Ipilimumab (Yervoy®)

We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the medical policy and a health plan or government program (e.g., TennCare), the express terms of the health plan or government program will govern.

POLICY

INDICATIONS

The indications below including FDA-approved indications and compendial uses are considered a covered benefit provided that all the approval criteria are met and the member has no exclusions to the prescribed therapy.

FDA-Approved Indications

Unresectable or Metastatic Melanoma

Yervoy is indicated as a single agent or in combination with nivolumab for the treatment of unresectable or metastatic melanoma in adult and pediatric patients 12 years and older.

Adjuvant Treatment of Melanoma

Yervoy is indicated for the adjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

Advanced Renal Cell Carcinoma

Yervoy, in combination with nivolumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer

Yervoy, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years of age and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).

Hepatocellular Carcinoma

Yervoy, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC).

Yervoy, in combination with nivolumab, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma who have been previously treated with sorafenib.

Metastatic Non-small Cell Lung Cancer

Yervoy, in combination with nivolumab, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
Yervoy, in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations.

Malignant Pleural Mesothelioma

Yervoy, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

Esophageal Cancer

Yervoy, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

Compendial Uses

Cutaneous melanoma
Uveal melanoma
Central nervous system (CNS) brain metastases
Non-small cell lung cancer
Renal cell carcinoma
Colorectal cancer, including appendiceal adenocarcinoma and anal adenocarcinoma
Pleural mesothelioma
Peritoneal mesothelioma
Hepatocellular carcinoma
Small bowel adenocarcinoma
Ampullary adenocarcinoma
Esophageal/Esophagogastric Junction Cancers
Kaposi Sarcoma
Bone Cancer
Biliary Tract Cancers

Cholangiocarcinoma
Gallbladder Cancer

Soft Tissue Sarcoma

Extremity/body wall sarcoma
Head/neck sarcoma
Retroperitoneal/intra-abdominal sarcoma
Rhabdomyosarcoma
Angiosarcoma

Merkel Cell Carcinoma
Gastric Cancer
Gestational trophoblastic neoplasia

All other indications are considered experimental/investigational and not medically necessary.

DOCUMENTATION

Submission of the following information is necessary to initiate the prior authorization review:

Documentation of laboratory report confirming MSI-H, mismatch repair deficient (dMMR), or polymerase epsilon/delta (POLE/POLD1) tumor status, where applicable.
Documentation of molecular testing for EGFR exon 19 deletions or exon 21 L858R mutations and ALK rearrangements, where applicable.

COVERAGE CRITERIA

Cutaneous Melanoma

Authorization of 6 months may be granted for treatment of cutaneous melanoma in any of the following settings:

The requested medication will be used as a single agent (for up to 4 doses) or in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) for metastatic or unresectable disease.
The requested medication will be used as a single agent (for up to 4 doses) or in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) as adjuvant treatment if no evidence of disease following metastasis-directed therapy (e.g., complete resection).
The requested medication will be used at a low dose in combination with pembrolizumab for disease progression following single-agent anti- PD-1 therapy as subsequent therapy for metastatic or unresectable disease.
The requested medication will be used as a single agent for resectable disease limited to nodal recurrence after prior anti-PD-1 therapy.
The requested medication will be used in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) as neoadjuvant treatment of resectable disease.

Uveal Melanoma

Authorization of 6 months may be granted as a single agent or in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) for treatment of uveal melanoma for unresectable or metastatic disease.

CNS Brain Metastases

Authorization of 6 months may be granted as a single agent or in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) for treatment of CNS brain metastases in members with melanoma.

Non-Small Cell Lung Cancer (NSCLC)

Authorization of 6 months may be granted for treatment of recurrent, advanced or metastatic non-small cell lung cancer if there are no EGFR exon 19 deletions or exon 21 L858R mutations or ALK rearrangements (unless testing is not feasible due to insufficient tissue) and the requested medication will be used in a regimen containing nivolumab.

Renal Cell Carcinoma

Authorization of 6 months may be granted for treatment of renal cell carcinoma in combination with nivolumab (for 4 doses, followed by single agent nivolumab) for relapsed, advanced, or stage IV disease with clear cell histology.

Colorectal Cancer

Authorization of 6 months may be granted for treatment of colorectal cancer, including appendiceal adenocarcinoma and anal adenocarcinoma, for microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR) or polymerase epsilon/delta (POLE/POLD1) tumors when used in combination with nivolumab (for 4 doses followed by nivolumab as a single agent).

Pleural or Peritoneal Mesothelioma

Authorization of 6 months may be granted in combination with nivolumab for treatment of pleural or peritoneal mesothelioma, including pericardial mesothelioma and tunica vaginalis testis mesothelioma.

Hepatocellular Carcinoma

Authorization of 6 months may be granted in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) for treatment of hepatocellular carcinoma.

Small Bowel Adenocarcinoma

Authorization of 6 months may be granted in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) for treatment of unresectable, medically inoperable, advanced or metastatic small bowel adenocarcinoma for microsatellite-instability high (MSI-H), mismatch repair deficient (dMMR) or polymerase epsilon/delta (POLE/POLD1) tumors.

Ampullary Adenocarcinoma

Authorization of 6 months may be granted in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) for treatment of progressive, unresectable, or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) ampullary adenocarcinoma.

Esophageal and Esophagogastric Junction Cancers

Authorization of 6 months may be granted in combination with nivolumab for the treatment of esophageal or esophagogastric junction cancer in members who are not surgical candidates or have unresectable locally advanced, recurrent or metastatic disease.
Authorization of 6 months may be granted in combination with nivolumab for neoadjuvant or perioperative treatment of esophageal or esophagogastric junction adenocarcinoma if tumor is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and member is medically fit for surgery.
Authorization of 6 months may be granted for induction therapy for relieving dysphagia in combination with nivolumab for members planned for esophagectomy.

Gastric Cancer

Authorization of 6 months may be granted in combination with nivolumab for treatment of gastric adenocarcinoma in members with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors who are not surgical candidates or have unresectable, recurrent or metastatic disease.
Authorization of 6 months may be granted in combination with nivolumab for neoadjuvant or perioperative treatment of gastric adenocarcinoma if tumor is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and member is medically fit for surgery.
Authorization of 6 months may be granted when the requested medication will be used in combination with nivolumab in members with early stage microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors and completed endoscopic resection.

Kaposi Sarcoma

Authorization of 6 months may be granted in combination with nivolumab for subsequent treatment of relapsed/refractory classic Kaposi Sarcoma.

Bone Cancer

Authorization of 6 months may be granted in combination with nivolumab for unresectable or metastatic disease when all of the following are met:

Disease has tumor mutation burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] tumors
Disease has progressed following prior treatment and has no satisfactory alternative treatment options

Biliary Tract Cancer (Cholangiocarcinoma and Gallbladder Cancer)

Authorization of 6 months may be granted in combination with nivolumab for treatment of unresectable or resected gross residual (R2) disease, or metastatic disease that is tumor mutation burden-high (TMB-H).

Authorization of 6 months may be granted in combination with nivolumab for neoadjuvant treatment of resectable locoregionally advanced gallbladder cancer that is tumor mutation burden-high (TMB-H).

Soft Tissue Sarcoma

Authorization of 6 months may be granted in combination with nivolumab for treatment of extremity/body wall sarcomas, head/neck sarcomas and retroperitoneal/intra-abdominal sarcomas, rhabdomyosarcoma and angiosarcoma.

Merkel Cell Carcinoma

Authorization of 6 months may be granted as a single agent or in combination with nivolumab (for 4 doses followed by nivolumab as a single agent) for treatment of unresectable, recurrent, or stage IV Merkel cell carcinoma.

Gestational Trophoblastic Neoplasia

Authorization of 6 months may be granted in combination with nivolumab for treatment of gestational trophoblastic neoplasia for multi-agent chemotherapy-resistant disease when either of the following criteria are met:

Member has recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor).
Member has high-risk disease.

CONTINUATION OF THERAPY

Adjuvant Treatment of Melanoma

Authorization of 6 months may be granted (up to 3 years) for continued treatment in members requesting reauthorization for adjuvant melanoma when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Cutaneous Melanoma, Renal Cell Carcinoma, Colorectal Cancer, Hepatocellular Cancer

Authorization of 6 months may be granted (up to 4 doses maximum, if member has not already received 4 doses) for continued treatment in members requesting reauthorization for cutaneous melanoma, renal cell carcinoma, colorectal cancer, and hepatocellular cancer when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Non-Small Cell Lung Cancer, Gastric/Esophageal/Esophagogastric Junction Cancers, or Pleural Mesothelioma

Authorization of 6 months may be granted (up to 24 months total) for continued treatment in members requesting reauthorization for non-small cell lung cancer, esophageal cancer, or pleural mesothelioma, including pericardial mesothelioma and tunica vaginalis testis mesothelioma subtypes, when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Biliary Tract Cancer

Authorization of 6 months may be granted (for 2 to 6 months total for neoadjuvant treatment, and for up 24 months total for other clinical settings) for continued treatment in members requesting reauthorization for biliary tract cancer when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

All Other Indications

Authorization of 6 months may be granted for continued treatment in members requesting reauthorization for all other indications listed in the Coverage Criteria section when treatment guidelines do not specify a limited number of total doses (see above) and there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

MEDICATION QUANTITY LIMITS

Drug Name	Diagnosis	Maximum Dosing Regimen
Yervoy (Ipilimumab)	Ampullary Adenocarcinoma, Colorectal Cancer including Appendiceal Adenocarcinoma and Anal Adenocarcinoma, Renal Cell Carcinoma, Small Bowel Adenocarcinoma	Route of Administration: Intravenous 1mg/kg every 3 weeks for 4 doses
Yervoy (Ipilimumab)	Biliary Tract Cancer: Gallbladder Cancer, Cholangiocarcinoma, Bone Cancer, Kaposi Sarcoma, Mesothelioma (Pleural, Peritoneal, Pericardial, or Tunica Vaginalis Testis), Non-Small Cell Lung Cancer	Route of Administration: Intravenous 1mg/kg every 6 weeks
Yervoy (Ipilimumab)	CNS Cancer : Brain Metastases	Route of Administration: Intravenous 3mg/kg every 3 weeks for 4 doses Initial: 10mg/kg every 3 weeks for 4 doses Maintenance: 10mg/kg every 12 weeks beginning with week 24
Yervoy (Ipilimumab)	Esophageal Cancer, Esophagogastric Junction Cancer	Route of Administration: Intravenous 1mg/kg every 6 weeks
Yervoy (Ipilimumab)	Gastric Cancer	Route of Administration: Intravenous 1mg/kg every 6 weeks for 2-3 doses
Yervoy (Ipilimumab)	Hepatocellular Carcinoma, Melanoma	Route of Administration: Intravenous 3mg/kg every 3 weeks for 4 doses
Yervoy (Ipilimumab)	Melanoma Cutaneous, Adjuvant	Route of Administration: Intravenous Initial: 3mg/kg every 3 weeks for 4 doses Maintenance: 3mg/kg every 12 weeks up to max 4 doses
Yervoy (Ipilimumab)	Merkel Cell Carcinoma	Route of Administration: Intravenous 3mg/kg every 3 weeks for 4 doses
Yervoy (Ipilimumab)	Soft Tissue Sarcoma: Angiosarcoma, Extremity/Body Wall Sarcoma, Head/Neck Sarcoma, Retroperitoneal/Intra-Abdominal Sarcoma, Rhabdomyosarcoma	Route of Administration: Intravenous 1mg/kg every 6 weeks

APPLICABLE TENNESSEE STATE MANDATE REQUIREMENTS

BlueCross BlueShield of Tennessee’s Medical Policy complies with Tennessee Code Annotated Section 56-7-2352 regarding coverage of off-label indications of Food and Drug Administration (FDA) approved drugs when the off-label use is recognized in one of the statutorily recognized standard reference compendia or in the published peer-reviewed medical literature.

ADDITIONAL INFORMATION

For appropriate chemotherapy regimens, dosage information, contraindications, precautions, warnings, and monitoring information, please refer to one of the standard reference compendia (e.g., the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) published by the National Comprehensive Cancer Network®, Drugdex Evaluations of Micromedex Solutions at Truven Health, or The American Hospital Formulary Service Drug Information).

REFERENCES

Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; April 2025.
The NCCN Drugs & Biologics Compendium 2025 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed May 13, 2025.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Anal Carcinoma. Version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf Accessed December 13, 2024.
Lexicomp [database online]. Hudson, OH: Lexi-Comp, Inc.; https://online.lexi.com/lco/action/home [available with subscription]. Accessed December 13, 2024.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer Version 4.2024.https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf Accessed December 13, 2024.

ORIGINAL EFFECTIVE DATE: 9/11/2011

MOST RECENT REVIEW DATE: 10/31/2025

ID_BT

Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

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