Anthem Yervoy (ipilimumab) Coverage Update

Coverage Criteria and Indications

Covered indications with criteria

Covered when ANY of the following diagnosis-specific ANDed criteria are met (selected entries from document window):

OR XII - Esophagectomy/palliative dysphagia: Individual is using ipilimumab to relieve dysphagia and is medically fit and planned for esophagectomy; has not received another anti-PD-1 or anti-PD-L1 agent; and is not receiving therapy for an autoimmune disease or chronic condition requiring systemic immunosuppressant therapy.

XIII - Gestational trophoblastic neoplasia: Individual has multi-agent chemotherapy-resistant gestational trophoblastic neoplasia with recurrent or progressive intermediate trophoblastic tumor or high-risk disease; ipilimumab is being used in combination with nivolumab; individual has not received another anti-PD-1 or anti-PD-L1 agent; and is not receiving systemic immunosuppressant therapy.

XIV - Advanced hepatocellular carcinoma: Individual has advanced hepatocellular carcinoma and is using ipilimumab in combination with nivolumab; individual has ECOG performance status 0-2; has not received another anti-PD-1 or anti-PD-L1 agent; and is not receiving systemic immunosuppressant therapy.ECOG 0-2

Relapsed/refractory advanced classic Kaposi sarcoma: Individual has relapsed/refractory advanced classic Kaposi sarcoma and is using ipilimumab in combination with nivolumab as subsequent systemic therapy; individual does not have multicentric Castleman Disease (MCD) or KSHV-associated inflammatory cytokine syndrome (KICS); and is not receiving systemic immunosuppressant therapy.

Unresectable malignant pleural or peritoneal mesothelioma - first line: Individual has unresectable malignant pleural or peritoneal mesothelioma and is using ipilimumab in combination with nivolumab as first-line therapy; individual has ECOG performance status 0-2; has not received another anti-PD-1 or anti-PD-L1 agent; and is not receiving systemic immunosuppressant therapy.ECOG 0-2

Malignant pleural or peritoneal mesothelioma - subsequent therapy: Individual has malignant pleural or peritoneal mesothelioma and is using ipilimumab in combination with nivolumab for subsequent therapy; individual has ECOG performance status 0-2 and is not receiving systemic immunosuppressant therapy.ECOG 0-2

Metastatic melanoma with brain metastases: Individual has primary diagnosis of melanoma with asymptomatic or BRAF-non-specific asymptomatic brain metastases and is using ipilimumab as single agent or in combination with nivolumab; has not received another anti-PD-1, anti-PD-L1, or anti-CTLA-4 agent.

Adjuvant or neoadjuvant melanoma (combination with nivolumab): Individual is using ipilimumab in combination with nivolumab for adjuvant therapy after complete resection (including lymphadenectomy) or for neoadjuvant treatment of resected advanced melanoma as specified by NCCN guidance.

Merkel cell carcinoma: Individual has Merkel cell carcinoma and is using ipilimumab as single agent or in combination with nivolumab for M1 disseminated disease when PD-1/PD-L1 therapy is contraindicated or disease progressed on PD-1/PD-L1 monotherapy; individual is not receiving systemic immunosuppressant therapy.

Adrenocortical carcinoma (neuroendocrine and adrenal tumors): Individual has locoregional unresectable or metastatic adrenocortical carcinoma and is using ipilimumab in combination with nivolumab per NCCN 2A.

NSCLC - first-line recurrent/advanced/metastatic: Individual is using ipilimumab in combination with nivolumab for first-line recurrent/advanced/metastatic NSCLC (with or without two cycles of platinum-doublet chemotherapy per variant); no actionable molecular markers are present (allowing KRAS G12C); ECOG performance status 0-2; has not received another anti-PD-1 or anti-PD-L1 agent; and is not receiving systemic immunosuppressant therapy.ECOG 0-2

NSCLC - continuation therapy: Individual is using ipilimumab in combination with nivolumab for continuation/maintenance treatment of recurrent, advanced, or metastatic NSCLC per NCCN guidance.

Melanoma single-agent use: Ipilimumab single-agent use is allowed as: 1) first-line single course of 4 treatments; or 2) second-line or subsequent single course of 4 treatments; or 3) retreatment limited to a 4-dose course for individuals who had no significant systemic toxicity during prior ipilimumab therapy and whose disease progressed after being stable for greater than 3 months with no intervening therapy.4-dose course limits

Low-dose ipilimumab with pembrolizumab in cutaneous melanoma: Low-dose ipilimumab (1 mg/kg every 3 weeks for four doses) in combination with pembrolizumab followed by pembrolizumab monotherapy for up to 2 years is covered as second-line or subsequent therapy for progression after anti-PD-1 therapy; individual has not received another anti-CTLA-4 agent and is not receiving systemic immunosuppressant therapy.

RCC - intermediate/poor risk: Individual has intermediate- or poor-risk advanced renal cell carcinoma and is using ipilimumab with nivolumab for four cycles followed by nivolumab maintenance as first-line therapy for previously untreated RCC with clear-cell component; individual has ECOG performance status 0-2 and is not receiving systemic immunosuppressant therapy.ECOG 0-2

Small bowel adenocarcinoma: Individual has advanced/metastatic or locally unresectable/medically inoperable small bowel adenocarcinoma with dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype (e.g., TMB > 50 mut/Mb); ipilimumab is used in combination with nivolumab; individual has ECOG 0-2; has not received another anti-PD-1 or anti-PD-L1 agent; and is not receiving systemic immunosuppressant therapy.ECOG 0-2; POLE/POLD1 TMB criteria

Soft tissue sarcoma - advanced/metastatic: Individual has advanced or metastatic soft tissue sarcoma and is using ipilimumab in combination with nivolumab; has not received another anti-PD-1 or anti-PD-L1 agent and is not receiving systemic immunosuppressant therapy.

Uterine neoplasms: Individual has recurrent MSI-H or dMMR uterine neoplasm OR achieved response/stable disease after first-line nivolumab + ipilimumab +/- chemotherapy; no actionable molecular markers are present (allowing KRAS G12C); ECOG performance status 0-2; and is not receiving systemic immunosuppressant therapy.ECOG 0-2

Vaginal cancer: Individual has recurrent or metastatic vaginal cancer and is using ipilimumab in combination with nivolumab as second-line or subsequent therapy; tumor PD-L1 CPS ≥ 1%; has not received another anti-PD-1 or anti-PD-L1 agent; and is not receiving systemic immunosuppressant therapy.PD-L1 CPS >=1%

Vulvar cancer: Individual has advanced or recurrent/metastatic vulvar cancer and is using ipilimumab in combination with nivolumab as second-line or subsequent therapy; has not received another anti-PD-1 or anti-PD-L1 agent; and is not receiving systemic immunosuppressant therapy.

NCCN/FDA-based covered indications

Covered when use aligns with NCCN category 2A recommendations or FDA-approved indications as detailed in policy sections for specific tumor types.

Tumor-specific coverage: Ipilimumab alone or in combination with nivolumab is covered for multiple tumor types when the request matches the tumor-specific NCCN 2A or FDA-labeled indication described in the policy (examples include biliary tract cancers in combination with nivolumab, colorectal cancer with MSI-H/dMMR in applicable settings, gastric/esophageal cancers, hepatocellular carcinoma in combination with nivolumab, classic Kaposi sarcoma, Merkel cell carcinoma in combination with nivolumab for M1 disease after progression on PD-1/PD-L1 monotherapy or if PD-1/PD-L1 is contraindicated, metastatic soft tissue sarcoma in combination with nivolumab, melanoma brain metastases per NCCN 2A).

Requests for Yervoy (ipilimumab) will not be approved when the agent is used in combination with Opdivo Qvantig (nivolumab hyaluronidase). In addition, requests that do not meet the specific diagnosis-, line-of-therapy-, biomarker-, and prior‑therapy requirements detailed in the coverage criteria section are not approvable per the policy statement.

When a tumor‑specific criterion explicitly requires no prior anti‑PD‑1/PD‑L1 therapy, requests following prior immunotherapy may be excluded and denied; documentation must show the patient meets the no‑prior‑immunotherapy requirement where specified. The policy also reflects updated NCCN guidance that removed the small cell lung cancer indication; use in that setting is no longer supported by the policy (see history and tumor‑specific sections).

Per the policy statement, requests that do not meet the listed NCCN, FDA, or label criteria within the policy window are not approved. Prior authorization must document that the requested use aligns with the tumor‑specific eligibility (including ECOG performance status, required biomarkers, line of therapy, and absence of contraindicating prior therapies) described in the coverage criteria.

The policy no longer supports ipilimumab for small cell lung cancer; this indication was removed based on label and NCCN changes and therefore requests for that indication are not supported by the current policy.

Regimens and Treatment Configurations

Regimen	Indication / Notes	Coverage status
Ipilimumab 1 mg/kg every 3 weeks for 4 doses combined with pembrolizumab, followed by pembrolizumab every 3 weeks as monotherapy for up to 2 years
Cutaneous melanoma: low‑dose ipilimumab (1 mg/kg q3w x4) with pembrolizumab, then pembrolizumab monotherapy for 2 years; combination used as second‑line or subsequent therapy for progression following anti‑PD‑1 therapy; patient must not have received another anti‑CTLA‑4 agent and must not be receiving systemic immunosuppressant therapy

Regimen	Indication / Notes	Coverage status
Ipilimumab in combination with nivolumab for four cycles followed by single‑agent nivolumab maintenance
Renal cell carcinoma (intermediate‑ or poor‑risk, clear‑cell component): Yervoy plus nivolumab for four cycles followed by nivolumab as first‑line therapy for previously untreated RCC; ECOG 0‑2 and not receiving systemic immunosuppressant therapy

Regimen	Indication / Notes	Coverage status
Ipilimumab monotherapy (single‑agent) — course limits: single course of 4 doses for first‑line or for second‑line/subsequent; retreatment permitted as a 4‑dose limit if prior course had no significant systemic toxicity and disease progressed after >3 months
Covered where supported by NCCN 2A or FDA label across multiple tumor types (examples include single‑agent ipilimumab for melanoma per course limits; ipilimumab + nivolumab for selected NSCLC settings [with or without platinum‑doublet chemotherapy per variant], hepatocellular carcinoma in combination with nivolumab, and other updated indications). Specific tumor‑type line‑of‑therapy and prior immunotherapy requirements must be met per policy.

Line of Therapy Specifications

first-line | second-line | subsequent (varies by indication)

Melanoma single-agent courses: First-line single course of 4 treatments; second-line or subsequent single course of 4 treatments; retreatment limited to a 4-dose course for individuals who had no significant systemic toxicity during prior ipilimumab therapy and whose disease progressed after being stable for greater than 3 months with no intervening therapy.

first-line

RCC first-line: Yervoy is used in combination with nivolumab for four cycles followed by single-agent nivolumab as first-line therapy for previously untreated intermediate- or poor-risk renal cell carcinoma with clear-cell component.

first-line | second-line | salvage

Line of therapy:

Biomarker and Molecular Test Requirements

dMMR / MSI-H — key biomarker requirement

RequirementDeficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) documented for the tumor when specified (e.g., small bowel adenocarcinoma, uterine neoplasms, select gastric/esophageal and other indications).

ContextdMMR/MSI-H is listed as a biomarker-based eligibility criterion for select diagnoses and is required when the tumor-specific criteria reference it (e.g., SBA, uterine neoplasms, gastric cancer).

Testing recommendationNCCN recommends testing for actionable/molecular markers including mismatch repair status prior to initiating therapy when relevant.

Tumor mutational burden (TMB) — thresholds

TMB-high threshold>= 10 mut/Mb defined for recurrent unresectable or metastatic TMB-high tumors (TMBH).

POLE/POLD1 ultra-hypermutated example

Billing and Diagnosis Codes

Prior Authorization

Prior Authorization Required

Prior authorization is required. Submit HCPCS J9228 and an ICD-10 diagnosis code that matches one of the listed malignant neoplasm codes. Include documentation supporting diagnosis-specific clinical criteria, dosing limits, and prior therapy history per policy.

PA required: Prior authorization is required with documentation showing the specific diagnosis and that all diagnosis-specific clinical criteria in the policy are met.
Coding: Use HCPCS J9228 for ipilimumab (1 mg). Include one appropriate ICD-10 code from the lists below that corresponds to the treated malignant neoplasm or relevant personal history code.
Dose/course limits: Single-agent ipilimumab (Yervoy) dose/course limits apply — commonly a single course of up to 4 doses for listed single-agent indications; retreatment limited to 4 doses when criteria for retreatment are met; combination regimens may have separate dosing rules as specified in the clinical criteria.

Documentation Required

Required Coding Documentation

Required coding documentation: Submit HCPCS J9228 and one appropriate ICD-10 diagnosis code from the malignant neoplasm ranges listed in the policy (examples include but are not limited to C00.0–C14.8, C15.3–C15.9, C16.0–C16.9, C17.0–C17.9, C18.0–C18.9, C19, C20, C21.8, C22.0, C22.1, C22.8, C22.9, C23, C24.0–C24.9, C33, C34.00–C34.92, C40.00–C40.92, C41.0–C41.9, C43.0–C43.9, C44.42, C45.0–C45.9, C46.0–C46.9, C48.1–C48.8, C49.0–C49.9, C4A.0–C4A.9, C51.0–C51.9, C52, C53.0–C53.9, C54.0–C54.9, C55, C58, C64.1–C65.9, C69.30–C69.32, C69.40–C69.42, C72.0, C72.1, C74.00–C74.02, C78.00–C78.02, C79.2, C79.31, C7A.8, C7B.8, Z85.038, Z85.118, Z85.528, Z85.53, Z85.820). Ensure the ICD-10 code aligns with the member’s documented malignant neoplasm or relevant personal history.

Provider Responsibilities and Authorization Requirements

Prior Authorization

Prior authorization required with diagnosis-specific criteria

Prior authorization is required and the request must document that the individual meets the diagnosis- and therapy-specific criteria in the policy (for example, the stated diagnosis, ECOG performance status 0–2 when specified, combination with nivolumab when required, and absence of prior anti-PD-1/PD-L1 therapy when required).

Provide evidence of the tumor diagnosis and the specific line of therapy requested.
Document ECOG 0–2 if the tumor-specific criteria require it.
Confirm whether prior anti-PD-1/PD-L1 or anti-CTLA-4 therapy has been given when the criteria exclude prior use.

Prior Authorization

Prior authorization required: document indication, prior treatments, and guideline/label alignment

Prior authorization is required for ipilimumab (alone or with nivolumab) and must include documentation of the indication, prior treatments, and that use aligns with NCCN category 2A recommendations or an FDA-approved indication.

Attach clinical rationale showing alignment with NCCN 2A tumor-specific guidance or FDA labeling.
List prior therapies and dates, including any prior checkpoint blockade.

Definitions and Terminology

Ipilimumab (Yervoy) is a monoclonal antibody that acts as a CTLA‑4 inhibitor and is used either as a single agent or in combination with a PD‑1 inhibitor (commonly nivolumab) for multiple tumor types per NCCN guidance and FDA labeling. Many covered indications require combination with nivolumab, specify performance status of ECOG 0‑2, and include biomarker‑driven criteria such as MSI‑H/dMMR, TMB‑high (≥10 mut/Mb) or tumor‑specific PD‑L1 CPS thresholds. Prior authorization is required and dosing/course limits apply for single‑agent use (for example, single courses of four doses and retreatment limits where specified).

Actionable molecular markers — definition & testing

Defined actionable markersActionable molecular markers are defined to include: EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET, ERBB2 (HER2), and NRG1.

Testing recommendationNCCN recommends testing for these actionable molecular markers prior to initiating therapy to guide treatment decisions.

Insufficient tissue guidanceIf insufficient tissue prevents testing for all markers, repeat biopsy or plasma testing is recommended; if not feasible, treat based on available results.

Background and Policy Scope

Ipilimumab (Yervoy) functions as a CTLA‑4 inhibitor and is used either alone or in combination with a PD‑1 inhibitor such as nivolumab for a range of malignancies per NCCN and FDA guidance. Coverage is diagnosis‑specific and frequently requires documentation of performance status (typically ECOG 0‑2), absence of certain prior immunotherapies when specified, and meeting any biomarker thresholds (for example, MSI‑H/dMMR or TMB‑high) that the tumor‑specific criteria require.

Document History and Changes

2026-02-20Annual Review (material)Latest

Separated NCCN criteria for appendiceal adenocarcinoma; clarified neoadjuvant biliary tract cancer criteria; added small cell neuroendocrine carcinoma of the cervix and peritoneal mesothelioma recommendations; added resected advanced melanoma neoadjuvant recommendation; added neuroendocrine and adrenal tumor recommendations; allowed KRAS G12C exception to actionable marker restrictions; updated small bowel adenocarcinoma disease-state criteria and added multiple gynecologic and other tumor indications; coding additions to ICD-10-CM list.

2025-08-15Select Review (material)

Clarified TMB wording for POLE/POLD1 mutations in colorectal cancer and small bowel adenocarcinoma and removed autoimmune disease language from 'may not be approved' criteria; wording and formatting updates.

OpenPayer

Yervoy (ipilimumab) coverage criteria

Coverage Criteria and Indications

Regimens and Treatment Configurations

Line of Therapy Specifications

Biomarker and Molecular Test Requirements

Billing and Diagnosis Codes

Provider Responsibilities and Authorization Requirements

Definitions and Terminology

Background and Policy Scope

Document History and Changes