Coverage Policy Manual
Policy #: 2022038
Category: Pharmacy
Initiated: October 2022
Last Review: October 2025
  Nivolumab and relatlimab-rmbw (e.g., Opdualag)
Description:
Nivolumab and relatlimab-rmbw is a combination of a programmed death receptor-1 (PD-1) blocking antibody and a lymphocyte activation gene-3 (LAG-3) blocking antibody which is FDA approved for the treatment of adult and pediatric individuals 12 years of age or older with unresectable or metastatic melanoma.
 
Regulatory Status
On March 18, 2022, the U.S. Food and Drug Administration approved nivolumab and relatlimab-rmbw (e.g., Opdualag) for the treatment of unresectable or metastatic (Stage III or IV) melanoma in adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Effective October 1, 2022, prior approval is required for Nivolumab and relatlimab-rmbw (e.g., Opdualag).
 
Effective December 1, 2022, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service when rendered for oncologic indications and is managed through the oncology benefits management program.
 
INITIAL AND CONTINUATION APPROVAL will be for duration of the treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.
 
Effective October 2025
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Nivolumab and relatlimab-rmbw (e.g., Opdualag) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:
 
INITIAL APPROVAL:
 
1. Individual has a diagnosis of unresectable or metastatic (Stage III or IV) melanoma (Opdualag, 2024; NCCN a and 2A); AND
2. Individual is 12 years of age or older and weighing at least 40 kg (Opdualag, 2024; Tawbi HA et.al. 2022); AND
3. Individual is using in one of the following circumstances:
a. Nivolumab; relatlimab-rmbw will be used as first-line systemic therapy; OR
b. The Individual has had previous adjuvant or neoadjuvant therapies containing a PD-1, CTLA-4, BRAF, or MEK inhibitor (or a combination of BRAF and MEK inhibitors); AND
4. Individual has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or a Lansky performance score greater than or equal to 80% for minors (12 to 17 years of age); AND
5. Will not be used:
a. For treatment of uveal melanoma; OR
b. If individual has active brain metastases or leptomeningeal metastases.
 
CONTINUATION OF THERAPY:
 
1. Individual continues to meet initial criteria for the medication;  AND
2. Documentation indicating disease response to treatment, such as stabilization of disease, decrease in size of tumor(s) or tumor spread.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Nivolumab and relatlimab-rmbw (e.g., Opdualag) as a combined product. for any indication or circumstance not described above, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without Primary Coverage Criteria, nivolumab and relatlimab-rmbw (e.g., Opdualag), for any indication or circumstance not described above, is considered not Medically Necessary or is investigational and is not covered. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
POLICY GUIDELINES
 
Prescribing provider responsible for ensuring individual does not have unacceptable toxicity from the drug, including myelosuppression, infections, anaphylactic reactions.
 
DOSAGE AND ADMINISTRATION
 
For FDA labeled indications, Nivolumab and relatlimab-rmbw (e.g., Opdualag) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.
 
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication below.
 
The recommended dose of nivolumab and relatlimab-rmbw (e.g., Opdualag) for adult individuals and pediatric individuals 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered IV simultaneously at initiation and every 4 weeks until evidence of disease progression or unacceptable toxicity.
 
Nivolumab and relatlimab-rmbw (e.g., Opdualag) is available as an injection: 240 mg of nivolumab and 80 mg of relatlimab per 20 mL (12 mg and 4 mg per mL) in a single-dose vial.
 
Nivolumab and relatlimab-rmbw (e.g., Opdualag) should be administered as an intravenous infusion by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Effective October 2023 to September 2025
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Nivolumab and relatlimab-rmbw meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
1. Individual has a diagnosis of unresectable or metastatic (Stage III or IV) melanoma (Opdualag, 2024; NCCN a and 2A); AND
2. Individual is 12 years of age or older and weighing at least 40 kg (Opdualag, 2024; Tawbi HA et.al. 2022); AND
3. Individual is using in one of the following circumstances:
a. Nivolumab; relatlimab-rmbw will be used as first-line systemic therapy; OR
b. The Individual has had previous adjuvant or neoadjuvant therapies containing a PD-1, CTLA-4, BRAF, or MEK inhibitor (or a combination of BRAF and MEK inhibitors); AND
4. Individual has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or a Lansky performance score > 80% for minors (12 to 17 years of age); AND
5. Will not be used:
a. For treatment of uveal melanoma; OR
b. If individual has active brain metastases or leptomeningeal metastases; AND
6. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for up to 1 year:
 
1. Met initial criteria for the medication;  AND
2. Documentation indicating disease response to treatment, such as stabilization of disease, decrease in size of tumor(s) or tumor spread; AND
3. Absence of unacceptable toxicity from the drug, including myelosuppression, infections, and anaphylactic reactions.   
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of nivolumab and relatlimab-rmbw for adult individuals and pediatric individuals 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered IV simultaneously at initiation and every 4 weeks until evidence of disease progression or unacceptable toxicity.
 
Nivolumab and relatlimab-rmbw is available as an injection: 240 mg of nivolumab and 80 mg of relatlimab per 20 mL (12 mg and 4 mg per mL) in a single-dose vial.
 
Nivolumab and relatlimab-rmbw should be administered as an intravenous infusion by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nivolumab and relatlimab-rmbw as a combined product. for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, nivolumab and relatlimab-rmbw, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective December 21, 2022 to September 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of nivolumab and relatlimab-rmbw meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
  1. Individual has a diagnosis of unresectable or metastatic (Stage III or IV) melanoma (FDA 2022 and NCCN); AND
  2. Individual is 12 years of age or older and weighing at least 40 kg (Label; Tawbi HA et.al. 2022) AND
  3. Individual is using in one of the following circumstances:
a.  Nivolumab; relatlimab-rmbw will be used as first-line systemic therapy; OR
b.  The Individual has had previous adjuvant or neoadjuvant therapies containing a PD-1, CTLA-4, BRAF, or MEK inhibitor (or a combination of BRAF and MEK inhibitors), AND
4. Individual has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or a Lansky performance score ≥ 80% for minors (12 to 17 years of age) AND
5. Must be dosed in accordance with the FDA label unless otherwise specified.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
The recommended dose of nivolumab and relatlimab-rmbw for adult individuals and pediatric individuals 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160mg relatlimab administered IV simultaneously at initiation and every 4 weeks until evidence of disease progression or unacceptable toxicity.
 
Nivolumab and relatlimab-rmbw is available as an injection: 240 mg of nivolumab and 80 mg of relatlimab per 20 mL (12 mg and 4 mg per mL) in a single-dose vial.
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nivolumab and relatlimab-rmbw as a combined product for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including but not limited to the following:
    1. For treatment of uveal melanoma; OR
    2. If individual has active brain metastases or leptomeningeal metastases, OR
    3. When the above criteria are not met and for all other indications.
 
For members with contracts without primary coverage criteria, nivolumab and relatlimab-rmbw, for any indication or circumstance not described above, is considered investigational including but not limited to the following:
    1. For treatment of uveal melanoma; OR
    2. If individual has active brain metastases or leptomeningeal metastases, OR
    3. When the above criteria are not met and for all other indications.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 1, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of nivolumab and relatlimab-rmbw meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
    1. Individual has a diagnosis of unresectable or metastatic (Stage III or IV) melanoma (FDA 2022 and NCCN); AND
    2. Individual is 12 years of age or older and weighing at least 40 kg (Label; Tawbi HA et.al. 2022) AND
    3. If individual has had previous adjuvant or neoadjuvant therapies containing a PD-1, CTLA-4, BRAF, or MEK inhibitor (or a combination of BRAF and MEK inhibitors), the therapy was completed at least 6 months before the date of disease recurrence; AND
    4. Individual has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or a Lansky performance score ≥ 80% for minors (12 to 17 years of age) AND
    5. Must be dosed in accordance with the FDA label unless otherwise specified.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
The recommended dose of nivolumab and relatlimab-rmbw for adult individuals and pediatric individuals 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160mg relatlimab administered IV simultaneously at initiation and every 4 weeks until evidence of disease progression or unacceptable toxicity.
 
Nivolumab and relatlimab-rmbw is available as an injection: 240 mg of nivolumab and 80 mg of relatlimab per 20 mL (12 mg and 4 mg per mL) in a single-dose vial.
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nivolumab and relatlimab-rmbw as a combined product for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including but not limited to the following:
 
    1. For treatment of uveal melanoma; OR
    2. If individual has active brain metastases or leptomeningeal metastases, OR
    3. When the above criteria are not met and for all other indications.
 
For members with contracts without primary coverage criteria, nivolumab and relatlimab-rmbw, for any indication or circumstance not described above, is considered investigational including but not limited to the following:
 
    1. For treatment of uveal melanoma; OR
    2. If individual has active brain metastases or leptomeningeal metastases, OR
    3. When the above criteria are not met and for all other indications.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.
 
In a phase 2-3, global, double-blind, randomized trial, relatlimab and nivolumab as a fixed-dose combination was evaluated as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review.
 
The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group.
 
The inhibition of two immune checkpoints, LAG-3 and PD-1 provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (ClinicalTrials.gov number, NCT03470922).
 
2023 Update
In the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progression-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination. Updated HRQoL results (median follow-up, 19.3 months) are presented.
 
Patients were randomized to receive intravenous NIVO + RELA (480 mg and 160 mg, respectively) or NIVO (480 mg) every 4 weeks. HRQoL was assessed using the Functional Assessment of Cancer Treatment-Melanoma (FACT-M) and EQ-5D-3L questionnaires at baseline, before dosing at each treatment cycle, and at follow-up (posttreatment) visits.
 
Consistent with the initial analysis, HRQoL remained stable with NIVO + RELA on treatment and was similar to that with NIVO. Mean changes from baseline did not exceed clinically meaningful thresholds. HRQoL results were consistent across instruments and scales/subscales. Despite an increased rate of grade three or four TRAEs with NIVO + RELA versus NIVO, the proportion of patients reporting that they were bothered 'quite a bit' or 'very much' by TRAEs was low and comparable between treatments.
 
Results from the RELATIVITY-047 trial show that the PFS benefit with NIVO + RELA FDC over NIVO was obtained with stable patient-reported HRQoL, supporting NIVO + RELA as a first-line treatment option for patients with advanced melanoma. (Schadendorf D, Tawbi H, Lipson EJ, 2023)
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2024. No new literature was identified that would prompt a change in the coverage statement.
 
2025 Update
Nivolumab plus relatlimab demonstrated a statistically significant improvement in progression-free survival (PFS), along with a clinically meaningful, but not statistically significant improvement in overall survival (OS) and a numerically higher objective response rate (ORR) compared with nivolumab in the RELATIVITY-047 trial (ClinicalTrials.gov identifier: NCT03470922). The report updated descriptive efficacy and safety results from RELATIVITY-047 with a median follow-up of 33.8 months. Median PFS was 10.2 months (95% CI, 6.5 to 15.4) with nivolumab plus relatlimab and 4.6 months (95% CI, 3.5 to 6.5) with nivolumab (hazard ratio [HR], 0.79 [95% CI, 0.66 to 0.95]); median OS was 51.0 months (95% CI, 34.0 to not reached) and 34.1 (95% CI, 25.2 to 44.7) months, respectively (HR, 0.80 [95% CI, 0.66 to 0.99]). ORR was 43.7% (95% CI, 38.4 to 49.0) with nivolumab plus relatlimab and 33.7% (95% CI, 28.8 to 38.9) with nivolumab. Efficacy across the majority of prespecified subgroups favored the combination. No new or unexpected safety signals were identified. Overall, at 3-year follow-up, the benefit observed with nivolumab plus relatlimab compared with nivolumab in patients with advanced melanoma was sustained, with the OS HR 95% CI upper bound now <1. This benefit is accompanied by a safety profile consistent with previous reports. (Tawbi, 2025)
CPT/HCPCS:
J9298Injection, nivolumab and relatlimab-rmbw, 3mg/1 mg
References: Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.: 2022. URL: http://www.clinicalpharmacology.com. Updated periodically.

DailyMed. Package inserts. U.S. National Library of Medicine, National Institutes of Health website. http://dailymed.nlm.nih.gov/dailymed/about.cfm. Accessed: March 24, 2022

DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated periodically.Lexi-Comp ONLINE™ with AHFS™, Hudson, Ohio: Lexi-Comp, Inc.; 2022; Updated periodically.

NCCN Clinical Practice Guidelines in Oncology™. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on March 24, 2022.

NCCN Clinical Practice Guidelines in Oncology™.(2022) Melanoma: Cutaneious V2.2022. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Revised January 26, 2022.

Opdualag(2024) Package Insert Bristol-Meyers Squibb Company. Princeton, NJ. Revised: 3/2024

Schadendorf D, Tawbi H, Lipson EJ, Stephen Hodi F, Rutkowski P, Gogas H, Lao CD, Grob JJ, Moshyk A, Lord-Bessen J, Hamilton M, Guo S, Shi L, Keidel S, Long GV.(2023) Health-related quality of life with nivolumab plus relatlimab versus nivolumab monotherapy in patients with previously untreated unresectable or metastatic melanoma: RELATIVITY-047 trial. Eur J Cancer. 2023 Jul;187:164-173. doi: 10.1016/j.ejca.2023.03.014. Epub 2023 Mar 22. PMID: 37167764.

Tawbi HA, Hodi FS, Lipson EJ, et.al.,(2024) Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047. J Clin Oncol. 2025 May;43(13):1546-1552. doi: 10.1200/JCO.24.01124. Epub 2024 Dec 13. PMID: 39671533; PMCID: PMC12054981.

Tawbi HA, Schadendorf D, Lipson EJ, et al.(2022) Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N. Engl J Med.2022;386(1):24-34. Accessed March 24, 2022.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.
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