for non-nasopharyngeal cancer if PD-L1 positive tumors in  [2A]

    • newly diagnosed T4b, N0-3, M0 disease, unresectable nodal disease with no metastases, or for patients who are unfit for surgery and performance status (PS) 3
    • metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable locoregional recurrence or second primary with prior radiation therapy (RT) and PS 0-2
    • unresectable locoregional recurrence without prior RT and PS 3
       

  • Systemic therapy as a preferred single agent second-line or subsequent therapy option for non-nasopharyngeal cancer if disease progression on or after platinum therapy, or for previously treated PD-L1 positive recurrent or metastatic nasopharyngeal cancer in [1 for non-nasopharyngeal cancer; 2B for nasopharyngeal cancer]

    • newly diagnosed T4b, N0-3, M0 disease, unresectable nodal disease with no metastases, or for patients who are unfit for surgery and performance status (PS) 3
    • metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable locoregional recurrence or second primary with prior radiation therapy (RT) and PS 0-2
    • unresectable locoregional recurrence without prior RT and PS 3
       

  • Systemic therapy as a preferred first-line, second-line, or subsequent therapy option for non-nasopharyngeal cancer in combination with fluorouracil and either carboplatin or cisplatin for [2A]:

    • metastatic (M1) disease at initial presentation
    • recurrent/persistent disease with distant metastases
    • unresectable locoregional recurrence or second primary with prior RT
       

• Hepatobiliary Cancers

  Gallbladder Cancer

  Intrahepatic Cholangiocarcinoma

  Extrahepatic Cholangiocarcinoma

  Hepatocellular Carcinoma

  Subsequent treatment as a single agent for progressive disease in patients (Child-Pugh Class A only) who  [2B]

  • Primary treatment as a single agent for unresectable or metastatic disease that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) [2A]
  • Treatment as a single agent for resected gross residual disease (R2) that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) [2A]
     
  • Primary treatment as a single agent for unresectable or metastatic disease that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) [2A]
  • Treatment as a single agent for resected gross residual disease (R2) that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) [2A]
     
  • Primary treatment as a single agent for unresectable or metastatic disease that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) [2A]
  • Treatment as a single agent for resected gross residual disease (R2) that is microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) [2A]
     
  • have unresectable disease and are not a transplant candidate
  • are inoperable by performance status or comorbidity, or have local disease or local disease with minimal extrahepatic disease only
  • have metastatic disease or extensive liver tumor burden
     

• Hodgkin Lymphoma

  Classic Hodgkin Lymphoma (Age ≥18 years)

  Third-line or subsequent systemic therapy as a single agent for [2A]

  Classic Hodgkin Lymphoma in Older Adults (Age >60 years)

  Palliative therapy as a single agent for [2A]

  • disease that has relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) ± brentuximab vedotin
  • patients with relapsed/refractory disease who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy
  • post-allogeneic transplant
     
  • disease that has relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) ± brentuximab vedotin
  • patients with relapsed/refractory disease who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy
  • post-allogeneic transplant
     

• Kidney Cancer

  Used in combination with axitinib for relapsed or stage IV disease [2A for all others; 1 for first-line therapy for poor/intermediate risk]

  • as preferred first-line therapy for clear cell histology and favorable risk
  • as preferred first-line therapy for clear cell histology and poor/intermediate risk
  • as subsequent therapy for clear cell histology

• Merkel Cell Carcinoma

  • May be considered as a treatment option for patients with recurrent locally advanced disease [2A]
  • Preferred treatment for disseminated, clinical M1 disease with or without surgery and/or radiation therapy [2A]
     

• Neuroendocrine and Adrenal Tumors

  Poorly Differentiated (High Grade)/Large or Small Cell

  May be considered as treatment for patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors that have progressed following prior treatment with no satisfactory alternative treatment options  [2A]

  Adrenal Gland Tumors

  Consider for the management of mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) unresectable/metastatic adrenocortical tumors that have progressed following prior treatment and have no satisfactory alternative treatment options [2A]

• Non-Small Cell Lung Cancer

  Footnotes*Pembrolizumab monotherapy can be considered for PD-L1 1-49% in patients with poor PS or other contraindications to combination chemotherapy.

  • Continuation maintenance therapy for recurrent, advanced or metastatic disease for PD-L1 expression positive (≥1%) tumors that are EGFR, ALK negative or unknown and no contraindications to the addition of pembrolizumab or atezolizumab and performance status 0-2, who achieve tumor response or stable disease following systemic or first-line therapy [1 for all others; 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 2A as a single agent for squamous cell histology]

    • as a single agent if pembrolizumab monotherapy given first-line for nonsquamous cell histology
    • in combination with pemetrexed if given first-line as part of a pembrolizumab/pemetrexed and either cisplatin or carboplatin regimen for nonsquamous cell histology
    • as a single agent if pembrolizumab was given as monotherapy or as part of a pembrolizumab/(cisplatin or carboplatin)/(paclitaxel or albumin-bound paclitaxel) regimen for squamous cell histology
       
  • Single-agent continuation maintenance therapy if given first line as part of a pembrolizumab/(carboplatin or cisplatin)/(paclitaxel or albumin-bound paclitaxel) regimen for recurrent, advanced or metastatic disease, squamous cell histology, in patients with performance status 0-2 who achieve tumor response or stable disease following initial systemic therapy [2A for all others; 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease]
  • Treatment for recurrent, advanced or metastatic disease as first-line therapy for PD-L1 expression-positive (≥1%) tumors that are EGFR, ALK negative or unknown and no contraindications to the addition of pembrolizumab or atezolizumab and performance status 0-2 [2A for combination with cisplatin and either paclitaxel or albumin-bound paclitaxel for squamous cell histology; 1 for all others; 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease, or for PD-L1 1-49%]
     
    • as a single agentFootnotes* (preferred if PD-L1 ≥50%)
    • in combination with pemetrexed and either carboplatin or cisplatin for nonsquamous cell histology (preferred if PD-L1 1-49%)
    • in combination with either carboplatin or cisplatin and either paclitaxel or albumin-bound paclitaxel for squamous cell histology (preferred if PD-L1 1-49%)
       
  • Continuation maintenance therapy in combination with pemetrexed if given first line as part of a pembrolizumab/pemetrexed and either cisplatin or carboplatin regimen for recurrent, advanced or metastatic disease, nonsquamous cell histology in patients with performance status 0-2, who achieve tumor response or stable disease following initial systemic therapy [1 for all others; 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease]
  • Treatment for recurrent, advanced or metastatic disease in combination with pemetrexed and either carboplatin or cisplatin (as preferred regimens if no contraindications to the addition of pembrolizumab or atezolizumab for nonsquamous cell histology), in combination with carboplatin and either paclitaxel or albumin-bound paclitaxel (as preferred regimens if no contraindications to the addition of pembrolizumab for squamous cell histology), or in combination with cisplatin and either paclitaxel or albumin-bound paclitaxel (if no contraindications to the addition of pembrolizumab for squamous cell histology) for patients with performance status 0-1 as [1 for use in combination with pemetrexed and either carboplatin or cisplatin, or in combination with carboplatin and either paclitaxel or albumin-bound paclitaxel; 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 2A for all others]
     
    • initial systemic therapy for EGFR, ALK, ROS1, BRAF negative or unknown, and PD-L1 <1% or unknown
    • first-line or subsequent therapy for BRAF V600E-mutation positive tumors
    • subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitinib, osimertinib, or dacomitinib therapy
    • subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigatinib therapy
    • subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib or ceritinib therapy
    • subsequent therapy for PD-L1 expression-positive (≥1%) tumors and EGFR, ALK negative or unknown and no prior platinum-doublet chemotherapy
       

  • Preferred single agent as subsequent therapy for recurrent, advanced or metastatic disease in patients with performance status 0-2 and tumors with PD-L1 expression levels ≥1% and no prior progression on a PD-1/PD-L1 inhibitor [2A for subsequent progression, 1 for first progression, 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease]

• Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

  Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

  Single-agent therapy for persistent disease or recurrence, useful in certain circumstances if microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) [2B for immediate treatment of biochemical relapse; 2A for clinical relapse]

• Pancreatic Adenocarcinoma

  • Therapy as a single agent (only for microsatellite instability-high or mismatch repair deficient tumors) in patients with good performance status for [2A]
     
    • local recurrence in the pancreatic operative bed after resection
    • metastatic disease with or without local recurrence if ≥6 months from completion of primary therapy
    • metastatic disease with or without local recurrence if less than 6 months from completion of primary therapy
       
  • Second-line therapy as a single agent (only for microsatellite instability-high or mismatch repair deficient tumors) for locally advanced or metastatic disease for patients with good performance status (ECOG PS 0-1) and disease progression [2A]
     

• Penile Cancer

  Used as a single agent (preferred) as subsequent-line systemic therapy if unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumor that has progressed following prior treatment and no satisfactory alternative treatment options [2A]

• Primary Cutaneous Lymphomas

  Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

  Therapy for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions, or cutaneous ALCL with regional nodes (excludes systemic ALCL), as a single agent for relapsed/refractory disease [2B]

  Mycosis Fungoides/Sezary Syndrome

  • Systemic therapy as treatment for [2A for stage III MF or Sezary syndrome; 2B for all others]
     
    • relapsed or persistent stage IA mycosis fungoides (MF) with B1 blood involvement, with or without skin-directed therapy
    • relapsed or persistent stage IB-IIA MF with B1 blood involvement, with or without skin-directed therapy
    • stage IIB MF with limited tumor lesions refractory to multiple previous therapies, with or without skin-directed therapy
    • relapsed or refractory stage IIB MF with generalized tumor lesions, with or without skin-directed therapies
    • stage IIB MF with generalized tumor lesions that is refractory to multiple previous therapies or progression
    • relapsed or persistent stage III MF, with or without skin-directed therapies
    • stage III MF that is refractory to multiple previous therapies
    • relapsed or persistent stage IV Sezary syndrome
    • relapsed or persistent stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control
    • large cell transformation (LCT) with limited cutaneous lesions that is refractory to multiple previous therapies
       
  • relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy
  • Systemic therapy as primary treatment for [2A]
     
    • stage III MF
    • stage IV Sezary syndrome
       

• Prostate Cancer

  Second-line or subsequent treatment as a single agent for patients who have progressed through at least one line of systemic therapy for castration-resistant distant metastatic (M1) disease that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), if pembrolizumab not previously received [2B]

• Rectal Cancer

  • Initial therapy as a single agent for patients with unresectable advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) who are not appropriate for intensive therapy [2A]
  • Primary treatment as a single agent for unresectable metachronous metastases (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months [2A]
  • Subsequent therapy as a single agent (if nivolumab or pembrolizumab not previously given) for unresectable advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy [2A]
     

• Small Bowel Adenocarcinoma

  Initial therapy as a single agent for advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) in patients with prior oxaliplatin exposure in the adjuvant setting or contraindication [2A]

  Subsequent therapy as a single agent for advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only)  [2A]

• Small Cell Lung Cancer

  Subsequent systemic therapy for patients with performance status 0-2 as a single agent for [2A]

  • relapse within 6 months following complete or partial response or stable disease with initial treatment
  • primary progressive disease
     

• Soft Tissue Sarcoma

  Undifferentiated Pleomorphic Sarcoma

  Single agent for the treatment of metastatic undifferentiated pleomorphic sarcoma [2B]

  Alveolar Soft Part Sarcoma

  Single-agent therapy for the treatment of alveolar soft part sarcoma (ASPS) [2B]

• T-Cell Lymphomas

  Extranodal NK/T-Cell Lymphoma, nasal type

  For relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used, if a clinical trial is unavailable [2A]

• Testicular Cancer

  Used as single-agent third-line therapy in patients with MSI-H/dMMR tumors [2A]

• Thymomas and Thymic Carcinomas

  Second-line therapy (for thymic carcinomas only) as a single agent for [2A]

  • unresectable disease following first-line chemotherapy for potentially resectable locally advanced disease, solitary metastasis, or ipsilateral pleural metastasis
  • extrathoracic metastatic disease
     

• Uterine Neoplasms

  Endometrial Carcinoma

  • Treatment of patients (useful in certain circumstances) with recurrent, metastatic, or high-risk microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors that have progressed following prior cytotoxic chemotherapy [2A]
  • Used in combination with lenvatinib [2B]
     
    • for disease suitable for primary surgery as additional treatment with vaginal brachytherapy for stage IA disease (preferred)
    • for disease suitable for primary surgery as additional treatment with or without sequential external beam radiation therapy (EBRT) with or without vaginal brachytherapy for stage IB-IV disease
    • for disease not suitable for primary surgery as primary treatment with or without sequential EBRT and with or without brachytherapy
       

  • Adjuvant treatment in combination with lenvatinib for surgically staged patients [2B]

    • with vaginal brachytherapy and/or sequential EBRT in patients with stage IB disease and histologic grade 3 tumors
    • with sequential EBRT with or without vaginal brachytherapy in patients with stage II disease and histologic grade 3 tumors
    • with sequential EBRT with or without vaginal brachytherapy for stage IIIA-IVA disease
    • with or without vaginal brachytherapy for stage IIIA-IVA disease
    • with or without sequential EBRT and vaginal brachytherapy for stage IVB disease
       

  • Primary treatment in combination with lenvatinib [2B]

    • may be considered for select patients with disease limited to the uterus that is not suitable for primary surgery
    • with or without sequential external beam radiation therapy (EBRT) and brachytherapy for disease not suitable for primary surgery in patients with suspected or gross cervical involvement
    • may be considered preoperatively for patients presenting with abdominal/pelvic confined disease that is suitable for primary surgery
    • with or without sequential EBRT and with or without brachytherapy for extrauterine disease that is not suitable for primary surgery
    • with or without EBRT and/or hormonal therapy for distant metastases
       

  • Used in combination with lenvatinib [2B]

    • may be considered for isolated metastases
    • for disseminated metastases that have progressed on hormonal therapy
    • with or without sequential palliative external beam radiation therapy (EBRT) for symptomatic, grade 2, 3, or large-volume disseminated metastases or for local/regional recurrence in patients with gross upper abdominal residual disease
    • with sequential EBRT with or without brachytherapy for local/regional recurrence in patients with disease confined to the vagina or in pelvic lymph nodes
    • with sequential EBRT for local/regional recurrence in patients with disease in para-aortic or common iliac lymph nodes
    • with or without sequential tumor-directed EBRT for local/regional recurrence in patients with microscopic residual upper abdominal or peritoneal disease
    • with or without sequential palliative EBRT for local/regional recurrence in patients who have received prior EBRT to site of recurrence
       

• Uveal Melanoma

  Consider as single agent therapy for distant metastatic disease  [2A]

• Vulvar Cancer

  Squamous Cell Carcinoma

  Second-line therapy as a single agent (useful under certain circumstances) for advanced, recurrent or metastatic disease if [2A]

  • microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors
  • disease progression on or after chemotherapy in patients whose tumors express PD-L1 (Combined Positive Score ≥1) as determined by an FDA-approved test.

Medicare National Coverage

N/A

References

1. NCCN Clinical Practice Guidelines in Oncology® Melanoma (Version 2.2018). National Comprehensive Cancer Network, Inc. January 2018.2019.

2. NCCN Clinical Practice Guidelines in Oncology® Non-Small Cell Lung Cancer (Version 3.2018). National Comprehensive Cancer Network, Inc. February 2018.

3. Keytruda [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp. 09/2019

4. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for determination of microstatellite instability in colorectal cancer. Cancer Res. 1998 Nov 15;58(22):5248-57

5.American Cancer Society. Cancer Facts & Figures 2015. http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf Accessed January 11, 2016.

6.Codigos ICD-9 y ICD-10 para melanoma maligno: ICD-9-CM to ICD-10-CM Based on FY2014 ICD-9-CM codes. 2014. Recuperado de:http://seer.cancer.gov/tools/conversion
Facts & Comparisons eAnswers. 2014. Keytruda® Monograph. Última modificación Octubre 2014. Wolters Kluwer Health, Inc. Recuperado de:

7.http://online.factsandcomparisons.com/MonoDisp.aspxmonoID=fandchcp19678&quick=1217558%7c5&search=1217558%7c5&isstemmed=True&NDCmapping=-1&fromTop=true#firstMatch Facts & Comparisons eAnswers. 2014. Keytruda® Monograph. Última modificación Octubre 2014. Recuperado de:

8.http://www.uptodate.com.ezproxylocal.library.nova.edu/contents/pembrolizumabdruginformation?source=search_result&search=keytruda&selectedTitle=1~16#F25857279 nov/2019

9. Skin Cancer Foundation. 2014. Melanoma. Recuperado de: http://www.skincancer.org/skin-cancer  information/melanoma http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm

10. Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck; September 2014.Merck Sharp and Dohme Co. 2014. Highlights of Prescribing Information.
Recuperado de:http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed on January,
2016.

11. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-esophageal-or-gej-carcinoma

12. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf

13    13 http://www.cms.gov/medicare-coverage-database/overview-and-quick-search.aspx

         14  Drugs@FDA [Internet]. Silver Spring (MD): US Food and Drug Administration; 2018. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name/. Accessed 9/4/18

         15 NCCN Content © National Comprehensive Cancer Network, Inc 2011-2023

       16 DailyMed [Internet]. Bethesda (MD): National Library of Medicine; 2018. Available from: http://dailymed.nlm.nih.gov/dailymed/index.cfm/. Accessed 9/4/18.

5.       17 NCCN Content © National Comprehensive Cancer Network, Inc 2011-2022, All Rights Reserved. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, NCCN TEMPLATES®, and NCCN COMPENDIUM® are trademarks owned by the National Comprehensive Cancer Network, Inc.

6.        18 Database: MICROMEDEX® 2.0 [online] Available: http://www.thomsonhc.com/home/dispatch [Accessed October, 2011]

7.         19. FDA Website:     http://www.fda.gov/orphan/designat/list.htm.

8         20. American Hospital Formulary Service (AHFS) (electronic version). Available at: http://www.ahfsdruginformation.com/

         21. Local Coverage Determination (LCD) For Label and Off-label Coverage of Outpatient Drugs and Biologics (L33915)

         22. Ley de Puerto Rico Núm. 194; Artículo 4.050

         23. Reglamento de Puerto Rico 7617, Reglamento para implantar las disposiciones de la ley número 194; Artículo 8, Sección 5, inciso A 1

2      24  Contract between Administración de Seguros de Salud de Puerto Rico (ASES) and Triple-S Salud, for Provision of Physical & Behavioral Health Services under the Government Health Plan Program (Contract No: 2019-000052)

    25. Normative Letter 21-0817: Política para asegurar el acceso a medicamentos, tratamiento y pruebas para el diagnóstico de Cáncer.

           26.  ASES-OC-2023/P003: Puerto Rico Health Insurance Administration Policy for Medication Exception Requests.

          27. Contract between Administración de Seguros de Salud de Puerto Rico (ASES) and Triple-S Salud, for Provision of Physical & Behavioral Health Services under the Government Health Plan Program (Contract No: 2023-000046)

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