Medical Drug Criteria (MDC)

Policy Num:       P1.001.014
Policy Name:     OPDUALAG™ (nivolumab and relatlimab-rmbw)
Policy ID:          [P1.001.014] [Ac/L/ M+/ P+ ]

Last Review:       September 22, 2025
Next Review:      September 20, 2026
 

Related MDC: NONE

OPDUALAG™ (nivolumab and relatlimab-rmbw)

Summary

OPDUALAG (nivolumab + relatlimab-rmbw) is a fixed-dose combination of two immune checkpoint inhibitors:

Nivolumab: Anti–PD-1 monoclonal antibody, blocking PD-1 interaction with PD-L1/PD-L2, enhancing T-cell anti-tumor response.
Relatlimab: Anti–LAG-3 monoclonal antibody, promoting T-cell activation, proliferation, and cytokine secretion.

Objective

Define evidence-based criteria for safe and medically necessary use of OPDUALAG. Standardize initiation, continuation, and renewal requirements across patient populations. Align payer coverage with FDA-approved labeling and NCCN Guidelines.

Policy Statements

OPDUALAG is considered medically necessary for eligible patients ≥12 years, ≥40 kg, with unresectable or metastatic melanoma when medical criteria are met.  

Therapy must be used as a single regimen and not combined with other systemic checkpoint inhibitors or targeted agents unless supported by NCCN.

Policy Guidelines

Authorization period: Initial approval for up to 12 months.
 
Use limitation: Must be used as a single-agent regimen (no concurrent systemic checkpoint inhibitors or targeted agents).
 
Continuation: Allowed if disease has not progressed and treatment remains tolerable.

DOSAGE/ADMINISTRATION

Fixed-dose combination (IV infusion):

480 mg nivolumab + 160 mg relatlimab every 4 weeks

Treatment duration: Continue until disease progression or unacceptable toxicity.

Route: Intravenous infusion over 30 minutes.

Population: Adults and pediatric patients ≥12 years and ≥40 kg.

REQUIRED MEDICAL INFORMATION

Initial Therapy
 
Approval requires ALL:
 
1. Diagnosis of unresectable or metastatic melanoma.
 
 
2. Patient age ≥12 years and weight ≥40 kg.
 
 
3. Used for ONE of:
 
First-line systemic therapy, OR
 
Second-line or subsequent therapy (checkpoint-naïve, except prior adjuvant/neoadjuvant setting), OR
 
Re-induction if relapse >3 months after initial benefit from prior nivolumab ± relatlimab, with no residual toxicity.
 
 
 
4. OPDUALAG used as monotherapy.
 
 
5. Dose does not exceed 480 mg nivolumab + 160 mg relatlimab every 4 weeks.
 
 
 
Renewal Criteria
 
Approval requires ALL:
 
1. Patient continues to meet initial criteria.
 
 
2. Disease has not progressed on OPDUALAG.
 
 
3. Treatment is tolerated without unresolved severe toxicity.
 
 
4. OPDUALAG continues as single regimen.

EXCLUSION CRITERIA

Patients <12 years or <40 kg.

Combination with other systemic immunotherapies not recommended by NCCN.

BENEFIT APPLICATION

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage

Background

Melanoma: Advanced unresectable/metastatic melanoma historically carried poor prognosis.

Checkpoint inhibition: PD-1 blockade has been a backbone of therapy; resistance mechanisms include T-cell exhaustion via LAG-3 signaling.

 Rationale for combination: Dual blockade of PD-1 and LAG-3 synergistically restores T-cell function and anti-tumor activity.

 RELATIVITY-047 trial: Demonstrated median PFS benefit (~10.2 vs. 4.6 months with nivolumab).

Regulatory Status

FDA: Approved March 2022 for advanced melanoma (≥12 years, ≥40 kg). PI revised March 2024.
 
EMA/International: Approved in the EU for unresectable/metastatic melanoma in adults and adolescents.

OTHER CRITERIA

NONE

Rationale

Efficacy: Clinical benefit established in pivotal RELATIVITY-047 study.

Safety: Toxicities include immune-mediated hepatitis, pneumonitis, colitis, endocrinopathies, myocarditis, and dermatologic reactions; monitoring and prompt immunosuppression are recommended.

Guidelines: NCCN Cutaneous Melanoma (v2.2025) lists OPDUALAG as a Category 1 preferred first-line systemic option for unresectable/metastatic melanoma.

Supplemental Information

Administration: IV over 30 minutes, every 4 weeks. 

Discontinuation: If grade ≥3 immune-related adverse events occur and cannot be reversed with corticosteroids.

Combination therapy: Not to be used with other immune checkpoint inhibitors outside NCCN recommendations.

Practice Guidelines and Position Statements

NCCN Guidelines (Cutaneous Melanoma v2.2025): OPDUALAG recommended as a preferred first-line systemic therapy for unresectable/metastatic melanoma; also listed as an option for subsequent therapy in checkpoint-naïve patients. 

NCCN Compendium (2025): Supports OPDUALAG for melanoma with strong consensus.

References

1. Clinical Pharmacology [Internet]. Gold Standard, Inc. 2023.
  
2. DRUGDEX® System. Micromedex, 2023.
  
3. National Cancer Institute. CTCAE v5.0. 2022.
 
 4. NCCN Guidelines: Cutaneous Melanoma, v2.2025.
  
5. NCCN Drugs & Biologics Compendium. 2025.
 
6. OPDUALAG Prescribing Information. Bristol-Myers Squibb. Revised March 2024.
 
7. FDA Orphan Drug Designations. 2023.

Codes

Applicable Modifiers

N/A

Policy History