Description
Nivolumab and relatimab-rmbw is a fixed-dose combination of two lgG4 kappa monoclonal antibodies (mAbs). Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2, and reduces PD-1 pathway mediated inhibition of the immune response, including the anti-tumor immune response. Relatlimab is a lymphocyte activation gene-3 (LAG-3) blocking antibody that binds to the LAG-3 receptor blocks interaction with its ligands, including MHC ll, and reduces LAG-3 pathway-mediated inhibition of the immune response. Antagonism of this pathway promotes T cell proliferation and cytokine secretion. The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone. In murine syngeneic tumor models, LAG-3 blockade potentiates the anti-tumor activity of PD-1 blockage, inhabiting tumor growth and promoting tumor regression.

Policy
Opdualag Criteria

1. Member meets one of the following:
   1. Used as first-line therapy for unresectable or metastatic melanoma, OR
   2. Will be Approved when being used as indicated by the National Comprehensive Cancer Network INCCN) guidelines as a grade 2A or better recommendation, AND
2. Member weighs at least 40 kg, AND
3. Member is 12 years of age or older, AND
4. Member does not have active or untreated brain or leptomeningeal metastases
5. Prescribed by or in consultation with oncologist/hematologist
6. Patient has not received previous therapy with a programmed death (PD-1/PD-L1)-directed therapy (e.g., cemiplimab, avelumab, pembrolizumab, atezolizumab, durvalumab, dostarlimab, etc.), unless otherwise specified. 

Auth Duration: 12 months

Rationale
Nivolumab is a monoclonal antibody that enhances the antitumor immune response by binding to the programmed death receptor-1 (PD-1) and blocking its interaction with ligand 1 and 2 (PD-L1 and PD-L2). Relatlimab is a monoclonal antibody that binds to the lymphocyte activation gene-3 (LAG-3) receptor which results in promoting T cell proliferation and cytokine secretion. The combined agents result in inhibition of tumor growth. Nivolumab; relatlimab-rmbw (Opdualag) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.

The initial safety and efficacy of nivolumab; relatlimab-rmbw (Opdualag) was evaluated in a randomized trial as compared to nivolumab alone in 714 patients with previously untreated unresectable or metastatic Stage III or IV melanoma. Patients were permitted to have received prior adjuvant or neoadjuvant melanoma therapy with anti-PD-1, anti-CTLA-4, or BRAF-MEK inhibitors if received at least 6 months between the last dose of therapy and the date of recurrence. Patients with active autoimmune disease, conditions requiring corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases were excluded. Patients received either nivolumab;relatlimab-rmbw or nivolumab every 4 weeks until disease progression or unacceptable toxicity. There were 41% of patients with PD-L1 expression greater than or equal to 1%, 75% of patients with LAG-3 expression greater than or equal to 1%, and 39% with BRAF V600 mutation-positive melanoma. The efficacy outcome measures were progression-free survival (PFS), overall survival (OS) and overall response rate (ORR). There was a significant improvement in PFS with the combination arm as compared to nivolumab alone (10.1 months vs. 4.6 months, p = 0.0055). The overall survival was not significant at the time of the analysis (34.2 months vs. 25.2 months) and the overall response rate was 43% for the combined group as compared to 33% with nivolumab alone. The most common adverse reactions that occurred in patients treated with nivolumab;relatlimab-rmbw included musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%). Other clinically relevant reactions that occurred in less than 15% of patients included vitiligo, adrenal insufficiency, myocarditis, and hepatitis. The most common lab abnormalities were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

National Comprehensive Cancer Network (NCCN) Guidelines for Melanoma include recommendations for the use of nivolumab; relatlimab-rmbw as a preferred first-line systemic therapy option for metastatic or unresectable disease. Metastatic disease includes stage III unresectable/borderline resectable disease with clinically positive node(s) or clinical satellite/in-transit metastases, unresectable local satellite/in-transit recurrence, unresectable nodal recurrence, and widely disseminated distant metastatic disease.

References

1. Opdualag (package insert). Princeton, NJ; Bristol-Myers Squibb Company; March 2022. Accessed March 2022.
2. Referenced with permission from the NCCN Drug & Biologics Compendium (NCCN Compendium®) nivolumab-relatimab. National Comprehensive Cancer Network, 2022. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed march 2022.
3. Tawbi HA, Schadendorf D, Lipson EJ; RELATIVITY-047 Investigators, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386;24-34.
4. MICROMEDEX Healthcare Series. Drugdex Evaluations. (2022, April). Nivolumab/Relatlimab-rmbw Retrieved April 2022 from MICROMEDEX Healthcare Series.
5. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2022 [cited 2022 Apr 28]. Available from: http://www.clinicalpharmacology.com/.
6. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2022 Apr 28].
7. National Cancer Institute. Common Terminology Criteria for Adverse Events. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed 04/28/22.
8. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Cutaneous melanoma, v3.2022. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 04/28/22.
9. NCCN Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network;2022. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/. Accessed 04/28/22.
10. Opdualag (nivolumab;relatlimab-rmbw) injection [package insert]. Bristol-Myers Squibb Company. Princeton, NJ. March 2022.
11. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2022 [cited 2022 Apr 28]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.

Coding Section

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