Atezolizumab (Tecentriq®) is a monoclonal antibody which binds to programmed death-ligand 1 (PD-L1) expressed on tumor cells or tumor-infiltrating immune cells and blocks its interaction with Programmed Death Receptor 1 (PD-1) and B7.1 receptors present on T cells and antigen-presenting cells, which releases the inhibition of the immune response and activates the antitumor response.

Avelumab (Bavencio®) binds PD-L1, blocking interaction with receptors PD-1 and B7.1. This blockade results in a release of the inhibitory effects of PD-L1 on the immune response and the restoration of antitumor immune responses.

Cemiplimab-rwlc (Libtayo®) binds PD-1 blocking interaction with PD-L1 and PD-L2 releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

Durvalumab (Imfinzi™) binds PD-L1, blocking interaction with PD-1 and CD80 (B7.1). This blockade reduces cytotoxic T-cell activity, proliferation, and cytokine production and allows for immune responses without inducing antibody dependent cell-mediated cytotoxicity.

Nivolumab (Opdivo®) is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

Pembrolizumab (Keytruda®) is a monoclonal antibody that binds to the PD-1 receptor, blocking its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

Atezolizumab (Tecentriq) may be considered medically necessary for ANY of the following conditions: 

U.S. Food and Drug Administration (FDA) Indications

• Locally advanced or metastatic urothelial carcinoma who:
  • Are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area), as determined by an FDA-approved test; or
  • Are not eligible for any platinum-containing chemotherapy regardless of PD-L1status; or
  • Have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy; or
• First line treatment of individuals with metastatic non-squamous non-small cell lung cancer (NSCLC) with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations in combination with bevacizumab, paclitaxel and carboplatin; or
• Metastatic non-small cell lung cancer who have disease progression during or following platinum-containing chemotherapy. Individuals with EGFR or ALK genomic tumor aberrations should have disease progression on FDA approved therapy for these aberrations prior to receiving atezolizumab (Tecentriq).

National Comprehensive Cancer Network (NCCN) Indications

Bladder (Urothelial) Cancer

• Used as first-line systemic therapy as a single agent (preferred*) in cisplatin ineligible individuals whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression for:
  • Stage II (cT2, N0) disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent chemoradiotherapy; or
  • 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; or
  • Stage IIIB (cT1-T4a, N2,3) disease as downstaging systemic therapy; or
  • Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with concurrent chemoradiotherapy; or
  • Stage IVA (cT4b, any N, M0; any T, any N, M1a) disease; or
  • Stage IVB (any T, any N, M1b) disease; or
  • Metastatic or local recurrence post cystectomy; or
• Used as subsequent systemic therapy post-platinum as a single agent (alternative preferred*) for:
  • Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with down staging systemic therapy; or
  • Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy; or
  • Stage IVB (any T, any N, M1b) disease; or
  • Metastatic or local recurrence post cystectomy.

Bladder (Urothelial) Cancer - Primary Carcinoma of the Urethra:

• Treatment of individuals with primary carcinoma of the urethra:
  • As a single agent for primary treatment for clinical stage T3-4, cN1-2 disease or cN1-2 palpable inguinal lymph nodes as first-line systemic therapy (preferred*) in cisplatin ineligible individuals whose tumors express PD-L1 or who are not eligible for any platinum containing chemotherapy regardless of PD-L1 expression (Note: Chemotherapy regimen based on histology); or
  • As a single agent for recurrent or metastatic disease as:
    • First-line therapy (preferred*) in cisplatin ineligible individuals whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression; or
    • Subsequent systemic therapy post-platinum (alternative preferred*) (Note: Chemotherapy regimen based on histology); or

Bladder (Urothelial) Cancer - Upper Genitourinary (GU) Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with upper GU tract tumors or urothelial carcinoma of the prostate:
  • Used as a single agent for metastatic disease as:
    • First-line therapy (preferred*) in cisplatin ineligible individuals (preferred*) whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression; or
    • Subsequent systemic therapy post-platinum (alternative preferred regimen*).

Non-Small Cell Lung Cancer (NSCLC) – Adenocarcinoma (with mixed subtypes), Large Cell Carcinoma

• Treatment for recurrent, advanced, or metastatic disease in combination with carboplatin, paclitaxel, and bevacizumab for patients with performance status (PS) 0-1, no contraindications to the addition of pembrolizumab or atezolizumab, and tumors of nonsquamous cell histology as
  • Initial systemic therapy for EGFR, ALK, ROS1, BRAF negative or unknown, and PDL1 <50% or unknown; or
  • First-line or subsequent therapy for BRAF V600E-mutation positive tumors; or
  • Subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitinib, osimertinib, or dacomitinib therapy; or
  • Subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigatinib therapy; or
  • Subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib or ceritinib therapy; or
  • Subsequent therapy for PD-L1 expression-positive (≥50%) tumors and EGFR, ALK negative or unknown and no prior platinum-doublet chemotherapy; or
• Continuation maintenance therapy as a single agent or in combination with bevacizumab (if previously received first-line atezolizumab/carboplatin/paclitaxel/bevacizumab regimen) for recurrent or metastatic disease in individuals with performance status 0-2, tumors of nonsquamous cell histology, who achieve tumor response or stable disease following initial systemic therapy.

Non-Small Cell Lung Cancer (NSCLC) – Squamous Cell Carcinoma, Adenocarcinoma (with mixed subtypes), Large Cell Carcinoma

• Preferred single agent as subsequent therapy for recurrent, advanced or metastatic disease in individuals with PS 0-2 and no prior progression on a PD-1/PD-L1 inhibitor.

Small Cell Lung Cancer – Small Cell Carcinoma

• Preferred initial treatment in combination with etoposide and carboplatin for extensive stage disease in individuals:
  • Without localized symptomatic sites or brain metastases and good PS (0-2); or
  • Without localized symptomatic sites or brain metastases and poor PS (3-4) due to small cell lung cancer; or
  • With localized symptomatic sites; or
  • With brain metastases.

The use of atezolizumab (Tecentriq) is considered experimental/investigational and, therefore, non-covered for any other indication not listed above. Scientific evidence does not support the use for any other indication.

Avelumab (Bavencio) may be considered medically necessary for ANY of the following conditions:

FDA Indications

Bladder (Urothelial) Carcinoma

• Treatment of idividuals with locally advanced or metastatic urothelial carcinoma (UC) who have:
  • Disease progression during or following platinum-containing chemotherapy; or
  • Disease progression within twelve (12) months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Merkel Cell Carcinoma (MCC)

·         Treatment of adult and pediatric individuals twelve (12) years of age and older with metastatic MCC

NCCN Indications

Bladder (Urothelial) Carcinoma

• Treatment of individuals with bladder (urothelial) carcinoma:
  • As subsequent systemic therapy post-platinum as a single agent (alternative preferred*) for:
    • Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with down staging systemic therapy; or
    • Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy; or
    • Stage IVB (any T, any N, M1b) disease; or
    • Metastatic or local recurrence post cystectomy.

Bladder Cancer - Upper GU Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with upper GU tract tumors or urothelial carcinoma of the prostate:
  • As single agent subsequent systemic therapy post-platinum (alternative preferred regimen*) (Note: Chemotherapy regimen based on histology).

Bladder Cancer – Primary Carcinoma of the Urethra

·         Treatment of individuals with primary carcinoma of the urethra as a single agent for recurrent or metastatic disease as subsequent systemic therapy post-platinum (alternative preferred regimen*) (Note: Chemotherapy regimen based on histology).

MCC

• Treatment for disseminated, clinical M1 disease with or without surgery and/or radiation therapy.

The use of avelumab (Bavencio) is considered experimental/investigational and, therefore, non-covered for any other indication. Scientific evidence does not support the use for any other indication.

Cemiplimab (Libtayo) may be considered medically necessary for ANY of the following conditions:

• Treatment of individuals with metastatic cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation; or
• Treatment of individuals with locally advanced CSCC who are not candidates for curative surgery or curative radiation.

The use of cemiplimab (Libtayo) is considered experimental/investigational and, therefore, non-covered for any other indication. Scientific evidence does not support the use for any other indication.

Durvalumab (Imfinzi) may be considered medically necessary for ANY of the following conditions:

FDA Indications

Bladder (Urothelial) Carcinoma

• Treatment of individuals with bladder (urothelial) carcinoma:
  • With locally advanced or metastatic urothelial carcinoma who:
    • Have disease progression during or following platinum-containing chemotherapy; or
    • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

NSCLC

·         Unresectable, Stage III disease which has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

NCCN Indications

Bladder (Urothelial) Carcinoma

• Used as subsequent systemic therapy post-platinum as a single agent (alternative preferred) for:
  • Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with down staging 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) disease
  • Metastatic or local recurrence post cystectomy

Bladder (Urothelial) Cancer -  Upper GU Tract Tumors or Urothelial Carcinoma of the Prostate

• Therapy for metastatic disease as a single agent subsequent systemic therapy post-platinum (alternative preferred*).

Bladder (Urothelial) Cancer - Primary Carcinoma of the Urethra

·           Single agent for recurrent or metastatic disease as subsequent systemic therapy post-platinum (alternative preferred*) (Note: Chemotherapy regimen based on histology).

NSCLC – Adenocarcinoma (with mixed subtypes), Squamous Cell Carcinoma, Large Cell Carcinoma

• Treatment of individuals with NSCLC:
  • As consolidation therapy for individuals with unresectable stage III disease, PS 0-1; and
  • No disease progression after two (2) or more cycles of definitive chemoradiation.

The use of durvalumab (Imfinzi) is considered experimental/investigational and, therefore, non-covered for any other indication not listed above. Scientific evidence does not support the use for any other indication.

Nivoluma (Opdivo) may be considered medically necessary for ANY of the following conditions:

FDA Indications

Melanoma

• Treatment of individuals with:
  • BRAF V600 wild-type unresectable or metastatic melanoma, as a single agent; or
  • BRAF V600 mutation positive unresectable or metastatic melanoma, as a single agent; or
  • Unresectable or metastatic melanoma, in combination with ipilimumab; or
  • Lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting.

NSCLC

• Treatment of individuals with: 
  • Metastatic NSCLC and progression on or after platinum-based chemotherapy. Individuals with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab (Opdivo); or
  • Metastatic small cell lung cancer with progression after platinum based chemotherapy and at least one other line of therapy.

Renal Cell Carcinoma

• Treatment of individuals with:
  • Advanced renal cell carcinoma who have received prior anti-angiogenic therapy; or
  • Intermediate or poor risk, previously untreated advanced renal cell carcinoma, in combination with ipilimumab.

Hodgkin Lymphoma

• Treatment of adult individuals with classical Hodgkin lymphoma that has relapsed or progressed after:
  • Autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vendotin; or
  • Three (3) or more lines of systemic therapy that includes autologous HSCT.

Head and Neck Cancer

• Treatment of individuals with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy.

Urothelial Carcinoma

• Treatment of individuals with locally advanced or metastatic urothelial carcinoma with:
  • Disease progression during or following platinum-containing chemotherapy; or
  • Disease progression within twelve (12) months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Colorectal Cancer

·         Treatment of adult and pediatric individuals twelve (12) years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic disease that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as a single agent or in combination with ipilimumab.

Hepatocellular Carcinoma (HCC)

• Treatment of individuals with HCC who have been previously treated with sorafenib.
  

NCCN Indications

Anal Carcinoma – Squamous Cell

• Treatment of individuals with anal carcinoma as single agent second-line therapy for metastatic disease

Bladder (Urothelial) Carcinoma

• Used as subsequent systemic therapy post-platinum as a single agent (alternative preferred*) for:
  • Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy; or
  • Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy; or
  • Stage IVB (any T, any N, M1b) disease; or
  • Metastatic or local recurrence post cystectomy.

Bladder (Urothelial) Carcinoma - Upper GU Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with primary carcinoma of the urethra, upper GU tract tumors or urothelial carcinoma of the prostate:
  • As single agent subsequent systemic therapy for metastatic disease post-platinum (alternative preferred*). 

Bladder (Urothelial) Cancer - Primary Carcinoma of the Urethra

• Single agent for recurrent or metastatic disease as subsequent systemic therapy post-platinum (alternative preferred*) (Note: Chemotherapy regimen based on histology).

Central nervous System Cancers - Brain Metastases – Limited or Extensive

• Treatment of individuals with melanoma with limited brain metastases in combination with ipilimumab:
  • For newly diagnosed brain metastases in select patients (eg, patients with small asymptomatic brain metastases) with newly diagnosed or stable systemic disease or reasonable systemic treatment options; or
  • For recurrent brain metastases; or
• Treatment of individuals with extensive brain metastases:
  • In combination with ipilimumab as treatment for recurrent brain metastases in individuals with melanoma and stable systemic disease or reasonable systemic treatment options.

Chronic Lymphocystic 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) in patients with del(17p)/TP53 mutation or who are chemotherapy refractory and unable to receive chemoimmunotherapy

Classical Hodgkin Lymphoma (cHL)

• Single agent treatment of adult individuals (greater than or equal to18 years of age) with cHL that has relapsed or progressed after:
  • Autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin; or
  • Three (3) or more lines of systemic therapy that includes autologous HSCT; or
• Palliative therapy as a single agent for relapsed or refractory disease in older adults (greater than 60 years of age) following:
  • Autologous HSCT and bretuximab vedotin; or
  • Three or more lines of systemic therapy that includes autologous HSCT.

Colon and Rectal Cancer - Adenocarcinoma

• Treatment of individuals with colon or rectal cancer:
  • As primary treatment as a single agent or in combination with ipilimumab for unresectable metachronous metastases (defective mismatch repair/high microsatellite instability [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or
  • As initial therapy as a single agent or in combination with ipilimumab for individuals with unresectable advanced or metastatic disease (dMMR/MSI-H only) who are not appropriate for intensive therapy; or
  • As subsequent therapy as a single agent (if nivolumab or pembrolizumab not previously given) or in combination with ipilimumab (if no previous treatment with a checkpoint inhibitor) for unresectable advanced or metastatic disease (dMMR/MSI-H only) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy.

Gestational Trophoblastic Neoplasia

• Single-agent therapy for:
  • 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.

Head and Neck Cancers – Squamous Cell Carcinoma with Mixed Subtypes

• Treatment of individuals with head and neck cancers (very advanced and recurrent/persistent):
  • As single agent second-line or subsequent therapy for non-nasopharyngeal cancer if disease progression on or after platinum-containing chemotherapy in:
    • Newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases, or  who are unfit for surgery and PS 3; or
    • Metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable loco regional recurrence or second primary with prior radiation therapy (RT) and PS 0-2; or
    • Unresectable loco regional recurrence without prior RT and PS 3.

HCC - Adenocarcinoma    

• Subsequent treatment as a single agent for progressive HCC:
  • In individuals who are Child-Pugh Class A or B7 only; and
    • Are non-transplant candidates with unresectable disease; or
    • Are inoperable by performance status or comorbidity, or have local disease or local disease with minimal extrahepatic disease only; or
    • Have extensive liver tumor burden; or
    • Metastatic disease.

Kidney (Renal) Cell Carcinoma (RCC) – Clear Cell or Non-Clear Cell

• Treatment of individuals with renal cancer:
  • As single-agent therapy for relapse or stage IV disease
    • As preferred subsequent therapy for predominant clear cell histology; or
    • As systemic therapy for non-clear cell histology; or
  • In combination with ipilimumab for four (4) cycles followed by single-agent nivolumab (Opdivo) the treatment of individuals with relapse or stage IV disease:
    • As first-line therapy for clear cell histology and favorable risk; or
    • As preferred first-line therapy for clear cell histology and poor/intermediate risk; or
    • As preferred subsequent therapy for clear cell histology.

Malignant Pleural Mesothelioma

• Treatment for individuals with malignant pleural mesothelioma as subsequent systemic therapy as a single agent or in combination with ipilimumab.

Melanoma - Cutaneous Melanoma

• Treatment of individuals with cutaneous melanoma:
  • As adjuvant therapy as a single agent:
    • For stage III sentinel node positive disease following active nodal basin ultrasound surveillance or after complete lymph node dissection (CLND); or
    • For stage III disease with clinically positive node(s) following wide excision of primary tumor and a complete therapeutic lymph node dissection; or
    • For stage III disease with clinical or microscopic satellite/in-transit metastases if no evidence of disease post-surgery; or
    • For local satellite/in-transit recurrence if no evidence of disease post-surgery; or
    • Following CLND and/or complete resection of nodal recurrence; or
    • Following complete resection of distant metastatic disease; or
  • As First-line therapy as a single agent or in combination with ipilimumab for unresectable or metastatic cutaneous melanoma; or
  • Second-line or subsequent therapy for metastatic or unresectable disease after disease progression or maximum clinical benefit from BRAF targeted therapy:
    • As a single agent or in combination with ipilmumab if checkpoint inhibitor immunotherapy was not previously used; or
    • In combination with ipilimumab for patients who progress on single-agent checkpoint inhibitor immunotherapy
    • May be considered as re-induction therapy (as a single agent or in combination with ipilimumb) if prior anti-PD-1 therapy (either alone or in combination with ipilimumab) resulted in disease control (complete response, partial response, or stable disease) and no residual toxicity, and disease progression/relapse occurred greater than three (3) months after treatment discontinuation.

MCC

• Preferred treatment for disseminated, clinical M1 disease with or without surgery and/or radiation therapy.

NSCLC – Adenocarcinoma (with mixed subtypes), Squamous Cell Carcinoma, Large Cell Carcinoma

• Treatment of individuals with recurrent, advanced or metastatic NSCLC as preferred single agent as subsequent therapy in individuals with PS 0-2 and no prior progression on a PD-1/PD-L1 inhibitor; or
• Activity against tumor mutational burden (TMB) as a single agent or in combination with ipilimumab.

Small Cell Lung Cancer (SCLC)

• Treatment of individuals with SCLC:
  • Subsequent systemic therapy for PS 0-2 as a single agent or in combination with ipilimumab for:
    • Relapse within six (6) months following complete or partial response or stable disease with initial treatment; or
    • Primary progressive disease. 

T-Cell Lymphomas – Extranodal NK/T-Cell Lymphoma, Nasal Type

• Treatment for relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used.

Uveal Melanoma

• Treatment of individuals with metastatic or unresectable uveal melanoma as single agent therapy or in combination with ipilimumab

The use of nivolumab (Opdivo) is considered experimental/investigational and, therefore, non-covered for any other indication not listed above. Scientific evidence does not support the use for any other indication.ific evidence does not support the use for any other indication.

Pembrolizumab (Keytruda) may be considered medically necessary for ANY of the following conditions:

FDA Indications

Melanoma

• Treatment of individuals with unresectable or metastatic disease.

NSCLC

• Treatment of individuals with metastatic NSCLC:
  • As first-line treatment in combination with pemetrexed and platinum chemotherapy for nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations; or
  • As first-line treatment in combination with carboplatin and either paclitaxel or nab-paclitaxel for metastatic squamous NSCLC; or
  • As first-line, single agent for tumors with high PD-L1 expression (Tumor Proportion Score (TPS) greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations; or
  • As a single agent for metastatic NSCLC for tumors with express PD-L1 (TPS greater than or equal to 1%) with disease progression on or after platinum-containing chemotherapy. Individuals with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberations prior to receiving pembrolizumab (Keytruda).

Head and Neck Squamous Cell Cancer – HNSCC

• Treatment of individuals with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

cHL

• Treatment of adult and pediatric individuals with:
  • Refractory cHL; or
  • Relapse after three (3) or more prior lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

• Treatment of adult and pediatric individuals with:
  • Refractory PMBCL; or
  • Relapse after two (2) or more prior lines of therapy

Limitation of Use: pembrolizumab (Keytruda) is not recommended for treatment of individuals with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

• Treatment of individuals with locally advance or metastatic Urothelial Carcinoma who:
  • Are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (combined Positive Score (CPS) greater than or equal to ten (10) as determined by an FDA-approved test; or
  • Are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status; or
  • Have disease progression during or following platinum-containing chemotherapy; or
  • Have disease progression with in twelve (12) months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

MSI-H Cancer

• Treatment of adult and pediatric individuals with unresectable or metastatic, MSI-H or mismatch repair deficient:
  • Solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options; or
  • Colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Limitation of use: The safety and effectiveness of pembrolizumab (Keytruda) in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

• Treatment of individuals with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma:
  • Whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test; and
  • With disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

Cervical Cancer

• Treatment of individuals with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS greater than or equal to one (1)) as determined by an FDA-approved test.

HCC

• Treatment of individuals with HCC who have been previously treated with sorafenib.

MCC

• Treatment of adult and pediatric individuals with recurrent locally advanced or metastatic MCC.

NCCN Indication

Anal Carcinoma – Squamous Cell Carcinoma

• Treatment of individuals with squamous cell anal carcinoma as second-line, single agent therapy for metastatic disease.

B-Cell Lymphomas – Diffuse Large B-Cell Lymphoma

• Treatment of individuals with relapsed or refractory primary mediastinal large B-cell lymphoma disease.

Bladder (Urothelial) Carcinoma

• Treatment of individuals with bladder (urothelial) carcinoma:
  • 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:
    • Stage II (cT2, N0) disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent chemoradiotherapy; or
    • 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; or
    • Stage IIIB (cT1-T4a, N2,3) disease as downstaging systemic therapy; or
    • Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with concurrent chemoradiotherapy; or
    • Stage IVA (cT4b, any N, M0; any T, any N, M1a) disease; or
    • Stage IVB (any T, any N, M1b) disease; or
    • Metastatic or local recurrence post cystectomy; or
  • As subsequent systemic therapy post-platinum as a single agent (preferred) for:
    • Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy; or
    • Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy; or
    • Stage IVB (any T, any N, M1b) disease; or
    • Metastatic or local recurrence post cystectomy.

Bladder (Urothelial) Cancer - Primary Carcinoma of the Urethra

• Treatment of individuals with primary carcinoma of the urethra:
  • Used as a single agent for recurrent or metastatic disease as:
    • First-line systemic therapy in cisplatin ineligible individuals whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression (preferred*); or
    • Subsequent systemic therapy post-platinum (alternative preferred*); or
  • Used as a single agent for primary treatment for clinical stage T3-4, cN1-2 disease or cN1-2 palpable inguinal lymph nodes as first-line systemic therapy in cisplatin ineligible individuals whose tumors express PD-L1 or who are not eligible for any platinum containing chemotherapy regardless of PD-L1 expression (preferred*).

Note: Chemotherapy regimen based on histology. 

Bladder Cancer - Upper GU Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with upper GU tract tumors or urothelial carcinoma of the prostate:
  • Used as a single agent for metastatic disease as:
  • First-line systemic therapy in cisplatin ineligible individuals whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression (preferred*); or
  • Subsequent systemic therapy post-platinum (alternative preferred*).

Central Nervous System Cancers - Limited Brain Metastases

• Single-agent treatment for brain metastases in individuals with melanoma or non-small cell lung cancer:
  • For newly diagnosed brain metastases in select patients (eg, patients with small asymptomatic brain metastases) with newly diagnosed or stable systemic disease or reasonable systemic treatment options; or
  • For recurrent brain metastases

Central Nervous System Cancers - Extensive Brain Metastases

• Single-agent treatment for recurrent brain metastases in patients with melanoma or non-small cell lung cancer and stable systemic disease or reasonable systemic treatment options.

Cervical Cancer – Squamous cell carcinoma, Aenocarcinoma

• Preferred second-line therapy as a single agent for recurrent or metastatic disease if:
  • MSI-H or dMMR tumors; or
  • Disease progression on or after chemotherapy in individuals whose tumors express PDL1 (CPS ≥1) as determined by an FDA-approved test.

cHL

• Treatment of Adult individuals aged 18 years and older as subsequent systemic therapy as a single agent for refractory diseas or for those who have relapsed after three (3) or more prior lines of therapy; or
• Treatment of individuals greater than 60 years of age as palliative therapy as a single agent for refractory disease or for individiuals who have relapsed after three (3) or more prior lines of therapy.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• 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

Esophageal and Esophagogastric Junction Cancers – Squamous Cell Carcinoma, Adenocarcinoma and Gastric Cancer - Adenocarcinoma

• Treatment of individuals as palliative therapy in non-surgical candidates or unresectable locally advance, recurrent, or metastatic disease and Karnofsky performance score greater than or equal to 60% or Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to two (2) as:
  • Preferred second-line or subsequent therapy as a single agent for MSI-H or dMMR tumors; or
  • Third – line or subsequent therapy as a single agent for PD-L1 positive disease.

Gestational Trophoblastic Neoplasia

• Single-agent therapy for:
  • 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

Hepatobiliary Cancer – Hepatocellular Carcinoma - Adenocarcinoma

• Subsequent treatment as a single agent for progressive disease in individuals (Child-Pugh Class A only) who:
  • Have unresectable disease and are not a transplant candidate; or
  • Are inoperable by performance status or comorbidity, or have local disease or local disease with minimal extrahepatic disease only; or
  • Have metastatic disease or extensive liver tumor burden.

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

MSI-H central nervous system cancers in pediatric individuals is considered experimental/investigational and, therefore, non-covered. The safety and effectiveness of pembrolizumab (Keytruda) in pediatric individuals with MSI-H central nervous system cancers have not been established.

• Treatment of individuals with ANY of the following MSHI-H/dMMR Cancers:
  • As a single agent for resected gross residual disease (R2):
    • Gallbladder Cancer – Adenocarcinoma; or
    • Intrahepatic Cholangiocarcinoma – Adenocarcinoma; or
    • Extrahepatic Cholangiocarcinoma – Adenocarcinoma; or
  • As single agent, primary therapy for unresectable or metastatic:
    • Gallbladder Adenocarcinoma; or
    • Intrahepatic Cholangiocarcinoma – Adenocarcinoma; or
    • Extrahepatic Cholangiocarcinoma – Adenocarcinoma; or
  • As single agent therapy for unresectable or metastatic disease with progression following prior treatment and have no satisfactory alternative treatment options for:
    • Ewing Sarcoma – mesenchymal chondrosarcoma; or
    • Osteosarcoma – dedifferentiated chondrosarcoma, High-Grade undifferentiated pleomorphic sarcoma (UPS); or
    • Penile Cancer; or
  • Treatment of individuals with recurrent, metastatic or high-risk tumors that had progression following prior cytotoxic chemotherapy for:
    • Endometrial Carcinoma; or
  • As single agent subsequent therapy for progression after at least one line of systemic therapy for castration-resistant distant metastatic (M1) disease, if pembrolizumab (Keytruda) not previously received for:
    • Prostate Cancer – Adenocarcinoma; or
      
  • As single agent subsequent or third line therapy for:
    • Testicular Pure Seminoma, Nonseminoma cancer; or
  • As single agent therapy for recurrent or persistent:
    • Ovarian Cancer/Fallopian Tube/Primary Peritoneal Cancer –Carcinosarcoma, Endometroid Clear Cell, Mucinous, Serous; or
  • As single agent, initial therapy for unresectable, advanced or metastatic disease for individuals who are not appropriate for intensive therapy for:
    • Rectal Adenocarcinoma; or
    • Colon Adenocarcinoma; or
  • As single agent therapy for unresectable metachronous metastases with previous FOLFOX or CapeOx with in the last twelve (12) months for:
    • Rectal Adenocarcinoma; or
  • As single agent, subsequent therapy for unresectable, advanced or metastatic disease following oxaliplatin- irinotecan- and/or fluoropyrimidine based therapy for:
    • Colon Adenocarcinoma; or
    • Rectal Adenocarcinoma; or
  • As single agent, primary therapy for unresectable disease with previous FOLFOX or CapeOx within the last twelve (12) months for:
    • Colon Adenocarcinoma; or
  • Consider for the management of unresectable metastatic adrenocortical tumors that have progressed following prior treatment with no satisfactory alternative treatment options.

Head and Neck Cancer – Very Advanced – Squamous Cell Carcinoma with Mixed Subtypes

• Therapy as single agent second line or subsequent therapy for non-nasopharyngeal cancer if disease progression on or after platinum-containing chemotherapy or for previously treated PD-L1 positive recurrent or metastatic nasopharyngeal cancer in:
  • Newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases or for individulas who are unfit for surgery and PS 3; or
  • 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; or
  • Unresectable locoregional recurrence without prior RT and PS 3.

Melanoma – Cutaneous Melanoma

• Adjuvant treatment as a single agent
  • For stage III SLN positive disease during active nodal basin ultrasound surveillance or after CLND; or
  • For stage III disease with clinically positive node(s) following wide excision of primary tumor and a complete therapeutic lymph node dissection; or
  • For stage III disease with clinical or microscopic satellite/in-transit metastases if no evidence of disease post-surgery; or
  • For local satellite/in-transit recurrence if no evidence of disease post surgery; or
  • Following CLND and/or complete resection of nodal recurrence; or
  • Following complete resection of distant metastatic disease; or
• First-line Single-agent therapy for metastatic or unresectable disease; or
• 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:
  • If anti-PD-1 checkpoint inhibitor immunotherapy was not previously used; or
  • 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 greater than three (3) months after treatment discontinuation; or

MCC

• Preferred treatment of individuals with disseminated, clinical M1 disease with or without surgery and/or radiation therapy.

Non-Hodgkin Lymphoma (NHL) – T-Cell Lymphomas

Mycosis Fungoides (MF)/Sezary Syndrome (SS)

• Treatment of individuals with MF/SS as:
  • Primary systemic therapy for:
    • Stage III MF; or
    • Stage IV Sezary syndrome; or
  • Systemic therapy as treatment for:
    • Relapsed or persistent stage IAMF with B1 blood involvement, with or without skin-directed therapy; or
    • Relapsed or persistent stage IB-IIA MF with B1 blood involvement, with or without skin-directed therapy; or
    • Stage IIB MF with limited tumor lesions refractory to multiple previous therapies, with or without skin-directed therapies; or
    • Relapsed or refractory stage IIB MF with generalized tumor lesions, with or without skin-directed therapies; or
    • Stage IIB MF with generalized tumor lesions that is refractory tomultiple previous therapies or progression; or
    • Stage III MF that is refractory to multiple previous therapies; or
    • Relapsed or persistent stage IV S; or
    • Relapsed or persistent stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control; or
    • Large cell transformation (LCT) with limited cutaneous lesions that is refractory to multiple previous therapies; or
    • Relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy.

Primary Cutaneous CD30+ T-Cell Lymphproliferative 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.

Extranodal Natural Killer T-Cell (NK/T-cell) Lymphoma, Nasal Type

• For treatment of relapsed/refractory disease following:
  • Additional therapy with clinical trial; or
  • Combination chemotherapy regimen (asparaginase-based) not previously used; or
  • Best supportive care.

NSCLC

• Treatment for recurrent, advanced or metastatic disease as first-line therapy for PD-L1 expression-positive (≥50%) tumors that are EGFR, ALK negative or unknown and no contraindications to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) and performance status 0-2:
  • As a single agent (preferred); or
  • In combination with pemetrexed and either carboplatin or cisplatin for nonsquamous cell histology; or
  • In combination with either carboplatin or cisplatin and either paclitaxel or albumin-bound paclitaxel for squamous cell histology;
• Continuation maintenance therapy for recurrent, advanced or metastatic disease for PD-L1 expression positive (≥50%) tumors that are EGFR, ALK negative or unknown and no contraindications to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) and performance status 0-2, who achieve tumor response or stable disease following systemic or first-line therapy:
  • As a single agent if pembrolizumab (Keytruda) monotherapy given first-line for nonsquamous cell histology; or
  • 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 (Keytruda) was given as monotherapy or as part of a pembrolizumab/(cisplatin or carboplatin)/(paclitaxel or albumin-bound paclitaxel) regimen for squamous cell histology
• Treatment for recurrent or metastatic disease in combination with pemetrexed and either carboplatin or cisplatin (as preferred regimens if no contraindications to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) 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 (Keytruda) or atezolizumab (Tecentriq) for squamous cell histology), or in combination with cisplatin and either paclitaxel or albumin-bound paclitaxel (if no contraindications to the addition of pembrolizumab (Keytruda) for squamous cell histology)  for individuals with performance status 0-1 as:
  • Initial systemic therapy for EGFR, ALK, ROS1, BRAF negative or unknown, and PDL1 <50% or unknown
  • First-line or subsequent therapy for BRAF V600E-mutation positive tumors; or
  • Subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitinib, osimertinib, or dacomitinib therapy; or
  • Subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib or brigatinib therapy; or
  • Subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib or ceritinib therapy; or
  • Subsequent therapy for PD-L1 expression-positive (greater than or equal to 50%) tumors and EGFR, ALK negative or unknown and no prior platinum-doublet chemotherapy; or
• Preferred single agent as subsequent therapy for recurrent, advanced, or metastatic disease in individuals with PS 0-2 and tumors with PD-L1 expression levels greater than or equal to 1% and no prior progression on a PD-1/PD-L1 inhibitor:
• 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 and tumors of nonsquamous cell histology, in patients with PS 0-2, who achieve tumor response or stable disease following initial cytotoxic therapy; or
• 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 and tumors of squamous cell histology, in individuals with PS 0-2 who achieve tumor response or stable disease following initial systemic therapy.

Malignant Pleural Mesothelioma – Epithelial, Sarcomatoid, Mixed

• Treatment for individuals with malignant pleural mesothelioma as:
  • Subsequent systemic therapy as a single agent.

Pancreatic Adenocarcinoma

• Treatment of individuals with MSI-H/dMMR tumors with good performance status:
  • As second-line therapy as a single agent for locally advanced or metastatic disease and disease progression; or
  • Single agent for:
    • Local recurrence in the pancreatic operative bed after resection; or
    • Metastatic disease with or without local recurrence if greater than or equal to six (6) months from completion of primary therapy; or
    • Metastatic disease with or without local recurrence if less than six (6) months from completion of primary therapy.

Small Cell Lung Cancer – Small Cell Carcinoma

• Subsequent systemic therapy for individuals with PS 0-2 as a single agent for:
  • Relapse within 6 months following complete or partial response or stable disease with initial treatment; or
  • Primary progressive disease.

Soft Tissue Sarcoma

• Single-agent therapy of Alveolar Soft Part Sarcoma; or
• Single agent for the treatment of metastatic undifferentiated pleomorphic sarcoma.

Uveal Melanoma

• Consider as single agent therapy for metastatic or unresectable disease.

Vulvar Cancer – Squamous Cell Carcinoma

• Second-line therapy as a single agent (useful under certain circumstances) for advanced, recurrent or metastatic disease if:
  • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors; or
  • Disease progression on or after chemotherapy in individuals whose tumors express PD-L1 (Combined Positive Score ≥1) as determined by an FDA-approved test.

The use of pembrolizumab (Keytruda) is considered experimental/investigational and, therefore, non-covered for any other indication. Scientific evidence does not support the use for any other indication.

NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Highmark may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits. 

* Note: Language derived from National Comprehensive Cancer Network (NCCN) guidelines.