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.

Dostarlimab-gxly (Jemperli®) is a programmed death receptor-1 (PD-1)–blocking antibody. 

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.

Nivolumab and relatlimab-rmbw (Opdualag™) is immune checkpoint inhibitor combination treatment comprised of  PD-1 inhibitor nivolumab and lymphocyte activation gene -3 (LAG-3)-blocking antibody relatilimab. This combination improves anti-tumor response by targeting two different immune checkpoints-LAG-3 and PD-1. 

Retifanlimab-dlwr (Zynyz™) is a humanized monoclonal antibody targeting PD-1 receptor on T cells inhibiting T-cell proliferation and cytokine production. 

Tislelizumab-jsgr (Tevimbra®) 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.

Toripalimab-tpzi (Loqtorzi™) is a humanized IgG4 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.

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

Alveolar Soft Part Sarcoma (ASPS)

·       Treatment of adult and pediatric individuals 2 years of age and older with unresectable or metastatic ASPS; or

Hepatocellular Carcinoma, HCC

• In combination with bevacizumab for the treatment of individuals 18 years of age and older with unresectable or metastatic HCC who have not received prior systemic therapy; or

Lung Cancer, Metastatic, Non-Small Cell Lung Cancer, NSCLC 

• As adjuvant treatment following resection and platinum-based chemotherapy for individuals 18 years of age and older with Stage II to IIIA NSCLC whose tumors have PD-L1 expression greater than or equal to 1% of tumor cells; or
• First -line treatment of individuals 18 years of age and older with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained greater than or equal to 50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells [IC] covering greater than or equal to 10% of the tumor area), with no EGFR or ALK genomic tumor aberrations; or
• In combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment of individuals 18 years of age and older with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations; or
• In combination with paclitaxel protein-bound and carboplatin for the first-line treatment of individuals 18 years of age and older with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations; or
• Treatment of individuals 18 years of age and older with metastatic NSCLC 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 NSCLC harboring these aberrations prior to receiving atezolizumab (Tecentriq); or

Lung Cancer, Small Cell Carcinoma 

• In combination with carboplatin and etoposide, for the first-line treatment of individuals 18 years of age and older with extensive-stage small cell lung cancer (ES-SCLC); or

Melanoma 

• In combination with cobimetinib and vemurafenib for the treatment of individuals 18 years of age and older with BRAF V600 mutation-positive unresectable or metastatic melanoma; or

The use of atezolizumab (Tecentriq) not meeting the criteria as indicated in this policy is considered not medically necessary. 

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

Bladder (Urothelial) Carcinoma, Locally Advanced or Metastatic

• Maintenance treatment of individuals who have not progressed with first-line platinum-containing chemotherapy; or
• Treatment of individuals with disease progression during or following platinum-containing chemotherapy; or
• Treatment of individuals with disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; or

Kidney (Renal) Cell Carcinoma

• In combination with axitinib for the first-line treatment of individuals with advanced renal cell carcinoma (RCC); or

 Merkel Cell Carcinoma, MCC

• Treatment of adult and pediatric individuals 12 years of age or older with metastatic MCC; or

The use of avelumab (Bavencio) not meeting the criteria as indicated in this policy is considered not medically necessary. 

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

Basal Cell Carcinoma (BCC)

• Treatment of individuals with locally advanced BCC (laBCC) previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate; or
• Treatment of individuals with metastatic BCC (mBCC) previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate; or

Non-Small Cell Lung Cancer (NSCLC)

• First-line treatment of individuals 18 years of age or older with NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥ 50%], with no EGFR, ALK or ROS1 aberrations, and is:
  • locally advanced where individuals are not candidates for surgical resection or definitive chemoradiation; or
  • metastatic; or
• In combination with platinum-based chemotherapy, for the first-line treatment of individuals 18 years of age or older with NSCLC with no EGFR, ALK or ROS1 aberrations and is:
  • locally advanced where individuals are not candidates for surgical resection or definitive chemoradiation; or
  • metastatic; or

Squamous Cell Carcinoma, Cutaneous, Locally Advanced or Metastatic 

• Treatment of individuals who are not candidates for curative surgery or curative radiation.

The use of cemiplimab (Libtayo) not meeting the criteria as indicated in this policy is considered not medically necessary. 

Dostarlimab-gxly (Jemperli) may be considered medically necessary for ANY of the following conditions:

Endometrial Cancer

• Individual is 18 years of age or older; and
• Individual is diagnosed with primary advanced or recurrent endometrial cancer that is mismatch repair deficient, as determined by an FDA-approved test, or microsatellite instability-high; and
• Used in combination with carboplatin and paclitaxel; or
• Used as a single agent for individuals who have disease progression on of following prior treatment with a platinum containing regimen and are not candidates for curative surgery or radiation; or

Mismatch Repair Deficient (dMMR)

• Treatment of individuals 18 years of age or older with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen in any setting and are not candidates for curative surgery or radiation; or
• Treatment of individuals 18 years of age or older with dMMR recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

The use of dostarlimab-gxly (Jemperli) not meeting the criteria as indicated in this policy is considered not medically necessary.

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

Lung Cancer, Non-Small Cell Lung Cancer, NSCLC 

• Treatment of individuals 18 years of age or older with unresectable, Stage III disease who have not progressed following concurrent platinum-based chemotherapy and radiation therapy; or
• In combination with tremelimumab- actl (Imjudo) and platinum-based chemotherapy, as treatment of individuals 18 years of age or older with metastatic NSCLC with no sensitizing EGFR or ALK genomic tumor aberrations; or

Lung Cancer, Small Cell 

• In combination with etoposide and either carboplatin or cisplatin, for the first-line treatment of individuals 18 years of age or older with extensive-stage small cell lung cancer; or

Biliary Tract Cancer

• In combination with gemcitabine and cisplatin, as treatment of individuals 18 years of age or older with locally advanced or metastatic biliary tract cancer; or

Hepatocellular Carcinoma (HCC)

• In combination with tremelimumab-actl (Imjudo), as treatment of individuals 18 years of age or older with unresectable HCC.

The use of durvalumab (Imfinzi) not meeting the criteria as indicated in this policy is considered not medically necessary. 

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

Colorectal Cancer 

• Treatment of individuals 12 years of age or 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; or

Esophageal Cancer

• Treatment of individuals with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy; or
• Treatment of individuals with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy; or
• Treatment of individuals with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy; or
• Treatment of individuals with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with ipilimumab; or

Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

• Treatment of individuals with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma in combination with fluoropyrimidine- and platinum-containing chemotherapy; or

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; or

 Hepatocellular Carcinoma, HCC 

• Treatment of individuals with HCC who have been previously treated with sorafenib, in combination with ipilimumab; or

Kidney (Renal) Cell Carcinoma 

• Treatment of individuals with intermediate or poor risk advanced renal cell carcinoma, as a first-line treatment in combination with ipilimumab; or
• Treatment of individuals with advanced renal cell carcinoma, as a first-line treatment in combination with cabozantinib; or
• Treatment of individuals with advanced renal cell carcinoma who have received prior anti-angiogenic therapy; or

Lung Cancer, Non-Small Cell Lung Cancer, NSCLC 

• Treatment of individuals 18 years of age or older with resectable (tumors greater than or equal to four (4) cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy; or
• Treatment of individuals 18 years of age or older with metastatic non-small cell lung cancer expressing PD-L1(greater than or equal to 1%), with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab; or
• Treatment of individual 18 years of age or older with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with ipilimumab and two (2) cycles of platinum-doublet chemotherapy; or
• 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

Lymphoma, Hodgkin Classic 

• Treatment of individuals 18 years of age or older 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; or

Melanoma 

• Treatment of individuals 12 years of age or older with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab; or
• Adjuvant treartment of individuals 12 years of age or older with completely resected stage IIB, IIC, III or IV melanoma; or

Mesothelioma, Malignant Pleural

• Treatment of individuals 18 years of age or older with unresectable malignant pleural mesothelioma, as first-line treatment in combination with ipilimumab; or

Urothelial Carcinoma

• Adjuvant treatment of individuals with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC; or
• In combination with cisplatin and gemcitabine for the first line treatment of unresectable or metastatic UC; or
• Individuals with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy; or
• Individuals with locally advanced or metastatic UC who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The use of nivolumab (Opdivo) not meeting the criteria as indicated in this policy is considered not medically necessary. 

Nivolumab and relatlimab-rmbw (Opdualag) may be considered medically necessary for ANY of the following conditions:

Melanoma

• Treatment of individuals 12 years of age or older with unresectable or metastatic melanoma.

The use of nivolumab and relatlimab-rmbw (Opdualag) not meeting the criteria as indicated in this policy is considered not medically necessary. 

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

Bladder (Urothelial) Carcinoma 

• In combination with enfortumab vedotin, for the treatment of individuals 18 years of age or older with locally advanced or metastatic urothelial carcinoma; or 
• Treatment of individuals with locally advance or metastatic Urothelial Carcinoma who:
  • Are not eligible for any platinum-containing chemotherapy; or
  • 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; or
• Treatment of individuals with Bacillus Calmette-Guerin (BCG) unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy; or

Biliary Tract Cancer (BTC)

• In combination with gemcitabine and cisplatin for the treatment of individuals 18 years of age or older with locally advanced unresectable or metastatic biliary tract cancer; or

Breast Cancer, Triple-Negative (TNBC)

• Treatment of individuals with high-risk early stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery; or
• In combination with chemotherapy, for the treatment of individuals with locally recurrent unresectable or metastatic TNBC whose tumor express PD-L1 (CPS greater than or equal to 10); or

Cervical Cancer 

• Incombination with chemoradiotherapy for the treatment with FIGO 2014 satge III-IVA cervical cancer; or
• In combination with chemotherapy, with or without bevacizumab, for the treatment of individuals with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 [Combined Positive Score (CPS) greater than or equal to one (1)]; or
• As a single agent for the 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)]; or

Cutaneous Squamous Cell Carcinoma (cSCC) 

• Treatment of individuals with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation; or

Endometrial Carcinoma 

• In combination with lenvatinib, for the treatment of individuals with advanced endometrial carcinoma and who:
  • Are not MSI-H or dMMR; and
  • Have disease progression following prior systemic therapy in any setting; and
  • Are not candidates for curative sugery or radiation; or
• As a single agent, for the treatment of individuals with advanced endometrial carcinoma and who:
  • Are MSI-H or dMMR; and
  • Have disease progression following prior systemic therapy in any setting; and
  • Are not candidates for curative surgery or radiation; or

Esophageal Cancer 

• Treatment of individuals with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
  • In combination with platinum- and fluoropyrimidine-based chemotherapy; or
  • As a single agent after one (1) or more prior lines of systemic therapy for individuals with tumors of squamous cell histology that express PD-L1 (CPS greater than or equal to 10); or

Gastric Cancer 

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

Head and Neck Squamous Cell Cancer, HNSCC 

• In combination with platinum and FU for first-line treatment of individuals with metastatic or unresectable, recurrent HNSCC; or
• As a single agent for the first line treatment of individuals with metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 (Combined Positive Score (CPS) greater than or equal to one(1); or
• As a single agent for the treatment of individuals with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy; or

Hepatocellular Carcinoma, HCC 

• Treatment of individuals with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1 containing regimen; or

Kidney (Renal) Cell Carcinoma, RCC 

• In combination with axitinib, for first-line treatment of adult individuals with advanced RCC; or
• In combination with Lenvatinib, for first-line treatment of adult individuals with advanced RCC; or
• Adjuvant treatment of individuals with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions; or

Lung Cancer, NSCLC 

• In combination with pemetrexed and platinum chemotherapy, as first-line treatment of individuals with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations; or
• In combination with carboplatin and either paclitaxel or nab-paclitaxel (paclitaxel protein-bound), as first-line treatment of individuals with metastatic squamous NSCLC; or
• As a single agent for the first-line treatment of individuals with NSCLC expressing PD-L1 (Tumor Proportion Score (TPS) greater than or equal to 1%), with no EGFR or ALK genomic tumor aberrations, and is:
  • Stage III in individuals who are not candidates for surgical resection or definitive chemoradiation; or
  • Metastatic; or
• As a single agent for the treatment of individuals with metastatic NSCLC whose tumors 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 aberrations prior to receiving pembrolizumab (Keytruda); or 
• As a single agent for adjuvant treatment following resection and platinum-based chemotherapy for individuals 18 years of age or older with stage Ib (T2a greater than or equal to 4cm), II, or IIIA NSCLC; or
• In combination with platinum chemotherapy as neoadjuvant treatment and then continued as a singe agent after surgery for the treatment of individuals with respectable (tumors greater than or equal to 4 cmor node positive) NSCLC; or

Lymphoma, Hodgkin, Classic, cHL 

• Treatment of individuals 18 years of age or older with relapsed or refractory cHL; or
• Treatment of pediatric individuals with refractory cHL, or cHL that has relapsed after two (2) or more prior lines of therapy; or

Lymphoma, Primary Mediastinal Large B-Cell (PMBCL)

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

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

Melanoma 

• Treatment of individuals with unresectable or metastatic disease; or
• Adjuvant treatment of individuals 12 years of age or older with Stage IIB, IIC, or III melanoma following complete resection; or

Merkel Cell Carcinoma, MCC 

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

Microsatellite Instability-High, MSI-H or Mismatch Repair Deficient Cancer 

• Treatment of adult and pediatric individuals with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options; or

• Treatment of individuals with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC); or

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

Tumor Mutational Burden-High (TMB-H) Cancer 

• Treatment of adult and pediatric individuals with unresectable or metastatic TMB-H [greater than or equal to 10 mutations/megabase (mut/Mb)] solid tumors, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

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

The use of pembrolizumab (Keytruda) not meeting the criteria as indicated in this policy is considered not medically necessary. 

Retifanlimab-dlwr (Zynyz) may be considered medically necessary for ANY of the following conditions:

Merkel Cell Carcinoma, MCC

·       Treatment of individuals 18 years of age or older with metastatic or recurrent locally advanced MCC.

The use of retifanlimab-dlwr (Zynyz) not meeting the criteria as indicated in this policy is considered not medically necessary. 

Tislelizumab-jsgr (Tevimbra) may be considered medically necessary for ANY of the following conditions:

Esophageal Squamous Cell Carcinoma, ESCC

• Treatment of individuals 18 years of age or older with unresectable or metastatic esophageal squamous cell carcinoma who have received prior treatment with systemic chemotherapy that did not include a PD-1 inhibitor

The use of tislelizumab-jsgr (Tevimbra) not meeting the criteria as indicated in this policy is considered not medically necessary.

Toripalimab-tpzi (Loqtorzi) may be considered medically necessary for ANY of the following conditions:

Nasopharyngeal Carcinoma, NPC

• Treatment in combination with cisplatin and gemcitabine in individuals 18 years of age or older with metastatic or recurrent locally advanced NPC; or
• Treatment of individuals 18 years of age or older with recurrent unresectable or metastatic NPC with disease progression on or after a platinum-containing chemotherapy.

The use of toripalimab-tpzi (Loqtorzi) not meeting the criteria as indicated in this policy is considered not medically necessary.

Compendia Sources

Atezolizumab (Tecentriq), avelumab (Bavencio), cemiplimab-rwlc (Libtayo), dostarlimab-gxly (Jemperli), durvalumab (Imfinzi), nivolumab (Opdivo), nivolumab and relatlimab-rmbw (Opdualag), pembrolizumab (Keytruda), retifanlimab-dlwr (Zynyz) toripalimab-tpzi (Loqtorzi) or tislelizumab-jsgr (Tevimbra) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

The use of PD-1/PD-L1 blocking antibodies not meeting the criteria as indicated in this policy is considered not medically necessary.

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.