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

  • Bone Cancer

  • Bladder Cancer/Urothelial Carcinoma

  • Central Nervous System Cancers

  • Cervical cancer

  • Diffuse Large B-Cell Lymphoma

  • Esophageal Cancer

  • 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

  • Vulvar Cancer

• 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 or subsequent 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***

        • 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 PD-L1 positive non-small cell lung cancer (NSCLC) in individuals with ANY ONE of the following:

      • • Recurrent disease with limited brain metastases

        • Newly-diagnosed-limited or recurrent-extensive brain metastases in stable disease or reasonable systemic treatment options

    • 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

    • Esophageal Cancer if ALL of the following:

    • • Used as a single agent

      • Diagnosis of recurrent, locally-advanced, or metastatic disease

      • Disease histology is squamous cell (SCC, squamous cell carcinoma)

      • Tumor expresses PD-L1 (CPS ≥ 10) as determined by an FDA-approved test***

      • Disease progression on or after at least one prior systemic treatment

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

    • 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

      • Individual 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 used for ANY ONE of the following:

    • • Retreatment of disease as re-induction or subsequent to progression or maximum clinical benefit from BRAF-targeted therapy

      • Metastatic or unresectable disease

      • Adjuvant treatment

      • Uveal Melanoma with distant metastatic disease

    • 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

        • Small Bowel Adenocarcinoma used as initial therapy for advanced or metastatic disease in patients with prior oxaliplatin therapy in the adjuvant setting (or contraindication) or as subsequent therapy for advanced or metastatic disease

        • 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, poorly differentiated high - grade neuroendocrine tumors [NET], 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 Mycosis Fungoides (MF) or Stage IV Sézary Syndrome (SS)

      • Systemic therapy for relapsed, refractory or persistent disease that is ANY ONE of the following:

      • • Stage IA MF with B1 blood involvement

        • Stage IB-IIA MF with B1 blood involvement

        • Stage IIB MF with limited tumor lesions refractory to multiple previous therapies

        • Stage IIB MF with generalized tumor lesions

        • Stage IIB MF with generalized tumor lesions refractory to multiple previous therapies or progression

        • Stage III MF

        • Stage III MF refractory to multiple previous therapies

        • Stage IV Sézary syndrome

        • Stage IV non-Sézary or visceral disease (solid organ)

        • Large cell transformation (LCT) with limited cutaneous lesions refractory to multiple previous therapies

        • Relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions

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

    • • Tumor has high PD-L1 expression [(Tumor Proportion Score (TPS) ≥1%)] as determined by an FDA-approved test*** if ANY ONE of the following:

      • • Used for recurrent (excluding locoregional recurrence or symptomatic local disease without evidence of disseminated disease), advanced, or metastatic disease and PS ≤ 2 used as ANY ONE of the following:

        • • Subsequent therapy, as a single agent, in patients with no prior progression on a PD-1/PD-L1 inhibitor therapy

          • Individual has tumors that are EGFR, ALK negative or unknown and have achieved tumor response or stable disease following initial therapy if used ANY ONE of the following:

          • • Continuation maintenance therapy if ANY ONE of the following:

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

              • As a single agent if pembrolizumab was given first-line or following cytotoxic therapy as a single agent for disease of squamous or non-squamous cell histology

            • Initial therapy if ANY ONE of the following:

            • • In combination with pemetrexed AND either carboplatin or cisplatin for nonsquamous cell histology

              • In combination with carboplatin or cisplatin AND either paclitaxel or albumin-bound paclitaxel for squamous cell histology

              • As single agent therapy

      • Used for recurrent (excluding locoregional recurrence or symptomatic local disease without evidence of disseminated disease), advanced, or metastatic disease if ANY ONE of the following:

      • • Used as continuation maintenance in patients with a PS ≤ 2 who have achieved tumor response or stable disease following initial systemic therapy if ANY ONE of the following

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

          • Used as a single agent if given first-line with carboplatin or cisplatin and paclitaxel/nab-paclitaxel for squamous cell histology

        • Used as systemic therapy in patients with PS ≤ 1 for ANY ONE of the following:

        • • With either carboplatin or cisplatin in combination with pemetrexed for nonsquamous cell histology OR in combination with paclitaxel/nab-paclitaxel for squamous cell histology as ANY ONE of the following:

          • • First-line therapy for genomic tumor aberration (e.g., EGFR, ALK, ROS1 and BRAF) negative or unknown**, and PD-L1 expression <1% or unknown

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

            • Subsequent therapy for genomic tumor aberration (e.g., EGFR, ALK, and ROS1) positive and prior targeted therapy§ or BRAF V600E mutation positive disease

            • Subsequent therapy for PD-L1 expression-positive (≥1%)*** tumors and EGFR, ALK negative or unknown and no prior platinum-doublet chemotherapy

      • Used as single-agent initial therapy in patients with stage III disease who aren’t 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

    • Renal Cell Carcinoma (Kidney Cancer) diagnosed as advanced, relapsed or metastatic disease if used in combination with axitinib as ANY ONE of the following:

    • • First-line treatment

      • Subsequent therapy for clear cell histology

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

    • • Disease is unresectable, recurrent, or metastatic

      • Used as ANY ONE of the following:

      • • First-line therapy as ANY ONE of the following:

        • • Single-agent for tumors expressing PD-L1 [(TPS ≥1%)] as determined by an FDA-approved test***

          • In combination with fluorouracil and a platinum chemotherapy agent

        • Subsequent therapy as single-agent therapy for disease that has progressed on or after platinum-containing chemotherapy or in combination with fluorouracil and a platinum chemotherapy agent for non-nasopharyngeal disease

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

    • • Used as subsequent single-agent therapy

      • 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 regimen, if not previously used and if a clinical trial is unavailable

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

    • • Unresectable disease following first-line chemotherapy for ANY ONE of the following:

      • • Potentially resectable locally advanced disease

        • Solitary metastasis

        • Ipsilateral pleural metastasis

      • Extra-thoracic 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.

***As confirmed using an immunotherapy assay http://www.fda.gov/companiondiagnostics 

RENEWAL CRITERIA

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

• • Individual continues to meet initial approval criteria

  • Disease response with treatment as defined by stabilization of disease or decrease in size of

  • tumor or tumor spread

  • 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

    • Esophageal Cancer

    • Hepatocellular Carcinoma (HCC)

    • 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) (Continuation maintenance therapy must meet initial criteria)

    • Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

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

    • Squamous Cell Lung Cancer (SCLC)

    • 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) as ANY ONE of the following:

  • •  Used for re-induction in individuals who experienced disease control (i.e., complete response, partial response, or stable disease with no residual toxicity) from prior checkpoint inhibitor therapy, but subsequently have disease progression/relapse > 3 months after treatment discontinuation

    • Used as subsequent therapy in individuals who experienced disease progression, as a single agent if a checkpoint-inhibitor was not previously used

  • Non-small cell lung cancer (NSCLC) for continuation maintenance therapy must meet initial criteria

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, Thymic, Esophageal& 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, June). AHFS DI. Pembrolizumab. Retrieved July 10, 2019 from Lexicomp Online with AHFS.

MICROMEDEX Healthcare Series. Drugdex Evaluations. (2019, June). Pembrolizumab. Retrieved July 10, 2019.

National Comprehensive Cancer Network. (2019). NCCN Drugs & Biologics Compendium®. Pembrolizumab. Retrieved July 10, 2019 from the National Comprehensive Cancer Network.

U. S. Food and Drug Administration. (2019, July). Center for Drug Evaluation and Research. Keytruda^® (pembrolizumab) for injection, for intravenous use. Retrieved August 12, 2019 from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s055s056lbl.pdf. 

ORIGINAL EFFECTIVE DATE:  9/18/2014

MOST RECENT REVIEW DATE:   12/31/2019

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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