BlueCross BlueShield of Tennessee Medical Policy Manual

Pembrolizumab

DESCRIPTION

Pembrolizumab is a human programmed death receptor (PD-1)-blocking humanized monoclonal antibody.  It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2 by binding to the PD-1 receptor which is found on T-cells.  This releases PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response, which results in decreased tumor growth.

POLICY

• Pembrolizumab for the treatment of the following is considered medically necessary if the medical appropriateness criteria are met: (See Medical Appropriateness below.)

• • Anal cancer

  • Bladder Cancer/Urothelial Carcinoma

  • Central Nervous System Cancer

  • Cervical cancer

  • Diffuse Large B-Cell Lymphoma

  • Gastric cancer

  • Gestational Trophoblastic Neoplasia

  • Head and Neck Cancers

  • Hepatocellular Carcinoma (HCC)

  • Hodgkin Lymphoma

  • Melanoma

  • Merkel cell carcinoma

  • Mesothelioma

  • Microsatellite Instability-High (MSI-H)/ Mismatch Repair Deficient (dMMR) Cancers

  • Mycosis Fungoides/Sézary Syndrome

  • Non-small cell lung cancer (NSCLC)

  • Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

  • Renal Cell Carcinoma (Kidney Cancer)

  • Small Cell Lung Cancer

  • Squamous Cell Carcinoma of the Head and Neck (SCCHN)

  • T-Cell Lymphoma/Extranodal NK, nasal type

  • Thymic carcinoma

• Pembrolizumab for the treatment of other conditions/diseases is considered investigational.

MEDICAL APPROPRIATENESS

INITIAL APPROVAL

• Pembrolizumab is considered medically appropriate if ALL of the following: 

• • Individual is 18 years of age or older unless otherwise specified

  • Individual has not received previous therapy with a programmed death (PD-1/PD-L1) -directed therapy (e.g., atezolizumab, avelumab, durvalumab, cemiplimab, nivolumab, etc.) unless otherwise specified

  • Diagnosis of ANY ONE of the following:

  • • Anal cancer as a single agent in second-line therapy for metastatic squamous cell disease

    • Bladder Cancer/Urothelial Carcinoma if ALL of the following:

    • • Used as a single agent

      • Further diagnosed as ANY ONE of the following:

      • • Primary Carcinoma of the Urethra as ANY ONE of the following:

        • • Recurrent or metastatic disease but does not have recurrent stage T3-4 disease or palpable inguinal lymph nodes

          • Used as primary treatment for clinical stage T3-4, cN1-2 disease or cN1-2 palpable inguinal lymph nodes

        • Locally advanced or metastatic Urothelial Carcinoma

        • Disease recurrence post-cystectomy

        • Metastatic Upper GU Tract Tumors

        • Metastatic Urothelial Carcinoma of the Prostate

      • Used as ANY ONE of the following:

      • • First-line therapy in cisplatin-ineligible patients and ANY ONE of the following:

        • • Individual is carboplatin-ineligible

          • Individual has a PD-L1 expression of >10% (as confirmed using an immunotherapy assay such as the PD-L1 IHC 22C3 pharmDx)

      • Subsequent therapy after previous platinum treatment*

    • Central Nervous System Cancer if ALL of the following:

    • • Used as a single agent for newly diagnosed or recurrent disease for brain metastases

      • Primary tumor is melanoma or NSCLC

    • Cervical Cancer if ALL of the following:

    • • Used as a single agent

      • Individual has recurrent, unresectable (or is not a candidate for surgery), locally advanced or metastatic disease

      • Tumor expresses PD-L1 (combined positive score [CPS] >1) as determined by an FDA-approved test

      • Disease progressed on or after chemotherapy

    • Diffuse Large B-Cell Lymphoma for treatment of relapsed or refractory primary mediastinal large B-cell lymphoma

    • Gastric cancer if ALL of the following:

    • • Used as a single agent

      • Diagnosis of gastric or gastro-esophageal junction (GEJ) adenocarcinoma

      • Disease is recurrent, unresectable, locally advanced or metastatic

      • Tumor expresses PD-L1 (CPS ≥1%) as determined by an FDA-approved test

      • Disease progression on or after minimum of two prior systemic treatments which must have included a fluoropyrimidine and platinum-containing regimen

      • Individuals with HER2 positive disease must have previously failed on HER2 directed therapy

    • Gestational Trophoblastic Neoplasia if used as single agent therapy for ANY ONE of the following:

    • • 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 if ALL of the following:

    • • Used as a single agent

      • Treatment is second-line or subsequent

      • Cancer is non-nasopharyngeal

      • Disease progression on or after platinum-containing chemotherapy

    • Hepatocellular Carcinoma (HCC) if ALL of the following:

    • • Used as a single agent

      • Progressed on or was intolerant to sorafenib

      • Laboratory confirmed diagnosis of hepatocellular carcinoma that is unresectable and not a transplant candidate

      • Child-Pugh Class A ONLY liver impairment (excluding Child-Pugh Class B and C)

    • Hodgkin lymphoma, diagnosed as classic Hodgkin lymphoma (cHL) if ALL of the following:

    • • Individual is 2 years of age or older

      • Used as a single agentfor ANY ONE of the following:

      • • Relapse after three or more prior lines of therapy

        • Refractory disease

    • Melanoma as a single agent for ANY ONE of the following:

    • • Disease is metastatic or unresectable

      • Used as adjuvant treatment

      • Used as induction therapy, second-line or subsequent (including re-treatment in individuals who experienced disease control, but subsequently have disease progression/relapse > 3 months after treatment discontinuation)

      • Individual has unresectable or metastatic Uveal Melanoma

    • Merkel cell carcinoma as a single agent for disseminated metastatic disease

    • Mesothelioma, Malignant Pleural, if used as subsequent therapy as a single agent

    • Microsatellite Instability-High (MSI-H) or mismatch repair deficient (dMMR) Cancer if ALL of the following:

    • • Used as a single agent

      • Individual is 2 years of age or older

      • Disease must be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

      • Pediatric individuals must NOT have a diagnosis of MSI-H central nervous system cancer

      • Disease is ANY ONE of the following:

      • • Bone Cancer (Ewing Sarcoma, Mesenchymal Chondrosarcoma, Osteosarcoma, Dedifferentiated Chondrosarcoma, or High-Grade Undifferentiated Pleomorphic Sarcoma)  Used for unresectable or metastatic disease after progression following prior treatment and individual has no satisfactory alternative treatment options

        • Cervical Cancer - Used second-line for recurrent or metastatic disease

        • Colorectal Cancer for initial therapy in individuals with unresectable or metastatic disease who are not candidates for intensive therapy OR Used as primary treatment in patients with unresectable or metastatic disease who failed adjuvant treatment with FOLFOX (fluorouracil, leucovorin and oxaliplatin) or CapeOX (capecitabine-oxaliplatin) in the previous 12 months OR for unresectable or metastatic disease that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan as subsequent therapy if nivolumab or pembrolizumab not previously given

        • Gastric adenocarcinoma OR esophageal/esophagogastric junction adenocarcinoma or squamous cell carcinoma  for subsequent therapy for unresectable (or not a candidate for) locally advanced, recurrent, or metastatic disease with performance score of Karnofsky performance score ≥60% or ECOG ≤ 2

        • Hepatobiliary Cancer (Gall bladder cancer, intra- /extra-hepatic cholangiocarcinoma) used as initial therapy for unresectable or metastatic disease or resected gross residual disease (R2)

        • Ovarian Cancer (included Epithelial Ovarian Cancer, Fallopian Tube Cancer and Primary Peritoneal Cancers) for persistent or recurrent disease and patient is not experiencing an immediate biochemical relapse

        • Pancreatic Adenocarcinoma for second-line therapy for locally advanced, recurrent or metastatic disease after progression for patients with good performance status (ECOG 0-1)

        • Penile Cancer for subsequent treatment of unresectable or metastatic disease that is progressive and there are no other satisfactory treatment options

        • Testicular Cancer as single agent

        • Uterine Cancer (Endometrial Carcinoma) for individuals with high risk tumors, or recurrent or metastatic disease, that have progressed following prior cytotoxic chemotherapy

        • Vulvar Squamous Cell Carcinoma for advanced, recurrent or metastatic disease as second-line therapy

        • Other Solid Tumor (e.g., Adrenal Gland Tumors, etc.) used for unresectable or metastatic disease progression following prior treatment and there are no satisfactory alternative treatment options

    • Mycosis Fungoides/Sézary Syndrome as systemic therapy for ANY ONE of the following:

    • • Primary treatment for stage III MF or stage IV SS

      • Treatment for stage III MF that is refractory to multiple previous therapies

    • Non-small cell lung cancer for ANY ONE of the following:

    • • Tumor with high PD-L1 expression (Tumor Proportion Score [TPS] ≥50%) as determined by an FDA-approved test, used for ANY ONE of the following:

      • • Continuation maintenance therapy for recurrent, advanced, or metastatic disease (excluding locoregional recurrent disease without evidence of dissemination) and PS ≤ 2 for ANY ONE of the following:

        • • Combination therapy with pemetrexed if pembrolizumab was given first-line in combination with pemetrexed and either carboplatin or cisplatin for non-squamous cell histology

          • Single agent therapy if ANY ONE of the following:

          • • Pembrolizumab was given first-line or following systemic therapy in combination with carboplatin or cisplatin AND paclitaxel or nab-paclitaxel for squamous cell histology

            • Pembrolizumab was given first-line or following systemic therapy as a single agent for squamous or non-squamous cell histology

        • Recurrent, advanced, or metastatic disease (excluding locoregional recurrent disease without evidence of dissemination) that is EGFR, ALK negative or unknown for ANY ONE of the following:

        • • With a PS≤2, initial therapy for ANY ONE of the following:

          • • Nonsquamous cell histology, in combination with pemetrexed and either carboplatin or cisplatin

            • Squamous cell histology, in combination with carboplatin or cisplatin and either paclitaxel or albumin-bound paclitaxel

            • Single agent therapy

          • With a PS≤1 and no prior platinum doublet therapy used as subsequent therapy, use for ANY ONE of the following:

          • • Nonsquamous cell histology in combination with either carboplatin or cisplatin

            • Squamous cell histology in combination with carboplatin or cisplatin AND either paclitaxel or albumin-bound paclitaxel

      • Tumor expresses PD-L1 (TPS ≥1%) as determined by an FDA-approved test used for ANY ONE of the following:

      • • Used as a single agent for recurrent, advanced, or metastatic disease (excluding locoregional recurrent disease without evidence of dissemination) with ALL of the following:

        • • Disease must have progressed during or following cytotoxic therapy

          • Genomic tumor aberrations must have progressed following systemic therapy for those aberrations (e.g., EGFR, ALK, ROS1, BRAF, etc.)

        • Used as single agent for the treatment of metastatic disease as first line therapy for no genomic tumor aberrations (e.g., EGFR or ALK)

      • Used for recurrent, advanced, or metastatic disease (excluding locoregional recurrent disease without evidence of dissemination)with PS ≤ 1 for ANY ONE of the following:

      • • Non-squamous cell histology in combination with pemetrexed AND carboplatin or cisplatin

        • Squamous cell histology in combination with carboplatin or cisplatin AND paclitaxel or nab-paclitaxel  used for ANY ONE of the following:

        • • First-line therapy for genomic tumor aberration  negative or unknown (e.g., EGFR, ALK, ROS1 and BRAF)** AND PD-L1 expression <50% or unknown;

          • First-line therapy for BRAF V600E-mutation positive tumors

          • Subsequent therapy for genomic tumor aberration positive (e.g., EGFR, BRAF V600E, ALK, or ROS1) and prior targeted therapy (see chart below)

        • Used for continuation maintenance therapy (excluding locoregional recurrent without evidence of disseminated disease)if ALL of the following:

        • • Tumor response or stable disease following initial systemic therapy;

          • Performance status 0-2

          • Recurrent, advanced, metastatic disease for ANY ONE of the following:

          • • As single agent if pembrolizumab monotherapy given first-line for nonsquamous cell histology

            • Given in combination with pemetrexed if given 1st line with carboplatin or cisplatin and pemetrexed for nonsquamous cell histology

            • Used as a single agent if given 1st line with carbo- cisplatin and paclitaxel or nab-paclitaxel for squamous cell histology

        • Used as initial therapy as a single agent for individuals with stage III disease who are not candidates for surgical resection or definitive chemoradiation

    • Primary Mediastinal Large B-Cell Lymphoma (PMBCL) for ALL of the following:

    • • Individual must be at least 2 years of age or older

      • Used as single agent

      • Individual  has relapsed or refractory disease

      • Used after two or more prior lines of therapy

    • Renal Cell Carcinoma (Kidney Cancer) diagnosed as advanced disease if used as first-line treatment in combination with axitinib

    • Squamous cell carcinoma of the head and neck (SCCHN) if ALL of the following:

    • • Disease progression on or after platinum-containing chemotherapy

      • Used as a single agent

      • Disease is unresectable, recurrent, persistent or metastatic

      • Individual has non-nasopharyngeal disease

    • Small Cell Lung Cancer (SCLC) if ALL of the following:

    • • Used as subsequent single-agent therapy

      • Performance status (PS) score of 0-2

      • Individual has ANY ONE of the following:

      • • Primary progressive disease

        • Relapsed within 6 months following a complete or partial response or after stable disease following initial treatment

    • T-Cell Lymphoma/Extranodal NK, nasal type if ALL of the following:

    • • Disease is relapsed or refractory

      • Disease progressed following additional treatment with asparaginase-based chemotherapy, clinical trials or other best supportive care

    • Thymic Carcinoma for second second-line therapy as a single agent for ANY ONE of the following:

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

      • Extrathoracic metastatic disease

    • Vulvar Cancer (squamous cell carcinoma) if ALL of the following:

    • • Second line as a single agent for advanced, recurrent or metastatic disease  after progression on or after chemotherapy

      • Tumor expresses PD-L1 (CPS ≥1%) as determined by an FDA-approved test

*If platinum treatment occurred greater than 12 months ago, the individual should be re-treated with platinum-based therapy. An individual with comorbidities (e.g., hearing loss, neuropathy, poor PS, renal insufficiency, etc.) may not be eligible for cisplatin. Carboplatin may be substituted for cisplatin particularly in those with a GFR <60 mL/min or a PS of 2.

** Every effort needs to be made to establish the genetic alteration status. A blood assay may be used if a tissue assay is not feasible.

RENEWAL CRITERIA

• Pembrolizumab is considered medically appropriate for renewal if ALL of the following criteria are met:

• • Individual continues to meet initial approval criteria

  • Tumor response as defined by lack of tumor progression, improvement in tumor size and/or improvement in symptoms

  • Absence of unacceptable toxicity from the agent, e.g., severe infusion reactions, immune-mediated adverse reactions such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction, skin reactions, etc.

  • For a diagnosis of ANY ONE of the following, the individual has not exceeded a maximum of twenty-four (24) months of therapy:

  • • Anal Cancer

    • Cervical Cancer

    • Classical Hodgkin Lymphoma (cHL)

    • Gastric/GEJ Adenocarcinoma

    • Malignant Pleural Mesothelioma

    • MSI-H Cancer (including the following cancers: colorectal, pancreatic, bone,  gastric/gastroesophageal, ovarian, uterine, penile, testicular, hepatobiliary and other solid tumors)

    • Non-small cell lung cancer (NSCLC)

    • Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

    • Squamous Cell Carcinoma of the Head and Neck (SCCHN)

    • Urothelial Carcinoma/Bladder Cancer

    • Vulvar Squamous Cell Carcinoma

    • Merkel Cell Carcinoma

    • Mycosis Fungoides/Sézary Syndrome

    • Renal Cell Carcinoma (Kidney Cancer)

  • Melanoma (metastatic or unresectable disease) and used for re-induction in individuals who experienced disease control but subsequently have disease progression/relapse > 3 months after treatment discontinuation

LENGTH OF AUTHORIZATION

Coverage will be provided for six months and may be renewed.

SCCHN, cHL, NSCLC, SCLC, HCC, Urothelial Carcinoma, MPM, MSI-H/dMMR, PMBCL, Cervical, Anal, Vulvar, MCC, Mycosis Fungoides/Sézary Syndrome, RCC & Gastric Cancers can be authorized up to a maximum of 24 months of therapy.

Adjuvant therapy in melanoma can be authorized up to a maximum of 12 months of therapy.

Refer to DOSAGE LIMITS below

APPLICABLE TENNESSEE STATE MANDATE REQUIREMENTS

BlueCross BlueShield of Tennessee’s Medical Policy complies with Tennessee Code Annotated Section 56-7-2352 regarding coverage of off-label indications of Food and Drug Administration (FDA) approved drugs when the off-label use is recognized in one of the statutorily recognized standard reference compendia or in the published peer-reviewed medical literature.

IMPORTANT REMINDER

We develop Medical Policies to provide guidance to Members and Providers.  This Medical Policy relates only to the services or supplies described in it.  The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy.  For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed.  If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.

ADDITIONAL INFORMATION 

For appropriate chemotherapy regimens, dosage information, contraindications, precautions, warnings, and monitoring information, please refer to one of the standard reference compendia (e.g., the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) published by the National Comprehensive Cancer Network®, Drugdex Evaluations of Micromedex Solutions at Truven Health, or The American Hospital Formulary Service Drug Information).

SOURCES 

Eastern Cooperative Oncology Group. (2015, May) ECOG Performance Status. Retrieved May 1, 2015 from http://ecog-acrin.org/resources/ecog-performance-status.

Lexicomp Online. (2019, February). AHFS DI. Pembrolizumab. Retrieved March 8, 2019 from Lexicomp Online with AHFS.

MICROMEDEX Healthcare Series. Drugdex Evaluations. (2019, April). Pembrolizumab. Retrieved May 24, 2019.

National Comprehensive Cancer Network. (2019). NCCN Drugs & Biologics Compendium®. Pembrolizumab. Retrieved January 17, 2019 from the National Comprehensive Cancer Network.

U. S. Food and Drug Administration. (2019, April). Center for Drug Evaluation and Research. Keytruda^® (pembrolizumab) for injection, for intravenous use. Retrieved May 24, 2019 from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514Orig1s054lbl.pdf.

ORIGINAL EFFECTIVE DATE:  9/18/2014

MOST RECENT REVIEW DATE:  9/30/2019

ID_MRx

Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

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