Nivolumab Plus Relatlimab Fails to Improve RFS in Resected Stage III/IV Melanoma

Adjuvant treatment with nivolumab and relatlimab-rmbw (Opdualag) did not improve recurrence-free survival (RFS) compared with nivolumab (Opdivo) monotherapy in patients with completely resected stage III/IV melanoma, missing the primary end point of the phase 3 RELATIVITY-098 trial (NCT05002569).1

In a news release, Bristol Myers Squibb noted that the safety profile of nivolumab and relatlimab was consistent with previously reported safety data.

“We are disappointed in the outcome of the RELATIVITY-098 trial and that LAG-3 inhibition in the adjuvant setting did not lead to the same improved efficacy outcomes seen in advanced melanoma,” Jeffrey Walch, MD, PhD, vice president, Opdualag global program lead, Bristol Myers Squibb, stated in a news release.

Previously, in March 2022, the FDA approved the fixed-dose combination of relatlimab and nivolumab for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma, based on data from the phase 2/3 RELATIVITY-047 trial (NCT03470922).2

“Patients whose tumors are completely resected before treatment may not have sufficient antitumor T cells in place for [nivolumab and relatlimab] to have its maximal effect. However, [nivolumab and relatlimab] remains a standard of care in the first-line treatment of unresectable or metastatic melanoma, and we continue to explore its potential across tumor types, including in non–small cell lung cancer,” Walch added.

RELATIVITY-098 Design and Patient Enrollment Criteria

The fixed-dose combination of nivolumab and relatlimab was evaluated against nivolumab monotherapy in this randomized, double-blind trial. Eligible participants needed to be at least 12 years of age with histologically confirmed stage IIIA (>1 mm tumor in lymph nodes), IIIB, IIIC, IIID, or stage IV melanoma; complete surgical resection with negative margins was required.3 Patients at least 18 years of age needed to have an ECOG performance status of 0 or 1, and adolescents 12 to 17 years of age needed a Karnofsky performance score of greater than 80%.

Surgery must have been completed within 90 days of randomization, and disease-free status needed to be confirmed through a physical examination within 14 days and imaging within 35 days prior to randomization. Tumor tissue needed to be available for biomarker analyses.

Key exclusion criteria include a history of ocular melanoma, untreated or unresected central nervous system metastases, and active autoimmune disease. Patients with severe or uncontrolled medical disorders, prior immunotherapy for melanoma, or recent COVID-19 infection within 4 weeks before screening were also ineligible, as were those with a history of myocarditis, regardless of cause.

Patients were randomly assigned to receive nivolumab plus relatlimab or nivolumab monotherapy cohort.

Along with the primary end point of RFS, secondary end points included overall survival, distant metastasis-free survival (DMFS), time to second progression, and safety. Safety end points included the incidence of serious adverse effects (AEs), severity of serious AEs, incidence of AEs leading to treatment discontinuation, incidence of immune-mediated AEs, incidence of death, and incidence of significant changes to clinical laboratory values.

Previously reported safety data for nivolumab plus relatlimab from the RELATIVITY-047 showed that the most common AEs reported in at least 20% of the patients treated with the doublet included musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).1 The most common laboratory abnormalities observed in at least 20% of patients consisted of decreased hemoglobin level (37%), decreased lymphocyte count (32%), increased aspartate aminotransferase level (30%), increased alanine aminotransferase level (26%), and decreased sodium level (24%).

References

1. Bristol Myers Squibb provides update on phase 3 RELATIVITY-098 trial. News release. Bristol Myers Squibb. February 13, 2025. Accessed February 14, 2025. https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Provides-Update-on-Phase-3-RELATIVITY-098-Trial/default.aspx
2. FDA approves Opdualag for unresectable or metastatic melanoma. FDA. March 18, 2022. Accessed February 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-opdualag-unresectable-or-metastatic-melanoma
3. A study to assess adjuvant immunotherapy with nivolumab plus relatlimab versus nivolumab alone after complete resection of stage III-IV melanoma. ClinicalTrials.gov. Updated January 20, 2025. Accessed February 14, 2025. https://clinicaltrials.gov/study/NCT05002569