Programmed Death Receptor (PD-1) / Programmed Death-Ligand (PD-L1) Blocking Antibodies

Programmed Death Receptor (PD-1)/ Programmed Death-Ligand (PD-L1) Blocking Antibodies

Policy ID: I-120-026

Section: Injections

Effective Date: January 01, 2019

Revised Date: January 06, 2021

Revision Effective Date: March 01, 2021

Last Reviewed: January 19, 2021

Description

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.

FDA--U.S. Food and Drug Administration

NCCN--National Comprehensive Cancer Network

NSCLC--Non-Small Cell Lung Cancer

Criteria

Coverage is subject to the specific terms of the member’s benefit plan.

Federal Employee Program members (FEP) should check with their Retail Pharmacy Program to determine if prior approval is required by calling the Retail Pharmacy Program at 1-800-624-5060 (TTY: 1-800-624-5077). FEP members can also obtain the list through the www.fepblue.org website.

Atezolizumab (Tecentriq) may be considered medically necessary foradult individuals 18 years of age and older for ANY of the following conditions:

Bladder (Urothelial) Cancer (NCCN)

Used as first-line systemic therapy as a single agent 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 two – three (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 two – three (2-3) months after primary treatment with concurrent chemoradiotherapy; or
- For non-cystectomy candidates with stage IIIA (cT3, N0; cT4a, N0; cT1-4a, N1) disease if tumor is present upon reassessment of tumor status 2-3 months after primary treatment; 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
- Muscle invasive local recurrence or persistent disease in a preserved bladder; or
- Metastatic or local recurrence post cystectomy; or
Used as second-line systemic therapy post-platinum as a single agent for:
- Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with down staging systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with first line systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (any T, any N, M1a) disease if stable disease or progression following reassessment of tumor status after primary treatment with first-line systemic therapy; or
- Stage IVB (any T, any N, M1b) disease; or
- Muscle invasive local recurrence or persistent disease in a preserved bladder; or
- Metastatic or local recurrence post cystectomy; or

Breast Cancer, Triple-Negative, TNBC (FDA)

Used in combination with paclitaxel protein-bound for the treatment of unresectable locally advanced or metastatic TNBC with tumors which express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA approved test; or

Breast Cancer, Invasive, Ductal/NST, Encapsulated or solid papillary carcinoma, Lobular, Metaplastic, Micropapillary, Mixed, Other rare forms, Pure Cribriform, Pure, Mucinous, Pure Tubular (NCCN)

Therapy in combination with albumin-bound paclitaxel for PD-L1 positive triple negative recurrent or stage IV (M1) disease; or

Hepatocellular Carcinoma, HCC (FDA)

Used in combination with bevacizumab for the treatment of individuals with unresectable or metastatic HCC who have not received prior systemic therapy; or

Hepatocellular Carcinoma, HCC (NCCN)

First-line treatment in combination with bevacizumab for 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; or

Lung Cancer, Metastatic, Non-Small Cell Lung Cancer, NSCLC (FDA)

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); or
First line treatment of individuals with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations in combination with bevacizumab, paclitaxel and carboplatin; or
For the first-line treatment of individuals 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), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations; or
In combination with paclitaxel protein-bound and carboplatin for the first-line treatment of individuals with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations; or

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

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; or
Continuation maintenance therapy for recurrent, advanced or metastatic disease for PD-L1 expression positive (greater than or equal to 50%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative and no contraindications to PD-1 or PD-L1 inhibitors in individuals with performance status 0-2 who achieve a response or stable disease following first-line therapy with single agent atezolizumab (Tecentriq); or
Treatment for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (greater than or equal to 50%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative and no contraindications to PD-1 or PD-L1 inhibitors and performance status 0-2; or

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

Treatment for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (greater than or equal to 1%) 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 in combination with carboplatin, paclitaxel, and bevacizumab for nonsquamous cell histology; or
Continuation maintenance therapy as a single agent or in combination with bevacizumab for recurrent, advanced or metastatic disease for PD-L1 expression positive (greater than or equal to 1%) tumors that are EGFR ALK negative or unknown and no contraindications to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) in individuals with performance status 0-2 who achieve tumor response or stable disease following first-line therapy with atezolizumab/carboplatin/paclitaxel/bevacizumab for nonsquamous cell histology; or
Treatment for recurrent, advanced, or metastatic disease in combination with carboplatin, paclitaxel, and bevacizumab or in combination with carboplatin and albumin-bound paclitaxel for individuals with performance status (PS) 0-1, no contraindications to PD-1 or PD-L1, and tumors of nonsquamous cell histology as:
- Initial systemic therapy for EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation and REP negative and PDL1 less than 1%; or
- First-line or subsequent therapy for NTRK gene fusion positive tumors; or
- First-line or subsequent therapy for MET exon 14 skipping mutation positive tumors; or
- First-line or subsequent therapy for RET rearrangement positive tumors; or
- First-line or subsequent therapy for BRAF V600E-mutation positive tumors; or
- Subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib (with or without ramucirumab or bevacizumab), 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
Continuation maintenance therapy in combination with bevacizumab for recurrent, advanced or metastatic disease and PD-L1 expression positive (greater than or equal to 1%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative and no contraindications to PD-1 or PD-L1 inhibitors in individuals with performance status 0-2 who achieve a response or stable disease following first-line therapy with atezolizumab/carboplatin/paclitaxel/bevacizumab for nonsquamous cell histology; or
Continuation maintenance therapy for recurrent, advanced or metastatic disease for PD-L1 expression positive (greater than or equal to 1%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative and no contraindications to PD-1 or PD-L1 inhibitors in individuals with performance status 0-2 who achieve a response or stable disease following first-line therapy with atezolizumab/carboplatin/albumin-bound paclitaxel for nonsquamous cell histology; or
Continuation maintenance therapy (if previously received first-line atezolizumab/carboplatin/albumin-bound paclitaxel) for recurrent, advanced or metastatic disease, performance status 0-2, and tumors of nonsquamous cell histology in individuals who achieve tumor response or stable disease following initial systemic therapy; or
Treatment for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (greater than or equal to 1%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative and no contraindications to PD-1 or PD-L1 inhibitors and performance status 0-2 for nonsquamous cell histology:
- in combination with bevacizumab, carboplatin and paclitaxel; or
- in combination with carboplatin and albumin-bound paclitaxel; 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, advanced or metastatic disease, performance status 0-2, and tumors of nonsquamous cell histology in individuals who achieve tumor response or stable disease following initial systemic therapy; or

Lung Cancer, Small Cell Carcinoma (FDA)

Used in combination with carboplatin and etoposide, for the first-line treatment of individuals with extensive-stage small cell lung cancer (ES-SCLC); or

Lung Cancer, Small Cell Carcinoma (NCCN)

Initial treatment in combination with etoposide and carboplatin followed by single agent maintenance 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; or

Melanoma (FDA)

Used in combination with cobimetinib and vemurafenib for the treatment of individuals with BRAF V600 mutation-positive unresectable or metastatic melanoma; or

Prostate Cancer, Small Cell/Neuroendocrine (NCCN)

Used in combination with carboplatin and etoposide for treatment (continue androgen deprivation therapy to maintain castrate levels of serum testosterone less than 50 ng/dL) of M1 castration-resistant small cell/neuroendocrine prostate cancer; or

Urothelial Cancer, Locally Advanced or Metastatic (FDA)

Individuals 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
Individuals who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status; or
Individuals who have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy; or

Urothelial Cancer, Upper Genitourinary (GU) or Prostate (NCCN)

Used as a single agent for metastatic disease as:
- First-line 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; or
- Second-line systemic therapy post-platinum; or

Urothelial Cancer, Urethra, Primary (NCCN)

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 (Note: Chemotherapy regimen based on histology); or
As a single agent for recurrent or metastatic disease as:
- First-line 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; or
- Subsequent systemic therapy post-platinum.

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.

Procedure Codes

J9022

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

Bladder (Urothelial) Carcinoma, Locally Advanced or Metastatic (FDA)

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

Bladder (Urothelial) Carcinoma (NCCN)

Used as single-agent maintenance therapy if there is no progression on first-line platinum-containing chemotherapy with gemcitabine and either cisplatin or carboplatin, or with DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, cisplatin); or
As second-line systemic therapy post-platinum as a single agent for:
- Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with down staging systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with first-line systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (any T, any N, M1a) disease if stable disease or progression following reassessment of tumor status after primary treatment with first-line systemic therapy; or
- Stage IVB (any T, any N, M1b) disease; or
- Muscle invasive local recurrence or persistent disease in a preserved bladder; or
- Metastatic or local recurrence post cystectomy; or

Genitourinary Tract Tumors, Upper, or Urothelial Carcinoma of the Prostate (Bladder) (NCCN)

Used as single-agent maintenance therapy if there is no progression on first-line platinum-containing chemotherapy with gemcitabine and either cisplatin or carboplatin, or with DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, cisplatin); or
As single agent second-line systemic therapy for metastatic disease post-platinum; or

Kidney (Renal) Cell Carcinoma (FDA)

First-line treatment, in combination with axitinib of individuals with advanced renal cell carcinoma (RCC); or

Kidney Cancer, Clear Cell (NCCN)

First-line or subsequent therapy, in combination with axitinib of individuals with relapse or stage IV disease and clear cell histology; or

Merkel Cell Carcinoma, MCC (FDA)

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

Merkel Cell Carcinoma, MCC (NCCN)

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

Urethra, Primary Carcinoma (Bladder) (NCCN)

Used as single-agent maintenance therapy if there is no progression on first-line platinum-containing chemotherapy with gemcitabine and either cisplatin or carboplatin, or with DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, cisplatin); or
Used as a single agent for recurrent or metastatic disease as second-line systemic therapy post-platinum.

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.

Procedure Codes

J9023

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

Squamous Cell Carcinoma, Cutaneous, Locally Advanced or Metastatic (FDA)

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

Squamous Cell Skin Cancer (NCCN)

Treatment as a single agent for:
- Inoperable or incompletely resected regional disease as systemic therapy alone if curative radiation therapy (RT) not feasible; or
- Regional recurrence or distant metastases if curative surgery and curative RT are not feasible; or
Treatment for complicated cases of locally advanced, high risk cutaneous squamous cell skin cancer in which curative surgery and curative radiation therapy (RT) are not feasible:
- As primary treatment for non-surgical candidates; or
- After surgery with positive margins; or
- If residual disease is present and further surgery is not feasible.

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.

Procedure Codes

J9119

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

Bladder (Urothelial) Carcinoma (FDA)

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; or

Bladder (Urothelial) Carcinoma (NCCN)

Used as second-line systemic therapy post-platinum as a single agent for:
- Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with down staging systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with first-line systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (any T, any N, M1a) disease if stable disease or progression following reassessment of tumor status after primary treatment with first-line systemic therapy; or
- Stage IVB (any T, any N, M1b) disease; or
- Muscle invasive local recurrence or persistent disease in a preserved bladder; or
- Metastatic or local recurrence post cystectomy; or

Genitourinary Tract Tumors, Upper (NCCN)

Therapy for metastatic disease as a single agent second-line systemic therapy post-platinum; or

Lung Cancer, Non-Small Cell Lung Cancer, NSCLC (FDA)

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

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

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; or

Lung Cancer, Small Cell (FDA)

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

Lung Cancer, Small Cell (NCCN)

Preferred initial treatment in combination with etoposide and either cisplatin or carboplatin followed by single agent maintenance for extensive stage disease in individuals:
- Without localized symptomatic sites or brain metastases and good performance status (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; or

Urothelial Cancer, Urethra, Primary or Prostate (Bladder) (NCCN)

Single agent for recurrent or metastatic disease as subsequent systemic therapy post-platinum.

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.

Procedure Codes

J9173

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

Anal Carcinoma – Squamous Cell (NCCN)

Preferred single agent second-line or subsequent therapy for metastatic disease; or

Central Nervous System Cancers - Brain Metastases – Extensive (NCCN)

Used as a single agent or in combination with ipilimumab for extensive bran metastases in individuals with melanoma:
- As primary treatment in select individuals (e.g., individuals with small asymptomatic brain metastases); or
- As treatment for recurrent brain metastases in individuals with stable systemic disease or reasonable systemic treatment options; or
Single-agent treatment for extensive brain metastases in individuals with PD-L1 positive non-small cell lung cancer:
- May be considered as primary treatment in select individuals (e.g., individuals with small asymptomatic brain metastases); or
- As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options; or

Central Nervous System Cancers - Brain Metastases – Limited (NCCN)

Treatment of individuals with melanoma with limited brain metastases as single agent or in combination with ipilimumab:
- For initial treatment for brain metastases in select individuals (e.g., individuals with small asymptomatic brain metastases); or
- For recurrent brain metastases; or
- Treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options; or

Used as single agent treatment for limited brain metastases in individuals with PD-L1 positive non-small cell lung cancer, NSCLC:
- As initial treatment in select individuals (e.g., individuals with small asymptomatic brain metastases); or
- As treatment for recurrent brain metastases; or
- Treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options; or

Colon, Adenocarcinoma (NCCN)

As primary treatment as a single agent or in combination with ipilimumab for unresectable metachronous metastases (dMMR/MSI-H only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or
Therapy as a single agent or in combination with ipilimumab in individuals (dMMR/MSI-H only) who are not appropriate for intensive therapy:
- As adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in individuals who have received previous chemotherapy; or
- As adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy*; or
As therapy as a single agent or in combination with ipilimumab (dMMR/MSI-H only) who are not appropriate for intensive therapy:
- As primary treatment for locally unresectable or medically inoperable disease; or
- For unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy; or
- As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction; or
- For synchronous unresectable metastases of other sites; or
- As primary treatment for unresectable metachronous metastases in individuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy; or
- For unresectable metachronous metastases that remain unresectable after primary treatment; or
As subsequent therapy as a single agent or in combination with ipilimumab (if no previous treatment with a checkpoint inhibitor) (dMMR/MSI-Honly) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy; or

Colorectal Cancer (FDA)

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 Squamous Cell Carcinoma (FDA)

Treatment of individuals with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy; or

Esophageal and Esophagogastric Junction Cancers, Squamous Cell Carcinoma (NCCN)

Palliative therapy for individuals who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and Karnofsky performance score greater than or equal to 60% or ECOG performance score less than or equal to 2 as preferred second-line or subsequent therapy for esophageal squamous cell carcinoma (SCC) if no previous treatment with a checkpoint inhibitor; or

Gestational Trophoblastic Neoplasia (NCCN)

Single agent for multiagent chemotherapy-resistant;
- High-risk disease; or
- Recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen; or

Head and Neck Cancer (FDA)

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

Head and Neck Cancers, Very Advanced, Squamous Cell Carcinoma with Mixed Subtypes (NCCN)

As single agent subsequent therapy for nasopharyngeal cancer if previously treated, recurrent or metastatic non-keratinizing disease in individuals with performance state 0-2 for:
- Recurrent/persistent disease with distant metastases; or
- Unresectable loco regional recurrence or second primary with prior radiation therapy (RT); or
Systemic therapy as a single agent subsequent-line option, if immunotherapy not previously used, for non-nasopharyngeal cancer if disease progression on or after platinum therapy in:
- Performance status (PS) 0-1 and persistent or progressive metastatic disease at initial presentation following first-line therapy; or
- PS 0-2 and recurrent/persistent disease with distant metastases; or
- PS 0-2 and unresectable locoregional recurrence or second primary with prior radiation therapy (RT); or
- PS 3 and unresectable locoregional recurrence without prior RT; or

Hepatocellular Carcinoma, HCC (FDA)

Treatment of individuals with HCC who have been previously treated with sorafenib, as a single agent or in combination with ipilimumab; or

Hepatocellular Carcinoma, HCC, Adenocarcinoma (NCCN)

First-line treatment as a single agent for individuals ineligible for tyrosine kinase inhibitors [TKIs] or other anti-angiogenic agents 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; or
Subsequent treatment as a single agent (Child-Pugh Class A or B only) or in combination with ipilimumab (Child-Pugh Class A only) for progressive disease in individuals who have not been previously treated with a checkpoint inhibitor 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
- Have metastatic disease; or

Kidney (Renal) Cell Carcinoma (FDA)

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

Kidney (Renal) Cell Carcinoma (RCC), Clear Cell or Non-Clear Cell (NCCN)

As single-agent therapy for relapse or stage IV disease
- As 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) for 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; or

Leukemia, Chronic Lymphocytic, CLL/Small Lymphocytic Lymphoma (NCCN)

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 individuals with del(17p)/TP53 mutation or who are chemotherapy refractory and unable to receive chemoimmunotherapy; or

Lung Cancer, Non-Small Cell Lung Cancer, NSCLC (FDA)

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
Individual 18 years of age or older with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy; or
MetastaticNSCLCand 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

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

Treatment for recurrent, advanced or metastatic disease in combination with ipilimumab, in combination with ipilimumab, pemetrexed, and either carboplatin or cisplatin for nonsquamous cell histology, or in combination with ipilimumab, paclitaxel and carboplatin for squamous cell histology for individuals with performance status (PS) 0-1 and no contraindications to PD-1 or PD-L1 inhibitors as:
- Initial systemic therapy for EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative* and PD-L1 less than 1%; or
- First-line or subsequent therapy for BRAF V600E-mutation positive tumors; or
- First-line or subsequent therapy for NTRK gene fusion positive tumors; or
- First-line or subsequent therapy for MET exon 14 skipping mutation positive tumors; or
- First-line or subsequent therapy for RET rearrangement positive tumors; or
- Subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib with or without (ramucirumab or bevacizumab), 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, entrectinib, or ceritinib therapy; or

Treatment of individuals with recurrent, advanced or metastatic NSCLC as single agent subsequent therapy in individuals with PS 0-2 and no prior progression on a PD-1/PD-L1 inhibitor;or
Treatment for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (greater than or equal to 1%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative* and no contraindications to PD-1 or PD-L1 inhibitors and performance status 0-2:
- In combination with ipilimumab; or
- In combination with ipilimumab, pemetrexed and either carboplatin or cisplatin for nonsquamous cell histology; or
- In combination with ipilimumab, paclitaxel and carboplatin for squamous cell histology; or

*if there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1, BRAF, MET and RET, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes

Activity against tumor mutational burden (TMB) as a single agent or in combination with ipilimumab; or

Lung Cancer, Small Cell, SCLC (FDA)

Individuals with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy; or

Lung Cancer, Small Cell, SCLC (NCCN)

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

Lymphoma, Diffuse Large B-Cell (NCCN)

Used with or without brentuximab vedotin to treat relapsed or refractory primary mediastinal large B-cell lymphoma; or

Lymphoma, Hodgkin Classic (FDA)

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 vedotin; or
- Three (3) or more lines of systemic therapy that includes autologous HSCT; or

Lymphoma, Hodgkin Classic, cHL (NCCN)

Second-line or subsequent systemic therapy (if not previously used) in adult individuals greater than or equal to 18 years of age for relapsed or refractory disease in combination with brentuximab vedotin; or
Third-line or subsequent systemic therapy for individuals greater than or equal to 18 years of age as a single agent for:
- Disease that has relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) ± brentuximab vedotin; or
- Relapsed/refractory disease in individuals who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy; or
- Post-allogeneic transplant; or
Palliative therapy as a single agent in adults greater than 60 years of age for:
- Disease that has relapsed or progressed after autologous HSCT with or without brentuximab vedotin; or
- Relapsed/refractory disease in individuals who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy; or
- Post-allogeneic transplant; or

Lymphomas, T-Cell, Extranodal NK/T-Cell Lymphoma, Nasal Type (NCCN)

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

Melanoma (FDA)

Unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab; or
Lymph node involvement or metastatic disease in individuals who have undergone complete resection, in the adjuvant setting; or

Melanoma, Cutaneous (NCCN)

As adjuvant therapy as a single agent:
- For resected stage III sentinel node positive disease during 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/in-transit metastases if no evidence of disease after complete excision to clear margins or if no evidence of disease after initial treatment with local or regional therapy; or
- For local satellite/in-transit recurrence if no evidence of diseaseafter complete excision to clear margins or if no evidence of disease after initial treatment with local or regional therapy; or
- Following therapeutic lymph node dissection 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
Preferred 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 ipilimumab if checkpoint inhibitor immunotherapy was not previously used; or
- In combination with ipilimumab for individuals who progress on single-agent anti-PD-1 checkpoint inhibitor immunotherapy; or
- As re-induction therapy (as a single agent or in combination with ipilimumab) if prior anti-PD-1 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

Melanoma, Uveal (NCCN)

Treatment of individuals with distant metastatic uveal melanoma as single agent therapy or in combination with ipilimumab; or

Merkel Cell Carcinoma, MCC (NCCN)

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

Mesothelioma, Malignant Pleural, Biphasic, Epithelial, Sarcomatoid (NCCN)

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

Neuroendocrine and Adrenal Tumors, Poorly Differentiated (High Grade)/Large or Small Cell (NCCN)

Consider for treatment in combination with ipilimumab for non-pancreatic neuroendocrine tumors if progression on first-line chemotherapy for metastatic disease; or

Rectal Cancer, Adenocarcinoma (NCCN)

Therapy as a single agent or in combination with ipilimumab for individuals with advanced or metastatic disease (dMMR/MSI-H only) who are not appropriate for intensive therapy:
- As adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in individuals who have received previous chemotherapy; or
- As adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy; or

Subsequent therapy for advanced or metastatic disease (dMMR/MSI-H only), if no previous treatment with a checkpoint inhibitor, following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy as a single agent or in combination with ipilimumab; or
Therapy as a single agent or in combination with ipilimumab in individuals (dMMR/MSI-H only) who are not appropriate for intensive therapy:
- As primary treatment for T3, N Any; T1-2, N1-2; T4, N Any or locally unresectable or medically inoperable disease if resection is contraindicated following neoadjuvant therapy; or
- For synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy; or
- Following palliative radiation therapy (RT) or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy; or
- As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction; or
- As primary treatment for synchronous unresectable metastases of other sites; or
- As primary treatment for unresectable metachronous metastases in individuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy; or
- For unresectable metachronous metastases that remain unresectable after primary treatment; or

Primary treatment as a single agent or in combination with ipilimumab for unresectable metachronous metastases (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or

Small Bowel Adenocarcinoma (NCCN)

Initial therapy as a single agent or in combination with ipilimumab for advanced or metastatic disease (dMMR/MSI-H only) in individuals with prior oxaliplatin exposure in the adjuvant setting or contraindication; or
Subsequent therapy as a single agent or in combination with ipilimumab for advanced or metastatic disease (dMMR/MSI-H only); or

Urothelial Carcinoma, Bladder Cancer(NCCN)

Used as second-line systemic therapy post-platinum as a single agent for:
- Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (any T, any N, M1a) disease if stable disease or progression following reassessment of tumor status after primary treatment with first-line systemic therapy; or
- Stage IVB (any T, any N, M1b) disease; or
- Muscle invasive local recurrence or persistent disease in a preserved bladder; or
- Metastatic or local recurrence post cystectomy; or

Urothelial Carcinoma, Upper GU Tract Tumors(NCCN)

Therapy for metastatic disease as a single agent for second-line systemic therapy post-platinum; or

Urothelial Carcinoma, Locally Advanced or Metastatic (FDA)

Individuals with disease progression during or following platinum-containing chemotherapy; or
Individuals with disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; or

Urothelial Cancer, Urethra, Primary (Bladder) (NCCN)

Single agent for recurrent or metastatic disease as second-line systemic therapy post-platinum (Note: Chemotherapy regimen based on histology); or

Urothelial Cancer, Urothelial, Carcinoma of the Prostate (Bladder) NCCN

Therapy for metastatic disease as a single agent for second-line systemic therapy post-platinum.

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.

Procedure Codes

J9299

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

Anal Carcinoma, Squamous Cell Carcinoma (NCCN)

Treatment of individuals with squamous cell anal carcinoma as second- line or subsequent, single agent therapy for metastatic disease; or

Bladder (Urothelial) Carcinoma (FDA)

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 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

Bladder (Urothelial) Carcinoma (NCCN)

As first-line systemic therapy as a single agent 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 two – three (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 two – three (2-3) months after primary treatment with concurrent chemoradiotherapy; or
- Non-cystectomy candidates with stage IIIA (cT3, N0; cT1-4a, N1) disease if tumor is present upon reassessment of tumor status two-three (2-3) months after primary treatment; 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
- Muscle invasive local recurrence or persistent disease in a preserved bladder; or
- Metastatic or local recurrence post cystectomy; or
As second-line systemic therapy post-platinum as a single agent for:
- Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with first-line systemic therapy or concurrent chemoradiotherapy; or
- Stage IVA (any T, any N, M1a) disease if stable disease or progression following reassessment of tumor status after primary treatment with first-line systemic therapy; or
- Stage IVB (any T, any N, M1b) disease; or
- Muscle invasive local recurrence or persistent disease in a preserved bladder; or
- Metastatic or local recurrence post cystectomy; or
Treatment of select individuals with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer with Tis with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy; or

Bladder (Urothelial) Cancer, Urethra, Primary (NCCN)

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; or
- Second-line systemic therapy post-platinum; or
- Subsequent-line systemic therapy; or
Therapy for metastatic disease as a single agent for:
- 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; or
- Second-line systemic therapy post-platinum; or
- Subsequent-line systemic therapy; or
Primary treatment as a single agent for clinical stage T3-4, cN1-2 disease or cN1-2 palpable inguinal lymph nodes as first-line systemic therapy 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

Bone Cancer – Chondrosarcoma (NCCN)

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

Bone Cancer – Ewing Sarcoma, Mesenchymal Chondrosarcoma (NCCN)

Single-agent therapy for individuals with unresectable or metastatic, MSI-H or dMMR tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options; or

Bone Cancer – Osteosarcoma (NCCN)

Single-agent therapy for individuals with unresectable or metastatic, MSI-H or dMMR tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options; or

Breast Cancer – Invasive Breast Cancer (NCCN)

Single agent therapy for recurrent or stage IV (M1) disease that is unresectable or metastatic and MSI-H or dMMR that has progressed following prior treatment and has no satisfactory alternative treatment options; or

Central Nervous System Cancers - Extensive Brain Metastases (NCCN)

Single-agent treatment for extensive brain metastases in individuals with melanoma or PD-L1-positive non-small cell lung cancer (NSCLC); or
Primary treatment in individuals with small asymptomatic brain metastases; or
Treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options; or

Central Nervous System Cancers - Limited Brain Metastases (NCCN)

Single-agent treatment for limited brain metastases in individuals with melanoma or PD-L1-positive non-small cell lung cancer, NSCLC:
- Initial treatment of individuals with small asymptomatic brain metastases; or
- For recurrent brain metastases; or
- Treatment for relapsed disease with either stable systemic disease or reasonable systemic treatment options; or

Cervical Cancer (FDA)

Treatment of individuals with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 [Combined Positive Score (CPS) greater than or equal to one (1)]; or

Cervical Cancer – Squamous cell carcinoma, Adenocarcinoma (NCCN)

Preferred second-line therapy as a single agent for recurrent or metastatic disease if:
- Instability-high, MSI-H, or mismatch repair deficient, dMMR tumors; or
- Disease progression on or after chemotherapy in individuals whose tumors express PDL1 (CPS ≥1); or
Treatment of individuals with unresectable or metastatic tumor mutational burden-high (TMB-H) (greater than or equal to 10 mut/Mb) that have progressed following prior treatment and who have no satisfactory alternative treatment options; or

Colon Adenocarcinoma (NCCN)

As single agent in individuals with dMMR/MSI-H only as:
- Adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in individuals who have received previous chemotherapy for colon adenocarcinoma; or
- Adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy for colon adenocarcinoma; or

Subsequent therapy as a single agent (if nivolumab or pembrolizumab not previously given) for advanced or metastatic disease dMMR/MSI-H only, if no previous treatment with a checkpoint inhibitor, following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy; or
Primary treatment as a single agent for unresectable metachronous metastases dMMR/MSI-H only and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or
Therapy as a single agent in individuals dMMR/MSI-H only:
- As primary treatment for locally unresectable or medically inoperable disease; or
- For unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy; or
- As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction; or
- For synchronous unresectable metastases of other sites; or
- As primary treatment for unresectable metachronous metastases in individuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy; or
- For unresectable metachronous metastases that remain unresectable after primary treatment; or

Cutaneous Squamous Cell Carcinoma (cSCC) (FDA)

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

Endometrial Carcinoma (FDA)

Treatment of individuals with advanced endometrial carcinoma that in not MSI-H or dMMR; and
Individual has disease progression following prior systemic therapy; and
Individual is not a candidate for curative surgery or radiation; and
Pembrolizumab (Keytruda) is given in combination with lenvatinib; or

Esophageal Cancer (FDA)

Treatment of individuals with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 [Combined Positive Score (CPS) greater than or equal to 10]; and
Disease progression after one (1) or more prior lines of systemic therapy; or

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

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) and if no previous treatment with a checkpoint inhibitor as:
- Second-line or subsequent therapy as a single agent for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors; or
- Second-line therapy for esophageal squamous cell carcinoma (SCC) with PD-L1 expression by CPS of levels greater than or equal to 10; or
- Third-line or subsequent therapy as a single agent for esophageal and EGJ adenocarcinoma with PD-L1 expression levels by CPS of greater than or equal to one (1); or

Gastric Cancer (FDA)

Treatment of individuals with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma:
- Whose tumors express PD-L1 [Combined Positive Score (CPS) greater than or equal to 1]; and
- With disease progression on or after two (2) or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy; or

Gastric Cancer, Adenocarcinoma (NCCN)

Palliative therapy for locoregional disease in individuals who are not surgical candidates or have recurrent, or metastatic disease and Karnofsky performance score greater than or equal to 60% or ECOG performance score less than or equal to 2 as:
- Second-line or subsequent therapy as a single agent for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors; or
- Third-line or subsequent therapy as a single agent for gastric adenocarcinoma with PD-L1 expression levels by CPS of greater than or equal to 1; or

Genitourinary, Upper Tract Tumors or Urothelial Carcinoma of the Prostate (Bladder) (NCCN)

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; or
- Second-line systemic therapy post-platinum; or
- Subsequent systemic therapy post-platinum; or

Gestational Trophoblastic Neoplasia (NCCN)

Single agent therapy for multiagent chemotherapy resistant:
- High risk disease; or
- Recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen; or

Head and Neck Squamous Cell Cancer, HNSCC (FDA)

Combination treatment with platinum and FU for first-line treatment of individuals with metastatic or unresectable, recurrent HNSCC; or
Single agent treatment for 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 1); or
Single agent treatment of individuals with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy; or

Head and Neck Cancer, Very Advanced, Squamous Cell Carcinoma with Mixed Subtypes (NCCN)

Therapy as single agent first-line therapy option for non-nasopharyngeal cancer tumors that express PD-L1 with CPS greater than or equal to one (1) in individuals with:
- PS 2 for newly diagnosed T4b, any N 0-3, M0 disease, unresectable nodal disease with no metastases, non-metastatic disease for individuals who are unfit for surgery or unresectable locoregional recurrence without prior radiation therapy (RT); or
- PS 0-2 for metastatic (M1) disease at initial presentation, recurrent/persistent disease with distant metastases, unresectable locoregional recurrence with prior RT or unresectable second primary with prior RT; or
- Unresectable locoregional recurrence without prior RT and PS 3; or
Therapy as a single agent subsequent therapy option, if immunotherapy not previously used for non-nasopharyngeal cancer if disease progression on or after platinum-containing chemotherapy in individuals with:
- PS 0-1 and persistent or progressive metastatic disease (M1) at initial presentation after first-line therapy; or
- PS 0-2 and recurrent/persistent disease with distant metastases; or
- PS 0-2 and unresectable locoregional recurrence or second primary with prior RT; or
- PS 3 and unresectable locoregional recurrence without prior RT; or
Systemic therapy as a first-line or subsequent therapy option for non-nasopharyngeal cancer and PS 0-1 for metastatic (M1) disease at initial presentation, recurrent/persistent disease with distant metastases, unresectable locoregional recurrent with prior RT, or unresectable second primary with prior RT in combination with fluorouracil and either carboplatin or cisplatin; or
Used as combination systemic therapy in non-nasopharyngeal cancer for resectable locoregional recurrence without prior RT given with fluorouracil and either carboplatin or cisplatin; or
Systemic therapy as a single agent subsequent-line option for nasopharyngeal cancer if previously treated, PD-L1-positive recurrent or metastatic disease in individuals with PS 0-2 for:
- Recurrent/persistent disease with distant metastases; or
- Unresectable locoregional recurrence or second primary with prior RT; or

Hepatobiliary Cancer, HCC (FDA)

Treatment of individuals with HCC who have been previously treated with sorafenib; or

Hepatocellular Carcinoma, Adenocarcinoma (NCCN)

Primary treatment as a single agent for unresectable or metastatic biliary tract cancers: gallbladder cancer (adenocarcinoma) that is MSI-H and/or dMMR; or
Primary treatment as a single agent for unresectable or metastatic biliary tract cancers: extrahepatic cholangiocarcinoma (adenocarcinoma) that is MSI-H) and/or dMMR; or
Subsequent treatment as a single agent for progression on or after systemic treatment for unresectable or metastatic biliary tract cancers: extrahepatic cholangiocarcinoma (adenocarcinoma) that is MSI-H and/or dMMR; or
Primary treatment as a single agent for unresectable or metastatic biliary tract cancers: intrahepatic cholangiocarcinoma (adenocarcinoma) that is MSI-H and/or dMMR; or
Subsequent treatment as a single agent for progression on or after systemic treatment for unresectable or metastatic biliary tract cancers: Intrahepatic Cholangiocarcinoma (adenocarcinoma) that is MSI-H and/or dMMR; or
Subsequent treatment as a single agent for progression on or after systemic treatment for unresectable or metastatic biliary tract cancers: gallbladder cancer (adenocarcinoma) that is MSI-H and/or dMMR; or
Subsequent treatment as a single agent for progressive disease in individuals (Child-Pugh Class A only) who have not been previously treated with a checkpoint inhibitor and:
- 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; or

Kidney (Renal) Cell Carcinoma, RCC (FDA)

Combination therapy with axitinib, for first line treatment of individuals with advanced RCC; or

Kidney Cancer, Clear Cell (NCCN)

Used in combination with axitinib for relapsed or stage IV disease;
- As preferred 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 subsequent therapy for clear cell histology; or

Leukemia, Chronic Lymphocytic /Small Lymphocytic Lymphoma (NCCN)

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); and
- For individuals with del(17p)/TP53 mutation; or
- Individuals who are chemotherapy refractory and unable to receive chemoimmunotherapy; or

Lung Cancer, NSCLC (FDA)

As first-line treatment in combination with pemetrexed and platinum chemotherapy for metastatic 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 (paclitaxel protein-bound) for metastatic squamous NSCLC; or
As first-line, single agent for 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 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 aberrations prior to receiving pembrolizumab (Keytruda); or

Lung Cancer, NSCLC, Adenocarcinoma (with mixed subtypes), Large Cell Carcinoma, Squamous Cell Carcinoma (NCCN)

Treatment for recurrent, advanced or metastatic disease as first-line therapy for PD-L1 expression-positive (≥1%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative*** and no contraindications to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) and performance status 0-2:
- As a single agent** (preferred if PD-L1 ≥50%; useful in certain circumstances if PD-L1 1-49%); or
- In combination with pemetrexed and either carboplatin or cisplatin for nonsquamous cell histology; or
- In combination with either carboplatin and either paclitaxel or albumin-bound paclitaxel for squamous cell histology; or

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

Continuation maintenance therapy for recurrent, advanced or metastatic disease for PD-L1 expression positive (≥1%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation and RET negative*** and no contraindications to PD-1 or PD-L1 inhibitors 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; or
- As a single agent if pembrolizumab (Keytruda) was given as monotherapy or as part of a pembrolizumab/carboplatin/paclitaxel or albumin-bound paclitaxel regimen for squamous cell histology; or
Treatment for recurrent, advanced or metastatic disease in combination with pemetrexed and either carboplatin or cisplatin (as preferred regimens if no contraindications to PD-1 or PD-L1 inhibitors for nonsquamous cell histology), in combination with carboplatin and either paclitaxel or albumin-bound paclitaxel (as preferred regimens if no contraindications to PD-1 or PD-L1 inhibitors for squamous cell histology) for individuals with performance status 0-1 as:
- Initial systemic therapy for EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative*** and PD-L1 <1%; or
- First-line or subsequent therapy for BRAF V600E-mutation positive tumors; or
- First-line or subsequent therapy for NTRK gene fusion positive tumors; or
- First-line or subsequent therapy for MET exon 14 skipping mutation positive tumors; or
- First-line or subsequent therapy for RET rearrangement positive tumors; or
- Subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib (with or without ramucirumab or bevacizumab), 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, entrectinib or ceritinib therapy; or

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; or

*** if there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1, BRAF, MET and RET, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes.

Lung Cancer, NSCLC, Adenocarcinoma (with mixed subtypes), Large Cell Carcinoma (NCCN)

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 individuals with PS 0-2, who achieve tumor response or stable disease following initial systemic therapy; or

Lung Cancer, NSCLC, Squamous Cell Carcinoma (NCCN)

Single-agent continuation maintenance therapy if given first line as part of a pembrolizumab/carboplatin/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; or

Lung Cancer, Small Cell (FDA)

Treatment of metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy; or

Lung Cancer, Small Cell, Small Cell Carcinoma (NCCN)

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

Lymphoma, B-Cell, Diffuse Large B-Cell Lymphoma (NCCN)

Treatment as a single agent for individuals with relapsed or refractory primary mediastinal large B-cell lymphoma disease; or

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

For treatment of relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used, if a clinical trial is unavailable; or

Lymphoma, Hodgkin, Classic, cHL (FDA)

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

Lymphoma, Hodgkin, Classic, cHL (NCCN)

Treatment of individuals age 18 years or older as third-line or subsequent systemic therapy as a single agent for:
- Disease that has relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) with or without brentuximab vedotin; or
- Relapsed/refractory disease in individuals who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy; or
- Post-allogeneic transplant; or
Treatment of individuals greater than 60 years of age as palliative therapy as a single agent for:
- Disease that has relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) ± brentuximab vedotin; or
- Relapsed/refractory disease in individuals who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy; or
- Post-allogeneic transplant; or

Lymphoma, Primary Mediastinal Large B-Cell (PMBCL) (FDA)

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.

Lymphoproliferative Disorders, Primary Cutaneous CD30+ T-Cell (NCCN)

Therapy for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions, or cutaneous ALCL with regional nodes (N1) (excludes systemic ALCL), as a single agent for relapsed/refractory disease; or

Melanoma (FDA)

Treatment of individuals with unresectable or metastatic disease; or
Adjuvant treatment of individuals with melanoma with involvement of lymph node(s) following complete resection; or

Melanoma – Cutaneous Melanoma (NCCN)

Adjuvant treatment as a single agent:
- For resected stage III sentinel lymph node, 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 satellite/in-transit metastases if no evidence of disease after initial treatment with local or regional therapy; or
- For local satellite/in-transit recurrence if no evidence of disease after complete excision to clear margins; or
- For local satellite in-transit recurrence if no evidence of disease after initial treatment with local or regional therapy; or
- Following total lymph node dissection 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

Melanoma, Uveal (NCCN)

Consider as single agent therapy for distant metastatic disease; or

Merkel Cell Carcinoma, MCC (FDA)

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

Merkel Cell Carcinoma, MCC (NCCN)

Treatment if curative surgery and curative rational therapy are not feasible for:
- Individuals with recurrent locally advanced disease; or
- Individuals with recurrent regional disease; or
Treatment for disseminated, clinical M1 disease with or without surgery and/or radiation therapy; or

Mesothelioma, Malignant Pleural, Epithelial, Sarcomatoid, Mixed (NCCN)

Subsequent systemic therapy as a single agent; or

Microsatellite Instability-High, MSI-H, Cancer (FDA)

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; or
- First-line 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.

Mycosis Fungoides (MF)/Sezary Syndrome (SS) (NCCN)

Primary systemic therapy for:
- Stage III MF; or
- Stage IV Sezary syndrome; or
Systemic therapy as treatment for:
- Relapsed or persistent stage IA MF with B1 blood involvement, with or without skin-directed therapy; or
- Relapsed or persistent stage IB-IIA MFwith 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 to multiple previous therapies or progression; or
- Relapsed or persistent stage III MF, with or without skin-directed therapies; or
- Stage III MF that is refractory to multiple previous therapies; or
- Relapsed or persistent stage IV SS; 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; or

Neuroendocrine and Adrenal Tumors (NCCN)

Treatment of metastatic adrenocortical carcinoma with or without mitotane; or
Treatment for individuals with dMMR, MSI-H or advanced tumor mutational burden-high (TMB-H) poorly differentiated (high grade/large or small cell neuroendocrine and adrenal tumors that have progressed following prior treatment with no satisfactory alternative treatment options; or

Occult Primary – Adenocarcinoma or Carcinoma Not Otherwise Specified (NCCN)

Used as a single agent (in individuals with MSI-H/dMMR tumors) in symptomatic individuals with PS 1-2 or asymptomatic individuals with PS 0 and aggressive disease for:
- Axillary involvement in men if clinically indicated; or
- Lung nodules or breast marker-negative pleural effusion; or
- Resectable liver disease; or
- Peritoneal mass or ascites with non-ovarian histology; or
- Retroperitoneal mass of non-germ cell histology in selected patients; or
- Unresectable liver disease or disseminated metastases; or

Ovarian, Epithelial/Fallopian Tube/Primary Peritoneal Cancers – Carcinosarcoma, Clear Cell, Endometrioid, Mucinous, Serous (NCCN)

Single-agent therapy for persistent disease or recurrence, if MSI-H or dMMR:
- As immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy; or
- For progression on primary, maintenance, or recurrence therapy; or
- For stable or persistent disease (if not on maintenance therapy); or
- For complete remission and relapse less than six (6) months after completing chemotherapy; or
- For radiographic and/or clinical relapse in individuals with previous complete remission and relapse after greater than or equal to six (6) months after completing prior chemotherapy; or

Pancreatic Adenocarcinoma (NCCN)

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

Penile Cancer (NCCN)

Single agent as subsequent-line systemic therapy if unresectable or metastatic, MSI-H or dMMR tumor that has progressed following prior treatment and no satisfactory alternative treatment options; or

Prostate Cancer – Adenocarcinoma (NCCN)

Single-agent second-line or subsequent treatment (continue androgen deprivation therapy to maintain castrate levels of serum testosterone less than 50 ng/dL) for individuals who have progressed through at least one line of systemic therapy for castration-resistant distant metastatic (M1) disease that is MSI-H or dMMR, if pembrolizumab (Keytruda) not previously received; or

Prostate, Urothelial (Bladder) Carcinoma (NCCN)

Therapy for metastatic disease as a single agent 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; or
- Second line systemic therapy post-platinum; or
- Subsequent systemic therapy; or

Rectal Cancer – Adenocarcinoma (NCCN)

Primary treatment as a single agent for unresectable metachronous metastases (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or
Therapy as a single agent for individuals (dMMR/MSI-H only):
- For synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy; or
- Following palliative radiation therapy (RT) or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy; or
- As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction; or
- As primary treatment for synchronous unresectable metastases of other sites; or
- As primary treatment for unresectable metachronous metastases in individuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy; or
- For unresectable metachronous metastases that remain unresectable after primary treatment; or

Therapy as a single agent for individuals (dMMR/MSI-H only)
- For synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy; or
- Following palliative RT or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy; or
- As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction; or
- As primary treatment for synchronous unresectable metastases of other sites; or
- As primary treatment for unresectable metachronous metastases in individuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy; or
- For unresectable metachronous metastases that remain unresectable after primary treatment; or

Therapy as a single agent for individuals with advanced or metastatic disease (MMR/MSI-H only):
- As adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in individuals who have received previous chemotherapy; or
- As adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy; or

Subsequent therapy as a single agent (if no previous treatment with a checkpoint inhibitor) for advanced or metastatic disease (dMMR/MSI-H only), following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy; or

Sarcoma, Soft Tissue (NCCN)

Single-agent therapy for Alveolar Soft Part Sarcoma (ASPS); or
Single agent for the treatment of metastatic undifferentiated pleomorphic sarcoma; or

Skin Cancer – Squamous Cell (NCCN)

Treatment as a single agent for regional recurrent or distant metastases if curative surgery and curative radiation therapy are not feasible; or

Small Bowel Adenocarcinoma (NCCN)

Subsequent therapy as a single agent for advanced or metastatic disease (dMMR/MSI-H only); or
Initial therapy as a single agent for advanced or metastatic disease (dMMR/MSI-H only) in individuals with prior oxaliplatin exposure in the adjuvant setting or contraindication; or

Testicular Cancer – Nonseminoma, Pure Seminoma (NCCN)

As single-agent third-line therapy in individuals with MSI-H/dMMR tumors; or

Thymic Carcinoma (NCCN)

Second-line therapy for thymic carcinoma as a single agent for unresectable disease following first-line chemotherapy for potentially resectable locally advanced disease, solitary metastasis, or ipsilateral pleural metastasis; or
Second-line therapy for thymic carcinoma as a single agent for extrathoracic metastatic disease; or

Tumor Mutational Burden-High (TMB-H) Cancer (FDA)

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; or

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

Thyroid Carcinoma – Anaplastic Carcinoma (NCCN)

For tumor mutational burden-high (TMB-H) (≥10 mutations/megabase [mut/Mb]) tumors, used as single agent therapy:
- As aggressive first-line therapy for metastatic disease; or
- As second-line therapy for metastatic disease; or

Thyroid Carcinoma - Hürthle Cell Carcinoma (NCCN)

For TMB-H (≥10 mutations/megabase [mut/Mb]) tumors, for treatment of:
- Unresectable locoregional recurrent or persistent disease not amenable to radioactive iodine (RAI) therapy; or
- Distant metastatic disease not amenable to RAI therapy; or

Thyroid Carcinoma – Medullary Carcinoma (NCCN)

Treatment for TMB-H (≥10 mutations/megabase [mut/Mb]) tumors in:
- Unresectable locoregional disease that is symptomatic or progressing by RECIST criteria; or
- Asymptomatic recurrent or persistent distant metastases if unresectable and progressing by RECIST criteria; or
- Recurrent or persistent distant metastases if symptomatic disease or progression; or

Thyroid Carcinoma – Follicular Carcinoma (NCCN)

For TMB-H (≥10 mutations/megabase [mut/Mb]) tumors, for treatment of:
- Unresectable locoregional recurrent or persistent disease not amenable to radioactive iodine (RAI) therapy; or
- Distant metastatic disease not amenable to RAI therapy; or

Thyroid Carcinoma – Papillary Carcinoma (NCCN)

For TMB-H (≥10 mutations/megabase [mut/Mb]) tumors, consider for treatment of:
- Unresectable locoregional recurrent or persistent disease not amenable to radioactive iodine (RAI) therapy; or
- Distant metastatic disease not amenable to RAI therapy; or

Uterine Neoplasms – Uterine Sarcoma (NCCN)

As single-agent therapy for individuals with unresectable or metastatic TMB-H [≥10 mutations/megabase (mut/Mb)] tumors, that have progressed following prior treatment and who have no satisfactory alternative treatment options; or

Uterine Neoplasms - Endometrial Carcinoma, Carcinosarcoma, Clear Cell Carcinoma, Endometrioid adenocarcinoma, Serous Carcinoma, Undifferentiated/dedifferentiated carcinoma

Treatment of individuals with:
- Recurrent, metastatic, or high-risk MSI-H or dMMR tumors that have progressed following prior systemic therapy; or
- Unresectable or metastatic TMB-H (≥10 mutations/megabase [mut/Mb]) tumors, that have progressed following prior treatment and who have no satisfactory alternative treatment options; or
- Used in combination with lenvatinib for advanced or recurrent disease that is not MSI-H or dMMR in individuals who are not candidates for curative surgery or radiation and have progressed on prior systemic therapy; or

Vulvar Cancer, Squamous Cell Carcinoma (NCCN)

As a single agent for advanced, recurrent, or metastatic disease:
- As second-line therapy for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors; or
- If disease progression on or after chemotherapy in individuals whose tumors express PD-L1 (Combined Positive Score ≥1); or
- In individuals with TMB-H (≥10 mutations/megabase [mut/Mb]) tumors, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

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.

Procedure Codes

J9271

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

Diagnosis Codes

Covered Diagnosis Codes for Procedure Codes J9119

C44.02	C44.121	C44.1221	C44.1222	C44.1291	C44.1292	C44.221
C44.222	C44.229	C44.320	C44.321	C44.329	C44.42	C44.520
C44.521	C44.529	C44.621	C44.622	C44.629	C44.721	C44.722
C44.729	C44.82	C44.92	Z85.828

Covered Diagnosis Codes for Procedure Code J9173

C33	C34.00	C34.01	C34.02	C34.10	C34.11	C34.12
C34.2	C34.30	C34.31	C34.32	C34.80	C34.81	C34.82
C34.90	C34.91	C34.92	C61	C65.1	C65.2	C65.9
C66.1	C66.2	C66.9	C67.0	C67.1	C67.2	C67.3
C67.4	C67.5	C67.6	C67.7	C67.8	C67.9	C68.0
C78.00	C78.01	C78.02	C79.31	C79.51	C79.52	C7A.1
D09.0	Z85.51	Z85.59

Covered Diagnosis Codes for Procedure Code J9299

C00.0	C00.1	C00.2	C00.3	C00.4	C00.5	C00.6
C00.8	C01	C02.0	C02.1	C02.2	C02.3	C02.4
C02.8	C02.9	C03.0	C03.1	C03.9	C04.0	C04.1
C04.8	C04.9	C05.0	C05.1	C06.0	C06.2	C06.80
C06.89	C06.9	C09.0	C09.1	C09.8	C09.9	C10.3
C11.0	C11.1	C11.2	C11.3	C11.8	C11.9	C12
C13.0	C13.1	C13.2	C13.8	C13.9	C14.0	C14.2
C14.8	C15.3	C15.4	C15.5	C15.8	C15.9	C16.0
C17.0	C17.1	C17.2	C17.3	C17.8	C17.9	C18.0
C18.1	C18.2	C18.3	C18.4	C18.5	C18.6	C18.7
C18.8	C18.9	C19	C20	C21.0	C21.1	C21.2
C21.8	C22.0	C22.8	C22.9	C30.0	C31.0	C31.1
C32.0	C32.1	C32.3	C32.8	C32.9	C33	C34.00
C34.01	C34.02	C34.10	C34.11	C34.12	C34.2	C34.30
C34.31	C34.32	C34.80	C34.81	C34.82	C34.90	C34.91
C34.92	C38.4	C4A.0	C4A.10	C4A.111	C4A.112	C4A.121
C4A.122	C4A.20	C4A.21	C4A.22	C4A.30	C4A.31	C4A.39
C4A.4	C4A.51	C4A.52	C4A.59	C4A.60	C4A.61	C4A.62
C4A.70	C4A.71	C4A.72	C4A.8	C4A.9	C43.0	C43.10
C43.111	C43.112	C43.121	C43.122	C43.20	C43.21	C43.22
C43.30	C43.31	C43.39	C43.4	C43.51	C43.52	C43.59
C43.60	C43.61	C43.62	C43.70	C43.71	C43.72	C43.8
C43.9	C44.00	C44.02	C44.09	C45.0	C61	C64.1
C64.2	C64.9	C65.1	C65.2	C65.9	C67.0	C67.1
C67.2	C67.3	C67.4	C67.5	C67.6	C67.7	C67.8
C67.9	C68.0	C69.30	C69.31	C69.32	C69.40	C69.41
C69.42	C69.60	C69.61	C69.62	C69.90	C69.91	C69.92
C7A.1	C7A.8	C7B.1	C7B.8	C76.0	C77.0	C78.00
C78.01	C78.02	C78.6	C78.7	C78.89	C79.31	C79.51
C79.52	C81.10	C81.11	C81.12	C81.13	C81.14	C81.15
C81.16	C81.17	C81.18	C81.19	C81.20	C81.21	C81.22
C81.23	C81.24	C81.25	C81.26	C81.27	C81.28	C81.29
C81.30	C81.31	C81.32	C81.33	C81.34	C81.35	C81.36
C81.37	C81.38	C81.39	C81.40	C81.41	C81.42	C81.43
C81.44	C81.45	C81.46	C81.47	C81.48	C81.49	C81.70
C81.71	C81.72	C81.73	C81.74	C81.75	C81.76	C81.77
C81.78	C81.79	C81.90	C81.91	C81.92	C81.93	C81.94
C81.95	C81.96	C81.97	C81.98	C81.99	C83.00	C83.01
C83.02	C83.03	C83.04	C83.05	C83.06	C83.07	C83.08
C83.09	C84.90	C84.91	C84.92	C84.93	C84.94	C84.95
C84.96	C84.97	C84.98	C84.99	C84.Z0	C84.Z1	C84.Z2
C84.Z3	C84.Z4	C84.Z5	C84.Z6	C84.Z7	C84.Z8	C84.Z9
C85.20	C85.21	C85.22	C85.23	C85.24	C85.25	C85.26
C85.27	C85.28	C85.29	C86.0	C91.10	C91.12	D09.0
D37.01	D37.02	D37.05	D37.09	D37.8	D37.9	D38.0
D38.5	D38.6	D39.2	D39.8	D39.9	Z85.00	Z85.01
Z85.038	Z85.068	Z85.118	Z85.21	Z85.22	Z85.51	Z85.59
Z85.71	Z85.810	Z85.818	Z85.819	Z85.820	Z85.821	Z85.858

Covered Diagnosis Codes for Procedure Code J9271

C00.0	C00.1	C00.2	C00.3	C00.4	C00.5	C00.6
C00.8	C01	C02.0	C02.1	C02.2	C02.3	C02.4
C02.8	C02.9	C03.0	C03.1	C03.9	C04.0	C04.1
C04.8	C04.9	C05.0	C05.1	C06.0	C06.2	C06.80
C06.89	C06.9	C09.0	C09.1	C09.8	C09.9	C10.3
C11.0	C11.1	C11.2	C11.3	C11.8	C11.9	C12
C13.0	C13.1	C13.2	C13.8	C13.9	C14.0	C14.2
C14.8	C15.3	C15.4	C15.5	C15.8	C15.9	C16.0
C16.1	C16.2	C16.3	C16.4	C16.5	C16.6	C16.8
C16.9	C17.0	C17.1	C17.2	C17.8	C17.9	C18.0
C18.1	C18.2	C18.3	C18.4	C18.5	C18.6	C18.7
C18.8	C18.9	C19	C20	C21.0	C21.1	C21.2
C21.8	C22.0	C22.1	C22.8	C22.9	C23	C24.0
C24.8	C24.9	C25.0	C25.1	C25.2	C25.3	C25.7
C25.8	C25.9	C31.0	C31.1	C32.0	C32.1	C32.2
C32.3	C32.8	C32.9	C33	C34.00	C34.01	C34.02
C34.10	C34.11	C34.12	C34.2	C34.30	C34.31	C34.32
C34.80	C34.81	C34.82	C34.90	C34.91	C34.92	C37
C38.4	C40.00	C40.01	C40.02	C40.10	C40.11	C40.12
C40.20	C40.21	C40.22	C40.30	C40.31	C40.32	C40.80
C40.81	C40.82	C40.90	C40.91	C40.92	C41.0	C41.1
C41.2	C41.3	C41.4	C41.9	C43.0	C43.10	C43.111
C43.112	C43.121	C43.122	C43.20	C43.21	C43.22	C43.30
C43.31	C43.39	C43.4	C43.51	C43.52	C43.59	C43.60
C43.61	C43.62	C43.70	C43.71	C43.72	C43.8	C43.9
C44.00	C44.02	C44.09	C44.121	C44.1221	C44.1222	C44.1291
C44.1292	C44.221	C44.222	C44.229	C44.320	C44.321	C44.329
C44.42	C44.520	C44.521	C44.529	C44.621	C44.622	C44.629
C44.721	C44.722	C44.729	C44.82	C44.92	C45.0	C48.0
C48.1	C48.2	C48.8	C49.0	C49.10	C49.11	C49.12
C49.20	C49.21	C49.22	C49.3	C49.4	C49.5	C49.6
C49.8	C49.9	C4A.0	C4A.10	C4A.111	C4A.112	C4A.121
C4A.122	C4A.20	C4A.21	C4A.22	C4A.30	C4A.31	C4A.39
C4A.4	C4A.51	C4A.52	C4A.59	C4A.60	C4A.61	C4A.62
C4A.70	C4A.71	C4A.72	C4A.8	C4A.9	C50.011	C50.012
C50.019	C50.021	C50.022	C50.029	C50.111	C50.112	C50.119
C50.121	C50.122	C50.129	C50.211	C50.212	C50.219	C50.221
C50.222	C50.229	C50.311	C50.312	C50.319	C50.321	C50.322
C50.329	C50.411	C50.412	C50.419	C50.421	C50.422	C50.429
C50.511	C50.512	C50.519	C50.521	C50.522	C50.529	C50.611
C50.612	C50.619	C50.621	C50.622	C50.629	C50.811	C50.812
C50.819	C50.821	C50.822	C50.829	C50.911	C50.912	C50.919
C50.921	C50.922	C50.929	C51.0	C51.1	C51.2	C51.8
C51.9	C53.0	C53.1	C53.8	C53.9	C54.0	C54.1
C54.2	C54.3	C54.8	C54.9	C55	C56.1	C56.2
C56.9	C57.00	C57.01	C57.02	C57.10	C57.11	C57.12
C57.20	C57.21	C57.22	C57.3	C57.4	C57.7	C57.8
C57.9	C60.0	C60.1	C60.2	C60.8	C60.9	C61
C62.00	C62.01	C62.02	C62.10	C62.11	C62.12	C62.90
C62.91	C62.92	C63.7	C63.8	C64.1	C64.2	C64.9
C65.1	C65.2	C65.9	C67.0	C67.1	C67.2	C67.3
C67.4	C67.5	C67.6	C67.7	C67.8	C67.9	C68.0
C69.30	C69.31	C69.32	C69.40	C69.41	C69.42	C69.60
C69.61	C69.62	C73	C74.00	C74.01	C74.02	C74.90
C74.91	C74.92	C76.0	C77.0	C78.00	C78.01	C78.02
C78.6	C78.7	C78.89	C79.31	C79.51	C79.52	C79.82
C7A.1	C7A.8	C7B.00	C7B.01	C7B.02	C7B.03	C7B.04
C7B.1	C7B.8	C80.0	C80.1	C81.10	C81.11	C81.12
C81.13	C81.14	C81.15	C81.16	C81.17	C81.18	C81.19
C81.20	C81.21	C81.22	C81.23	C81.24	C81.25	C81.26
C81.27	C81.28	C81.29	C81.30	C81.31	C81.32	C81.33
C81.34	C81.35	C81.36	C81.37	C81.38	C81.39	C81.40
C81.41	C81.42	C81.43	C81.44	C81.45	C81.46	C81.47
C81.48	C81.49	C81.70	C81.71	C81.72	C81.73	C81.74
C81.75	C81.76	C81.77	C81.78	C81.79	C81.90	C81.91
C81.92	C81.93	C81.94	C81.95	C81.96	C81.97	C81.98
C81.99	C83.00	C83.01	C83.02	C83.03	C83.04	C83.05
C83.06	C83.07	C83.08	C83.09	C84.00	C84.01	C84.02
C84.03	C84.04	C84.05	C84.06	C84.07	C84.08	C84.09
C84.10	C84.11	C84.12	C84.13	C84.14	C84.15	C84.16
C84.17	C84.18	C84.19	C84.90	C84.91	C84.92	C84.93
C84.94	C84.95	C84.96	C84.97	C84.98	C84.99	C84.Z0
C84.Z1	C84.Z2	C84.Z3	C84.Z4	C84.Z5	C84.Z6	C84.Z7
C84.Z8	C84.Z9	C85.20	C85.21	C85.22	C85.23	C85.24
C85.25	C85.26	C85.27	C85.28	C85.29	C86.0	C86.6
C91.10	C91.12	D09.0	D15.0	D37.01	D37.02	D37.05
D37.09	D37.1	D37.8	D37.9	D38.0	D38.5	D38.6
D39.2	D39.8	D39.9	Z85.00	Z85.01	Z85.028	Z85.038
Z85.068	Z85.07	Z85.118	Z85.21	Z85.22	Z85.3	Z85.43
Z85.47	Z85.49	Z85.51	Z85.59	Z85.71	Z85.810	Z85.818
Z85.819	Z85.820	Z85.821	Z85.830	Z85.831	Z85.858

Covered Diagnosis Codes for Procedure Code J9022

C22.0	C22.8	C22.9	C33	C34.00	C34.01	C34.02
C34.10	C34.11	C34.12	C34.2	C34.30	C34.31	C34.32
C34.80	C34.81	C34.82	C34.90	C34.91	C34.92	C50.011
C50.012	C50.019	C50.021	C50.022	C50.029	C50.111	C50.112
C50.119	C50.121	C50.122	C50.129	C50.211	C50.212	C50.219
C50.221	C50.222	C50.229	C50.311	C50.312	C50.319	C50.321
C50.322	C50.329	C50.411	C50.412	C50.419	C50.421	C50.422
C50.429	C50.511	C50.512	C50.519	C50.521	C50.522	C50.529
C50.611	C50.612	C50.619	C50.621	C50.622	C50.629	C50.811
C50.812	C50.819	C50.821	C50.822	C50.829	C50.911	C50.912
C50.919	C50.921	C50.922	C50.929	C61	C65.1	C65.2
C65.9	C66.1	C66.2	C66.9	C67.0	C67.1	C67.2
C67.3	C67.4	C67.5	C67.6	C67.7	C67.8	C67.9
C68.0	C7A.1	C7A.8	C78.00	C78.01	C78.02	C79.31
C79.51	C79.52	D09.0	Z85.3	Z85.51	Z85.59	Z85.118

Covered Diagnosis Codes for Procedure Code J9023

C4A.0	C4A.10	C4A.111	C4A.112	C4A.121	C4A.122	C4A.20
C4A.21	C4A.22	C4A.30	C4A.31	C4A.39	C4A.4	C4A.51
C4A.52	C4A.59	C4A.60	C4A.61	C4A.62	C4A.70	C4A.71
C4A.72	C4A.8	C4A.9	C61	C64.1	C64.2	C64.9
C65.1	C65.2	C65.9	C66.1	C66.2	C66.9	C67.0
C67.1	C67.2	C67.3	C67.4	C67.5	C67.6	C67.7
C67.8	C67.9	C68.0	C7B.1	D09.0	Z85.51	Z85.528
Z85.59	Z85.821

Professional Statements and Societal Positions Guidelines

Not Applicable

ND Committee Review

Internal Medical Policy Committee 11-14-2019 Coding update

Internal Medical Policy Committee 1-22-2020 Atezolizumab (Tecentriq®), Avelumab (Bavencio®), Cemiplimab-rwlc (Libtayo®), Durvalumab (Imfinzi™), Nivolumab (Opdivo®), Pembrolizumab (Keytruda®) - will require pre-certification as of 2/1/2020

Internal Medical Policy Committee 1-19-2021 FDA indications and/or NCCN recommendations updated for atezolizumab (Tecentriq), avelumab (Bavencio), cemiplimab (Libtayo), durvalumab (Imfinzi), nivolumab (Opdivo) and pembrolizumab (Keytruda)

Links

References (PDF)

Disclaimer

Current medical policy is to be used in determining a Member's contract benefits on the date that services are rendered. Contract language, including definitions and specific inclusions/exclusions, as well as state and federal law, must be considered in determining eligibility for coverage. Members must consult their applicable benefit plans or contact a Member Services representative for specific coverage information. Likewise, medical policy, which addresses the issue(s) in any specific case, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving and the Company reserves the right to review and update medical policy periodically.

Section: Injections

Effective Date: February 01, 2020

Revised Date: January 27, 2020

Archived Date: February 28, 2021

Description

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.

FDA--U.S. Food and Drug Administration

NCCN--National Comprehensive Cancer Network

NSCLC--Non-Small Cell Lung Cancer

Criteria

Coverage is subject to the specific terms of the member’s benefit plan.

Atezolizumab (Tecentriq) may be considered medically necessary foradult individuals 18 years of age and older for ANY of the following conditions:

Bladder (Urothelial) Cancer (NCCN)

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 two – three (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 two – three (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; or

Breast Cancer, Triple-Negative, TNBC (FDA)

Used in combination with paclitaxel protein-bound for the treatment of unresectable locally advanced or metastatic TNBC with tumors which express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA approved test; or

Breast Cancer, Invasive, Mucinous, Ductal, Lobular, Mixed, Metaplastic, Tubular, Inflammatory, Papillary, Unknown (NCCN)

Preferred therapy in combination with albumin-bound paclitaxel for PD-L1 positive triple negative recurrent or stage IV (M1) disease; or

Lung Cancer, Metastatic, Non-Small Cell Lung Cancer, NSCLC (FDA)

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); or
First line treatment of individuals with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations in combination with bevacizumab, paclitaxel and carboplatin; or

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

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; or

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

Treatment for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (greater than or equal to 1%) tumors that are EGFR, ALK negative or unknown and no contraindicaionts to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) and performance status 0-2 in combination with carboplatin, paclitaxel, and bevacizumab for nonsquamous cell histology; or
Continuation maintenance therapy as a single agent or in combination with bevacizumab for recurrent, advanced or metastatic disease for PD-L1 expression positive (greater than or equal to 1%) tumors that are EGFR ALK negative or unknown and no contraindications to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) in individuals with performance status 0-2 who achieve tumor response or stable disease following first-line therapy with atezolizumab/carboplatin/paclitaxel/bevacizumab for nonsquamous cell histology; or
Treatment for recurrent, advanced, or metastatic disease in combination with carboplatin, paclitaxel, and bevacizumab for individuals with performance status (PS) 0-1, no contraindications to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq), and tumors of nonsquamous cell histology as:
- Initial systemic therapy for EGFR, ALK, ROS1, BRAF negative or unknown, and PDL1 <1% 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 (≥1%) 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, advanced or metastatic disease, performance status 0-2, and tumors of nonsquamous cell histology in individuals who achieve tumor response or stable disease following initial systemic therapy; or

Lung Cancer, Small Cell Carcinoma (FDA)

Used in combination with carboplatin and etoposide, for the first-line treatment of individuals with extensive-stage small cell lung cancer (ES-SCLC); or

Lung Cancer, Small Cell Carcinoma (NCCN)

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; or

Urothelial Cancer, Locally Advanced or Metastatic (FDA)

Individuals 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
Individuals who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status; or
Individuals who have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy; or

Urothelial Cancer, Upper Genitourinary (GU) or Prostate (NCCN)

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*); or

Urothelial Cancer, Urethra, Primary (NCCN)

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.

Procedure Codes

J9022

Avelumab (Bavencio) may be considered medically necessary forANYof the following conditions:

Bladder (Urothelial) Carcinoma, Locally Advanced or Metastatic (FDA)

Individuals with disease progression during or following platinum-containing chemotherapy; or
Individuals with disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; or

Bladder (Urothelial) Carcinoma (NCCN)

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 concurrent chemoradiotherapy; or
- Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy or concurrent chemoradiotherapy; or
- Stage IVB (any T, any N, M1b) disease; or
- Metastatic or local recurrence post cystectomy; or

Genitourinary Tract Tumors, Upper, or Urothelial Carcinoma of the Prostate (Bladder) (NCCN)

As single agent subsequent systemic therapy for metastatic disease post-platinum (alternative preferred regimen*); or

Kidney (Renal) Cell Carcinoma (FDA)

First-line treatment, in combination with axitinib of individuals with advanced renal cell carcinoma (RCC); or

Kidney Cancer, Clear Cell (NCCN)

First-line or subsequent therapy, in combination with axitinib of individuals with relapse or stage IV disease and clear cell histology; or

Merkel Cell Carcinoma, MCC (FDA)

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

Merkel Cell Carcinoma, MCC (NCCN)

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

Urethra, Primary Carcinoma (Bladder) (NCCN)

Treatment of individuals with primary carcinoma of the urethra as a single agent for recurrent or metastatic disease as subsequent systemic therapy post-platinum

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.

Procedure Codes

J9023

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

Squamous Cell Carcinoma, Cutaneous, Locally Advanced or Metastatic (FDA and NCCN)

Treatment of individuals 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.

Procedure Codes

J9119

Durvalumab (Imfinzi) may be considered medically necessary forANYof the following conditions:

Bladder (Urothelial) Carcinoma (FDA)

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; or

Bladder (Urothelial) Carcinoma (NCCN)

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

Genitourinary Tract Tumors, Upper, or Urothelial Carcinoma of the Prostate (Bladder) (NCCN)

Therapy for metastatic disease asasingle agent subsequent systemic therapy post-platinum (alternative preferred*); or

Lung Cancer, Non-Small Cell Lung Cancer, NSCLC (FDA)

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

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

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; or

Urothelial Cancer, Urethra, Primary (Bladder) (NCCN)

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

Procedure Codes

J9173

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

Anal Carcinoma – Squamous Cell (NCCN)

Preferred single agent second-line or subsequent therapy for metastatic disease; or

Bladder (Urothelial) Carcinoma (NCCN)

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; or

Central Nervous System Cancers - Brain Metastases – Limited or Extensive (NCCN)

Treatment of individuals with melanoma with limited brain metastases as single agent or in combination with ipilimumab:
- For newly diagnosed brain metastases in select individuals (e.g., individuals with small asymptomatic brain metastases) stable systemic disease or reasonable systemic treatment options; or
- For recurrent brain metastases; or
Treatment of individuals with non-small cell lung cancer, NSCLC, with limited brain metastases as a single agent for newly diagnosed brain metastases in select individuals (e.g., individuals with small asymptomatic brain metastases) and stable systemic disease or reasonable systemic treatment options; or
Treatment of individuals with extensive brain metastases:
- Used as a single agent or in combination with ipilimumab as treatment for recurrent brain metastases in individuals with melanoma and stable systemic disease or reasonable systemic treatment options; or

Colon or Rectal Cancer, Adenocarcinoma (NCCN)

As primary treatment as a single agentor in combination with ipilimumabfor 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 agentor in combination with ipilimumabfor 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 (Opdivo) or pembrolizumab (Keytruda) not previously given) or in combination with ipilimumab (if no previous treatment with a checkpoint inhibitor) for unresectable advanced or metastatic disease (dMMR/MSI-Honly) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy; or

Colorectal Cancer (FDA)

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

Genitourinary Tract Tumors, Upper, or Urothelial Carcinoma of the Prostate (Bladder) (NCCN)

As single agent subsequent systemic therapy for metastatic disease post-platinum (alternative preferred*); or

Gestational Trophoblastic Neoplasia (NCCN)

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

Head and Neck Cancer (FDA)

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

Head and Neck Cancers, Very Advanced, Squamous Cell Carcinoma with Mixed Subtypes (NCCN)

As single agent second-line or subsequent therapy for non-nasopharyngeal cancer if disease progression on or after platinum-containing chemotherapy or for nasopharyngeal disease if previously treated, recurrent or metastatic non-keratinizing disease 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; or

Hepatocellular Carcinoma, HCC (FDA)

Treatment of individuals withHCCwho have been previously treated with sorafenib; or

Hepatocellular Carcinoma, HCC, Adenocarcinoma (NCCN)

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; or

Kidney (Renal) Cell Carcinoma (FDA)

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

Kidney (Renal) Cell Carcinoma (RCC), Clear Cell or Non-Clear Cell (NCCN)

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 forfour (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; or

Leukemia, Chronic Lymphocytic, CLL/Small Lymphocytic Lymphoma (NCCN)

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 individuals with del(17p)/TP53 mutation or who are chemotherapy refractory and unable to receive chemoimmunotherapy; or

Lung Cancer, Non-Small Cell Lung Cancer, NSCLC (FDA)

MetastaticNSCLCand 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 (1) other line of therapy; or

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

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; or

Lung Cancer, Small Cell Lung Cancer, SCLC (NCCN)

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; or

Lymphoma, Hodgkin Classic (FDA)

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; or

Lymphoma, Hodgkin Classic, cHL (NCCN)

Second-line or subsequent systemic therapy (if not previously used) in adult individuals greater than or equal to 18 years of age for relapsed or refractory disease in combination with brentuximab vendotin; or
Third-line or subsequent systemic therapy for adults individuals greater than or equal to 18 years of age as a single agent for:
- Disease that has relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) ± brentuximab vedotin; or
- Relapsed/refractory disease in individuals who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy; or
- Post-allogeneic transplant; or
Palliative therapy as a single agent in older adults (greater than 60 years of age) for:
- Disease that has relapsed or progressed after autologous HSCT with or without bretuximab vedotin; or
- Relapsed/refractory disease in individuals who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy; or
- Post-allogeneic transplant; or

Lymphomas, T-Cell, Extranodal NK/T-Cell Lymphoma, Nasal Type (NCCN)

Treatmentfor relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used; or

Melanoma (FDA)

Unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab; or
Lymph node involvement or metastatic disease in individulas who have undergone complete resection, in the adjuvant setting; or

Melanoma, Cutaneous (NCCN)

As preferred* adjuvant therapy as a single agent:
- For resected stage III sentinel node positive disease during 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
Preferred second-line or subsequent therapy for metastatic or unresectable disease after disease progression or maximum clinical benefit from BRAF targeted therapy:
- Asa single agent or in combination with ipilmumab if checkpoint inhibitor immunotherapy was not previously used; or
- Incombination with ipilimumab for individuals who progress on single-agent checkpoint inhibitor immunotherapy; or
- May be considered as re-induction therapy (as a single agent or in combination with ipilimumb)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

Melanoma, Uveal (NCCN)

Treatment of individuals with distant metastatic uveal melanoma as single agent therapy or in combination with ipilimumab; or

Merkel Cell Carcinoma, MCC (NCCN)

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

Mesothelioma, Malignant Pleural, Epithelial, Sarcomatoid, or Mixed (NCCN)

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

Prostate Cancer, Urothelial (Bladder) Carcinoma (NCCN)

Therapy for metastatic disease as single agent subsequent systemic therapy post-platinum; or

Small Bowel Adenocarcinoma (NCCN)

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

Urothelial Carcinoma, Locally Advanced or Metastatic (FDA)

Individuals with disease progression during or following platinum-containing chemotherapy; or
Individuals with disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; or

Urothelial Cancer, Urethra, Primary (Bladder) (NCCN)

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

Procedure Codes

J9299

Pembrolizumab (Keytruda) may be considered medically necessary forANYof the following conditions:

Anal Carcinoma, Squamous Cell Carcinoma (NCCN)

Treatment of individuals with squamous cell anal carcinoma as second- line or subsequent, single agent therapy for metastatic disease; or

Bladder (Urothelial) Carcinoma (FDA)

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 within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; or

Bladder (Urothelial) Carcinoma (NCCN)

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 two – three (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 two – three (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; or

Bladder (Urothelial) Cancer, Urethra, Primary (NCCN)

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*); or

Central Nervous System Cancers - Extensive Brain Metastases (NCCN)

Single-agent treatment for recurrent brain metastases in individuals with melanoma or PD-L1-positive non-small cell lung cancer and stable systemic disease or reasonable systemic treatment options; or

Central Nervous System Cancers - Limited Brain Metastases (NCCN)

Single-agent treatment for brain metastases in individuals with melanoma or PD-L1-positive non-small cell lung cancer, NSCLC:
- For newly diagnosed brain metastases in select individuals (e.g., individuals with small asymptomatic brain metastases) and stable systemic disease or reasonable systemic treatment options; or
- For recurrent brain metastases; or

Cervical Cancer (FDA)

Treatment of individuals with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 [Combined Positive Score (CPS) greater than or equal to one (1)]; or

Cervical Cancer – Squamous cell carcinoma, Adenocarcinoma (NCCN)

Preferred second-line therapy as a single agent for recurrent or metastatic disease if:
- Instability-high, MSI-H, or mismatch repair deficient, dMMR tumors; or
- Disease progression on or after chemotherapy in individuals whose tumors express PDL1 (CPS ≥1); or

Endometrial Carcinoma (FDA)

Treatment of individuals with advanced endometrial carcinoma that in not MSI-H or dMMR; and
Individual has disease progression following prior systemic therapy; and
Individual is not a candidate for curative surgery or radiation; and
Pembrolizumab (Keytruda) is given in combination with lenvatinib; or

Esophageal Cancer (FDA)

Treatment of individuals with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 [Combined Positive Score (CPS) greater than or equal to 10]; and
Disease progression after one (1) or more prior lines of systemic therapy; or

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

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 microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors; or
- Second-line therapy for esophageal squamous cell carcinoma (SCC), esophageal adenocarcinoma and EGJ adenocarcinoma with PD-L1 expression by CPS of levels greater than or equal to 10; or
- Third-line or subsequent therapy as a single agent for esophageal and EGJ adenocarcinoma with PD-L1 expression levels by CPS of greater than or equal to one (1); or

Gastric Cancer (FDA)

Treatment of individuals with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma:
- Whose tumors express PD-L1 [Combined Positive Score (CPS) greater than or equal to 1]; and
- With disease progression on or after two (2) or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy; or

Gastric Cancer, Adenocarcinoma (NCCN)

Palliative therapy for unresectable locally advanced, recurrent, or metastatic disease and Karnofsky performance score ≥60% or ECOG performance score ≤2 as:
- Preferred second-line or subsequent therapy as a single agent for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors; or
- Third-line or subsequent therapy as a single agent for gastric adenocarcinoma with PD-L1 expression levels by CPS of ≥1; or

Genitourinary, Upper Tract Tumors or Urothelial Carcinoma of the Prostate (Bladder) (NCCN)

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 (preferred*); or

Gestational Trophoblastic Neoplasia (NCCN)

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

Head and Neck Squamous Cell Cancer, HNSCC (FDA)

Combination treatment with platinum and FU for first-line treatment of individuals with metastatic or unresectable, recurrent HNSCC; or
Single agent treatment for 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 1); or
Single agent treatment of individuals with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy; or

Head and Neck Cancer, Very Advanced, Squamous Cell Carcinoma with Mixed Subtypes (NCCN)

Therapy as single agent first-line therapy option for non-nasopharyngeal cancer if PD-L1 positive tumors in:
- Newly diagnosed T4b, any N 0-3, 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; or
Therapy as a preferred single agent second line or subsequent therapy option 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 0-3, 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; or
Systemic therapy as a preferred first-line, second-line, or subsequent therapy option for non-nasopharyngeal cancer in combination with fluorouracil and either carboplatin or cisplatin for:
- Metastatic (M1) disease at initial presentation; or
- Recurrent/persistent disease with distant metastases; or
- Unresectable locoregional recurrence or second primary with prior RT; or

Hepatobiliary Cancer, HCC (FDA)

Treatment of individuals with HCC who have been previously treated with sorafenib; or

Hepatocellular Carcinoma, Adenocarcinoma (NCCN)

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; or

Kidney (Renal) Cell Carcinoma, RCC (FDA)

Combination therapy with axitinib, for first line treatment of individuals with advanced RCC; or

Kidney Cancer, Clear Cell (NCCN)

Used in combination with axitinib for relapsed or stage IV disease;
- As preferred 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 subsequent therapy for clear cell histology; or

Leukemia, Chronic Lymphocytic /Small Lymphocytic Lymphoma (NCCN)

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); and
- For individuals with del(17p)/TP53 mutation; or
- Individuals who are chemotherapy refractory and unable to receive chemoimmunotherapy; or

Lung Cancer, NSCLC (FDA)

As first-line treatment in combination with pemetrexed and platinum chemotherapy for metastatic 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 (paclitaxel protein-bound) for metastatic squamous NSCLC;or
As first-line, single agent for 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 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); or

Lung Cancer, NSCLC, Adenocarcinoma (with mixed subtypes), Large Cell Carcinoma, Squamous Cell Carcinoma (NCCN)

Treatment for recurrent, advanced or metastatic disease as first-line therapy for PD-L1 expression-positive (≥1%) tumors that are EGFR, ALK negative or unknown and no contraindications to the addition of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) and performance status 0-2:
- As a single agent** (preferred if PD-L1 ≥50%); or
- In combination with pemetrexed and either carboplatin or cisplatin for nonsquamous cell histology (preferred if PD-L1 1-49%); or
- In combination with either carboplatin or cisplatin and either paclitaxel or albumin-bound paclitaxel for squamous cell histology (preferred if PD-L1 1-49%); or

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

Continuation maintenance therapy for recurrent, advanced or metastatic disease for PD-L1 expression positive (≥1%) tumors that are EGFR, ALK negative or unknown and no contraindications to the addition of pembrolizumab (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; or
- 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; or
Treatment for recurrent, advanced or metastatic disease in combination with pemetrexed and either carboplatin or cisplatin (as preferred regimens if no contraindications to the addition of pembrolizumab (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 incombination 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 <1% 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 (greater than or equal to 1%) tumors and EGFR, ALK negative or unknown and no prior platinum-doubletchemotherapy; 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; or

Lung Cancer, NSCLC, Adenocarcinoma (with mixed subtypes), Large Cell Carcinoma (NCCN)

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 individuals with PS 0-2, who achieve tumor response or stable disease following initial systemic therapy; or

Lung Cancer, NSCLC, Squamous Cell Carcinoma (NCCN)

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; or

Lung Cancer, Small Cell (FDA)

Treatment of metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy; or

Lung Cancer, Small Cell, Small Cell Carcinoma (NCCN)

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

Lymphoma, B-Cell, Diffuse Large B-Cell Lymphoma (NCCN)

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

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

For treatment of relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used, if a clinical trial is unavailable; or

Lymphoma, Hodgkin, Classic, cHL (FDA)

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

Lymphoma, Hodgkin, Classic, cHL (NCCN)

Treatment of Adult individuals aged 18 years and older as third-line or subsequent systemic therapy as a single agent for:
- Disease that has relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) with or without brentuximab vedotin; or
- Relapsed/refractory disease in individuals who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy; or
- Post-allogeneic transplant; or
Treatment of individuals greater than 60 years of age as palliative therapy as a single agent for:
- Disease that has relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) ± brentuximab vedotin; or
- Relapsed/refractory disease in individuals who are transplant-ineligible based on comorbidity or failure of second-line chemotherapy; or
- Post-allogeneic transplant; or

Lymphoma, Primary Mediastinal Large B-Cell (PMBCL) (FDA)

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.

Lymphproliferative Disorders, Primary Cutaneous CD30+ T-Cell (NCCN)

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; or

Melanoma (FDA)

Treatment of individuals with unresectable or metastatic disease; or
Adjuvant treatment of individuals with melanoma with involvement of lymph node(s) following complete resection; or

Melanoma – Cutaneous Melanoma (NCCN)

Adjuvant treatment as a single agent:
- For stage III sentinel lymph node, 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

Melanoma, Uveal (NCCN)

Consider as single agent therapy for distant metastatic disease; or

Merkel Cell Carcinoma, MCC (FDA)

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

Merkel Cell Carcinoma, MCC (NCCN)

Preferred treatment of individuals with disseminated, clinical M1 disease with or without surgery and/or radiation therapy; or
Treatment for individuals with recurrent locally advanced disease; or

Mesothelioma, Malignant Pleural, Epithelial, Sarcomatoid, Mixed (NCCN)

Subsequent systemic therapy as a single agent; or

Microsatellite Instability-High, MSI-H, Cancer (FDA)

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; 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.

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

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.

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:
- Chondrosarcoma; or
- 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:
- Uterine neoplasms, Endometrial Carcinoma; or
As single agent second-line or subsequent therapy for progression after at least one (1) 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 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:
- Colon Adenocarcinoma; or
- Rectal Adenocarcinoma; or
As single agent, primary therapy for unresectable metachronous metastases with previous adjuvant FOLFOX or CapeOx with in the last 12 months for:
- Colon Adenocarcinoma; or
- Rectal Adenocarcinoma; or
As single agent, subsequent therapy (if nivolumab (Opdivo) or pembrolizumab (Keytruda) not previously given) for unresectable, advanced or metastatic disease following oxaliplatin- irinotecan- and/or fluoropyrimidine based therapy for:
- Colon Adenocarcinoma; or
- Rectal Adenocarcinoma; or
Treatment of unresectable/metastatic adrenocortical tumors that have progressed following prior treatment with no satisfactory alternative treatment options; or
Treatment of dMMR or MSI-H, poorly differentiated (high grade)/large or small cell neuroendocrine and adrenal tumors that have progressed following prior treatment with no satisfactory alternative treatment options; or

Mycosis Fungoides (MF)/Sezary Syndrome (SS) (NCCN)

Primary systemic therapy for:
- Stage III MF; or
- Stage IV Sezary syndrome; or
Systemic therapy as treatment for:
- Relapsed or persistent stage IA MF with B1 blood involvement, with or without skin-directed therapy; or
- Relapsed or persistent stage IB-IIA MFwith 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 to multiple previous therapies or progression; or
- Relapsed or persistent stage III MF, with or without skin-directed therapies; or
- Stage III MF that is refractory to multiple previous therapies; or
- Relapsed or persistent stage IV SS; 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; or

Pancreatic Adenocarcinoma (NCCN)

Treatment of individuals with microsatellite instability-high or mismatch repair deficient tumors MSI-H/dMMR tumors with good performance status (ECOG PS 0-1):
- 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; or

Prostate, Urothelial (Bladder) Carcinoma (NCCN)

Therapy for metastatic disease as a single agent 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; or
- Subsequent systemic therapy post-platinum (preferred regimen*); or

Sarcoma, Soft Tissue (NCCN)

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

Thymic Carcinoma (NCCN)

Second-line therapy for thymic carcinoma as a single agent for unresectable disease following first-line chemotherapy for potentially resectable locally advanced disease, solitary metastasis, or ipsilateral pleural metastasis; or
Second-line therapy for thymic carcinoma as a single agent for extrathoracic metastatic disease; or

Vulvar Cancer, Squamous Cell Carcinoma (NCCN)

Second-line therapy as a single agent 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)

Procedure Codes

J9271

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. Blue Cross Blue Shield of North Dakota 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.

Diagnosis Codes

Covered Diagnosis Codes for Procedure Codes J9119

C44.02	C44.121	C44.1221	C44.1222	C44.1291	C44.1292	C44.221
C44.222	C44.229	C44.320	C44.321	C44.329	C44.42	C44.520
C44.521	C44.529	C44.621	C44.622	C44.629	C44.721	C44.722
C44.729	C44.82	C44.92	Z85.828

Covered Diagnosis Codes for Procedure Code J9173

C33	C34.00	C34.01	C34.02	C34.10	C34.11	C34.12
C34.2	C34.30	C34.31	C34.32	C34.80	C34.81	C34.82
C34.90	C34.91	C34.92	C61	C65.1	C65.2	C65.9
C66.1	C66.2	C66.9	C67.0	C67.1	C67.2	C67.3
C67.4	C67.5	C67.6	C67.7	C67.8	C67.9	C68.0
D09.0	Z85.51	Z85.59

Covered Diagnosis Codes for Procedure Code J9299

C00.0	C00.1	C00.2	C00.3	C00.4	C00.5	C00.6
C00.8	C01	C02.0	C02.1	C02.2	C02.3	C02.4
C02.8	C02.9	C03.0	C03.1	C03.9	C04.0	C04.1
C04.8	C04.9	C05.0	C05.1	C06.0	C06.2	C06.80
C06.89	C06.9	C09.0	C09.1	C09.8	C09.9	C10.3
C11.0	C11.1	C11.2	C11.3	C11.8	C11.9	C12
C13.0	C13.1	C13.2	C13.8	C13.9	C14.0	C14.2
C14.8	C17.0	C17.1	C17.2	C17.3	C17.8	C17.9
C18.0	C18.1	C18.2	C18.3	C18.4	C18.5	C18.6
C18.7	C18.8	C18.9	C19	C20	C21.0	C21.1
C21.2	C21.8	C22.0	C22.9	C31.0	C31.1	C32.0
C32.1	C32.3	C32.8	C32.9	C33	C34.00	C34.01
C34.02	C34.10	C34.11	C34.12	C34.2	C34.30	C34.31
C34.32	C34.80	C34.81	C34.82	C34.90	C34.91	C34.92
C38.4	C4A.0	C4A.10	C4A.111	C4A.112	C4A.121	C4A.122
C4A.20	C4A.21	C4A.22	C4A.30	C4A.31	C4A.39	C4A.4
C4A.51	C4A.52	C4A.59	C4A.60	C4A.61	C4A.62	C4A.70
C4A.71	C4A.72	C4A.8	C4A.9	C43.0	C43.10	C43.111
C43.112	C43.121	C43.122	C43.20	C43.21	C43.22	C43.30
C43.31	C43.39	C43.4	C43.51	C43.52	C43.59	C43.60
C43.61	C43.62	C43.70	C43.71	C43.72	C43.8	C43.9
C44.00	C44.02	C44.09	C45.0	C61	C64.1	C64.2
C64.9	C65.1	C65.2	C65.9	C66.1	C66.2	C66.9
C67.0	C67.1	C67.2	C67.3	C67.4	C67.5	C67.6
C67.7	C67.8	C67.9	C68.0	C69.30	C69.31	C69.32
C69.40	C69.41	C69.42	C69.60	C69.61	C69.62	C69.90
C69.91	C69.92	C7A.1	C7B.1	C76.0	C77.0	C78.00
C78.01	C78.02	C78.6	C78.7	C78.89	C79.31	C79.51
C79.52	C81.10	C81.11	C81.12	C81.13	C81.14	C81.15
C81.16	C81.17	C81.18	C81.19	C81.20	C81.21	C81.22
C81.23	C81.24	C81.25	C81.26	C81.27	C81.28	C81.29
C81.30	C81.31	C81.32	C81.33	C81.34	C81.35	C81.36
C81.37	C81.38	C81.39	C81.40	C81.41	C81.42	C81.43
C81.44	C81.45	C81.46	C81.47	C81.48	C81.49	C81.70
C81.71	C81.72	C81.73	C81.74	C81.75	C81.76	C81.77
C81.78	C81.79	C81.90	C81.91	C81.92	C81.93	C81.94
C81.95	C81.96	C81.97	C81.98	C81.99	C83.00	C83.01
C83.02	C83.03	C83.04	C83.05	C83.06	C83.07	C83.08
C83.09	C84.90	C84.91	C84.92	C84.93	C84.94	C84.95
C84.96	C84.97	C84.98	C84.99	C84.Z0	C84.Z1	C84.Z2
C84.Z3	C84.Z4	C84.Z5	C84.Z6	C84.Z7	C84.Z8	C84.Z9
C86.0	C91.10	C91.12	D09.0	D37.01	D37.02	D37.05
D37.09	D38.0	D38.5	D38.6	D39.2	D39.8	D39.9
Z85.038	Z85.068	Z85.118	Z85.21	Z85.22	Z85.51	Z85.528
Z85.59	Z85.71	Z85.810	Z85.818	Z85.819	Z85.820	Z85.821

Covered Diagnosis Codes for Procedure Code J9271

C00.0	C00.1	C00.2	C00.3	C00.4	C00.5	C00.6
C00.8	C01	C02.0	C02.1	C02.2	C02.3	C02.4
C02.8	C02.9	C03.0	C03.1	C03.9	C04.0	C04.1
C04.8	C04.9	C05.0	C05.1	C06.0	C06.2	C06.80
C06.89	C06.9	C09.0	C09.1	C09.8	C09.9	C10.3
C11.0	C11.1	C11.2	C11.3	C11.8	C11.9	C12
C13.0	C13.1	C13.2	C13.8	C13.9	C14.0	C14.2
C14.8	C15.3	C15.4	C15.5	C15.8	C15.9	C16.0
C16.1	C16.2	C16.3	C16.4	C16.5	C16.6	C16.8
C16.9	C17.0	C17.1	C17.2	C17.8	C17.9	C18.0
C18.1	C18.2	C18.3	C18.4	C18.5	C18.6	C18.7
C18.8	C18.9	C19	C20	C21.0	C21.1	C21.2
C21.8	C22.0	C22.1	C22.9	C23	C24.0	C24.8
C24.9	C25.0	C25.1	C25.2	C25.3	C25.7	C25.8
C25.9	C31.0	C31.1	C32.0	C32.1	C32.2	C32.3
C32.8	C32.9	C33	C34.00	C34.01	C34.02	C34.10
C34.11	C34.12	C34.2	C34.30	C34.31	C34.32	C34.80
C34.81	C34.82	C34.90	C34.91	C34.92	C37	C38.4
C40.00	C40.01	C40.02	C40.10	C40.11	C40.12	C40.20
C40.21	C40.22	C40.30	C40.31	C40.32	C40.80	C40.81
C40.82	C40.90	C40.91	C40.92	C41.0	C41.1	C41.2
C41.3	C41.4	C41.9	C43.0	C43.10	C43.111	C43.112
C43.121	C43.122	C43.20	C43.21	C43.22	C43.30	C43.31
C43.39	C43.4	C43.51	C43.52	C43.59	C43.60	C43.61
C43.62	C43.70	C43.71	C43.72	C43.8	C43.9	C44.00
C44.02	C44.09	C45.0	C48.1	C48.2	C48.8	C49.0
C49.10	C49.11	C49.12	C49.20	C49.21	C49.22	C49.4
C49.5	C49.6	C49.8	C49.9	C4A.0	C4A.10	C4A.111
C4A.112	C4A.121	C4A.122	C4A.20	C4A.21	C4A.22	C4A.30
C4A.31	C4A.39	C4A.4	C4A.51	C4A.52	C4A.59	C4A.60
C4A.61	C4A.62	C4A.70	C4A.71	C4A.72	C4A.8	C4A.9
C51.0	C51.1	C51.2	C51.8	C51.9	C53.0	C53.1
C53.8	C53.9	C54.0	C54.1	C54.2	C54.3	C54.8
C54.9	C55	C56.1	C56.2	C56.9	C57.00	C57.01
C57.02	C57.10	C57.11	C57.12	C57.20	C57.21	C57.22
C57.3	C57.4	C57.7	C57.8	C57.9	C60.0	C60.1
C60.2	C60.8	C60.9	C61	C62.00	C62.01	C62.02
C62.10	C62.11	C62.12	C62.90	C62.91	C62.92	C63.7
C63.8	C64.1	C64.2	C64.9	C65.1	C65.2	C65.9
C66.1	C66.2	C66.9	C67.0	C67.1	C67.2	C67.3
C67.4	C67.5	C67.6	C67.7	C67.8	C67.9	C68.0
C69.30	C69.31	C69.32	C69.40	C69.41	C69.42	C69.60
C69.61	C69.62	C69.90	C69.91	C69.92	C74.00	C74.01
C74.02	C74.90	C74.91	C74.92	C76.0	C77.0	C78.00
C78.01	C78.02	C78.6	C78.7	C78.89	C79.31	C79.51
C79.52	C79.82	C79.89	C79.9	C7A.1	C7A1	C7B.00
C7B.01	C7B.02	C7B.03	C7B.04	C7B.1	C7B.8	C81.10
C81.11	C81.12	C81.13	C81.14	C81.15	C81.16	C81.17
C81.18	C81.19	C81.20	C81.21	C81.22	C81.23	C81.24
C81.25	C81.26	C81.27	C81.28	C81.29	C81.30	C81.31
C81.32	C81.33	C81.34	C81.35	C81.36	C81.37	C81.38
C81.39	C81.40	C81.41	C81.42	C81.43	C81.44	C81.45
C81.46	C81.47	C81.48	C81.49	C81.70	C81.71	C81.72
C81.73	C81.74	C81.75	C81.76	C81.77	C81.78	C81.79
C81.90	C81.91	C81.92	C81.93	C81.94	C81.95	C81.96
C81.97	C81.98	C81.99	C83.00	C83.01	C83.02	C83.03
C83.04	C83.05	C83.06	C83.07	C83.08	C83.09	C84.00
C84.01	C84.02	C84.03	C84.04	C84.05	C84.06	C84.07
C84.08	C84.09	C84.10	C84.11	C84.12	C84.13	C84.14
C84.15	C84.16	C84.17	C84.18	C84.19	C84.90	C84.91
C84.92	C84.93	C84.94	C84.95	C84.96	C84.97	C84.98
C84.99	C84.Z0	C84.Z1	C84.Z2	C84.Z3	C84.Z4	C84.Z5
C84.Z6	C84.Z7	C84.Z8	C84.Z9	C85.20	C85.21	C85.22
C85.23	C85.24	C85.25	C85.26	C85.27	C85.28	C85.29
C86.0	C86.6	C91.10	C91.12	D09.0	D15.0	D37.01
D37.02	D37.05	D37.09	D37.1	D37.8	D37.9	D38.0
D38.5	D38.6	D39.2	D39.8	D39.9	Z85.00	Z85.01
Z85.028	Z85.038	Z85.068	Z85.07	Z85.118	Z85.21	Z85.22
Z85.43	Z85.46	Z85.47	Z85.49	Z85.51	Z85.528	Z85.59
Z85.71	Z85.810	Z85.818	Z85.819	Z85.820	Z85.821	Z85.830
Z85.831	Z85.858

Covered Diagnosis Codes for Procedure Code J9022

C33	C34.00	C34.01	C34.02	C34.10	C34.11	C34.12
C34.2	C34.30	C34.31	C34.32	C34.80	C34.81	C34.82
C34.90	C34.91	C34.92	C50.011	C50.012	C50.019	C50.021
C50.022	C50.029	C50.111	C50.112	C50.119	C50.121	C50.122
C50.129	C50.211	C50.212	C50.219	C50.221	C50.222	C50.229
C50.311	C50.312	C50.319	C50.321	C50.322	C50.329	C50.411
C50.412	C50.419	C50.421	C50.422	C50.429	C50.511	C50.512
C50.519	C50.521	C50.522	C50.529	C50.611	C50.612	C50.619
C50.621	C50.622	C50.629	C50.811	C50.812	C50.819	C50.821
C50.822	C50.829	C50.911	C50.912	C50.919	C50.921	C50.922
C50.929	C61	C65.1	C65.2	C65.9	C66.1	C66.2
C66.9	C67.0	C67.1	C67.2	C67.3	C67.4	C67.5
C67.6	C67.7	C67.8	C67.9	C68.0	C7A.1	C78.00
C78.01	C78.02	C79.31	C79.51	C79.52	D09.0	Z85.3
Z85.51	Z85.59	Z85.118

Covered Diagnosis Codes for Procedure Code J9023

C4A.0	C4A.10	C4A.111	C4A.112	C4A.121	C4A.122	C4A.20
C4A.21	C4A.22	C4A.30	C4A.31	C4A.39	C4A.4	C4A.51
C4A.52	C4A.59	C4A.60	C4A.61	C4A.62	C4A.70	C4A.71
C4A.72	C4A.8	C4A.9	C61	C64.1	C64.2	C64.9
C65.1	C65.2	C65.9	C66.1	C66.2	C66.9	C67.0
C67.1	C67.2	C67.3	C67.4	C67.5	C67.6	C67.7
C67.8	C67.9	C68.0	C7B.1	D09.0	Z85.51	Z85.528
Z85.59	Z85.821

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