Medicare Advantage

Medical Policy

Title:

Nivolumab and relatlimab-rmbw (Opdualag™) for intravenous use

Policy #:

MA08.152d

Policy

In the absence of coverage criteria from applicable Medicare statutes, regulations, NCDs, LCDs, CMS manuals, or other Medicare coverage documents, this policy uses internal coverage criteria developed by the Company in consideration of peer-reviewed medical literature, clinical practice guidelines, and/or regulatory status.

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

MELANOMA: CUTANEOUS

Nivolumab and relatlimab-rmbw (Opdualag), administered as an intravenous (IV) infusion, is considered medically necessary and, therefore, covered for adult and pediatric individuals 12 years of age or older with unresectable or metastatic* melanoma, as National Comprehensive Cancer Network (NCCN)-preferred systemic therapy** for any of the following therapies:

First-line therapy (NCCN-preferred combination checkpoint blockade therapy)
Second-line or subsequent therapy for disease progression, intolerance and/or projected risk of progression with b-rapidly accelerated fibrosarcoma (BRAF)-targeted therapy
Re-induction therapy if prior combination anti-PD-1/LAG-3 therapy (e.g., Opdualag) resulted in disease control (complete response, partial response, or stable disease) with no residual toxicity, and disease progression/relapse more than 3 months after treatment discontinuation

*Metastatic disease includes stage III unresectable/borderline resectable disease with clinically positive node(s) or clinical satellite/in-transit metastases, or as well as unresectable/borderline resectable local satellite/in-transit recurrence, unresectable nodal recurrence, and widely disseminated distant metastatic disease.

**Systemic therapy is NCCN-preferred for unresectable or widely disseminated distant metastatic disease.

Nivolumab and relatlimab-rmbw (Opdualag) is considered medically necessary and, therefore, covered for adult individuals with resectable melanoma as neoadjuvant therapy for any of the following therapies:

Primary treatment for stage III clinically positive, resectable nodal disease
Initial and/or subsequent treatment for:

Limited resectable stage III disease with clinical satellite/in-transit metastases
Limited resectable local satellite/in-transit recurrence

Treatment for resectable disease limited to nodal recurrence

EXPERIMENTAL/INVESTIGATIONAL

All other uses for nivolumab and relatlimab-rmbw (Opdualag) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

There is no Medicare coverage determination addressing nivolumab and relatlimab-rmbw (Opdualag); therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the applicable Evidence of Coverage, nivolumab and relatlimab-rmbw (Opdualag) is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

For Medicare Advantage members, certain drugs are available through either the member's medical benefit (Part B benefit) or pharmacy benefit (Part D benefit), depending on how the drug is prescribed, dispensed, or administered. This medical policy only addresses instances when nivolumab and relatlimab-rmbw (Opdualag) is covered under a member's medical benefit (Part B benefit). It does not address instances when nivolumab and relatlimab-rmbw (Opdualag) is covered under a member’s pharmacy benefit (Part D benefit).

US FOOD AND DRUG ADMINISTRATION STATUS

Nivolumab and relatlimab-rmbw (Opdualag) was approved by the US Food and Drug Administration (FDA) on March 18, 2022, for the treatment of adult and pediatric individuals 12 years of age or older with unresectable or metastatic melanoma. It is administered by intravenous infusion.

PEDIATRIC USE

The safety and effectiveness in pediatric individuals for the treatment of unresectable or metastatic melanoma have been established in those who weigh at least 40 kg.

The safety and effectiveness in pediatric individuals 12 years of age or older who weigh less than 40 kg, and pediatric individuals younger than 12 years of age have not been established.

Description

Malignant melanoma is a common skin cancer that arises from melanin cells within the upper layer of the skin or from similar cells that may be found in moles. Early-stage melanomas are mostly treatable; however, melanomas have high metastatic potential and can spread to other organs very quickly.

Opdualag is a first-in-class immune checkpoint inhibitor that combines nivolumab (Opdivo), a programmed death-1 (PD-1)–blocking antibody, and relatlimab-rmbw, a lymphocyte-activation gene 3 (LAG-3)–blocking antibody. Nivolumab is a human monoclonal antibody and immune checkpoint inhibitor that competes with the tumor for the PD-1 receptor on T cells and blocks the T cells' interaction with the tumor's PD-L1 and PD-L2 ligands. Consequently, the tumor is no longer able to inactivate the T cells and the antitumor response continues. Relatlimab-rmbw reduces LAG-3 pathway-mediated inhibition of the immune response and promotes T-cell proliferation and cytokine secretion. The combination of these two drugs results in increased T-cell activation compared to the activity of either antibody alone.

PEER-REVIEWED LITERATURE

Summary

Tawbi et al. (2022) evaluated the safety and efficacy of nivolumab and relatlimab-rmbw (Opdualag) in the phase 2/3 trial called A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma (RELATIVITY-047), a double-blind, randomized (1:1) trial that evaluated nivolumab and relatlimab-rmbw (Opdualag) versus nivolumab alone in 714 individuals 12 years of age or older with previously untreated metastatic or unresectable stage III or IV melanoma who had expression of LAG-3 and programmed death ligand-1 (PD-L1) that could be evaluated in tumor tissue. Individuals were eligible to participate if they had received previous adjuvant or neoadjuvant therapies containing a PD-1, CTLA-4, BRAF, or MEK inhibitor (or a combination of BRAF and MEK inhibitors) if the therapy was completed at least 6 months before the date of recurrence; individuals who received previous treatment with interferon were eligible if the last dose was received at least 6 weeks before randomization. Participants were randomly assigned to receive nivolumab 480 mg and relatlimab 160 mg (Opdualag) by intravenous infusion every 4 weeks (n=355) or nivolumab 480 mg by intravenous infusion every 4 weeks (n=359) until disease progression or unacceptable toxicity. The primary endpoint of the trial was progression-free survival (PFS). The results showed a statistically significant improvement in median PFS of 10.1 months in the nivolumab and relatlimab-rmbw (Opdualag) arm compared with 4.6 months in the nivolumab arm (HR 0.75; 95 percent confidence interval (CI), 0.62–0.92]). The most common immune-mediated adverse events were hypothyroidism or thyroiditis (18 percent with combination vs. 13.9 percent with nivolumab), rash (9.3 percent vs. 6.7 percent), and diarrhea/colitis (6.8 percent vs. 3.1 percent). The most common grade 3 or 4 toxicities were hepatitis (3.9 percent) and adrenal insufficiency (1.4 percent) with the combination and rash (1.4 percent) and diarrhea/colitis (1.4 percent) with nivolumab, all immune-mediated. Three treatment-related deaths occurred with the combination (hemophagocytic lymphohistiocytosis, acute pulmonary edema, and pneumonitis) and in two with nivolumab (sepsis/myocarditis and pneumonia).

OFF-LABEL INDICATION

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Cancer Society (ACS). What is melanoma skin cancer? [ACS Web site). 10/27/2023. Available at: https://www.cancer.org/cancer/melanoma-skin-cancer/about/what-is-melanoma.html. Accessed March 26, 2025.

American Hospital Formulary Service (AHFS). Drug Information 2025. Nivolumab and relatlimab-rmbw (Opdualag^TM). [UpToDate Lexidrug Web site]. 02/17/2025. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 26, 2025.

Elsevier's Clinical Pharmacology Compendium. Nivolumab and relatlimab-rmbw (Opdualag^TM). [Clinical Key Web site]. 11/14/2024. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed March 26, 2025.

Merative Micromedex® DRUGDEX® (electronic version). Nivolumab and relatlimab-rmbw (Opdualag^TM). [Micromedex Web site]. 02/27/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed March 26, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Melanoma: cutaneous; V2.2025. 01/28/2025. [NCCN Web site]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf [via free subscription]. Accessed March 26, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium^®. [NCCN Web site]. Nivolumab and relatlimab-rmbw (Opdualag^TM). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed March 26, 2025.

Tawbi HA, Schadendorf D, Lipson EJ, et al; RELATIVITY-047 Investigators. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34.

PA House Bill – HB 427; Act 6. Signed February 12, 2020. Available at: https://www.legis.state.pa.us/cfdocs/billinfo/billinfo.cfm?syear=2019&sind=0&body=H&type=B&bn=0427. Accessed March 26, 2025.

UpToDate^® Lexidrug^TM. Nivolumab and relatlimab-rmbw (Opdualag^TM). [UpToDate Lexidrug Web site]. 03/25/2025. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed March 26, 2025.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Nivolumab and relatlimab-rmbw (Opdualag^TM) prescribing information and approval letter [FDA Web site]. 03/06/2024. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed March 26, 2025.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

HCPCS Level II Code Number(s)

J9298 Injection, nivolumab and relatlimab-rmbw, 3 mg/1 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA08.152d:

03/04/2026	This policy has been reissued in accordance with the Company's annual review process.
06/16/2025	This version of the policy will become effective 06/16/2025. Policy criteria were revised in accordance with the National Comprehensive Cancer Network (NCCN) compendium (accessed 03/26/2025) and guideline for Melanoma: cutaneous V2.2025 (01/28/2025). All of the ICD-10 CM codes have been removed from this policy, since they are informational. Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

03/04/2026

This policy has been reissued in accordance with the Company's annual review process.

06/16/2025

This version of the policy will become effective 06/16/2025.

Policy criteria were revised in accordance with the National Comprehensive Cancer Network (NCCN) compendium (accessed 03/26/2025) and guideline for Melanoma: cutaneous V2.2025 (01/28/2025).

All of the ICD-10 CM codes have been removed from this policy, since they are informational. Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

Revisions From MA08.152c:

04/08/2024

This version of the policy will become effective 04/08/2024.

This policy has been updated to communicate the coverage criteria in alignment with recommendations from National Comprehensive Cancer Network (NCCN).

The indication of neoadjuvant therapy for resectable melanoma has been added as Medically Necessary.

The following ICD-10 CM codes have been added to this policy as medically necessary:

C44.89 Other specified malignant neoplasm of overlapping sites of skin
C44.99 Other specified malignant neoplasm of skin, unspecified

Revisions From MA08.152b:

01/01/2024	Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.
03/13/2023	This version of the policy will become effective 03/13/2023. This policy was updated to communicate the expanded Medically Necessary regimens of first-line, second-line, and re-induction therapies, in alignment with US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN).

Revisions From MA08.152a:

10/01/2022

This version of the policy will become effective 10/01/2022.

Inclusion of a policy in a Code Update memo does not imply that a full review of
the policy was completed at this time.

The following HCPCS code has been added to this policy:

J9298 Injection, nivolumab and relatlimab-rmbw, 3 mg/1 mg

Revisions From MA08.152:

07/18/2022

This version of the policy will become effective 07/18/2022.

The following new policy has been developed to communicate the Company's coverage criteria for nivolumab and relatlimab-rmbw (Opdualag).

Version Effective Date:

6/16/2025

Version Issued Date: