Adjuvant Nivolumab/Relatlimab Shows No Added Benefit in Resected Melanoma

Adjuvant treatment with nivolumab plus relatlimab (Opdualag) did not significantly improve recurrence-free survival (RFS) vs nivolumab (Opdivo) alone in completely resected stage III to IV melanoma, failing to meet the primary end point of the phase 3 RELATIVITY-098 trial (NCT05002569).¹

Initially announced in February 2025² and later presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, the primary and final results recently published in Nature revealed no difference in RFS between patients treated with the combination and monotherapy (HR, 1.01; 95% CI, 0.83–1.22; P =.928), with similar incidences of recurrence (36.7% vs 37.7%, respectively). As the primary end point was not met, the trial’s key secondary end point of overall survival was not assessed, and the trial was subsequently terminated.

Since 2022, nivolumab plus relatlimab has been indicated for treatment of adult and pediatric patients aged 12 years or older with unresectable or metastatic melanoma.³ Its approval was based on positive data from the phase 3 RELATIVITY-047 trial (NCT03470922). After 4 years of follow-up, the combination demonstrated sustained, clinically meaningful benefits in both progression-free survival (HR, 0.78; 95% CI, 0.65–0.93) and overall survival (HR, 0.77; 95% CI, 0.64–0.94) compared with nivolumab monotherapy.

While PD-1 immune checkpoint inhibitors, such as nivolumab and pembrolizumab (Keytruda), remain the standard-of-care adjuvant therapy for completely resected stage IIB, IIC, III, or IV melanoma, a pressing unmet need persists in this population, of whom 50% experience disease recurrence.¹ The outcomes from RELATIVITY-098 underscore a need for continued investigation into other adjuvant strategies and deeper understanding of the biologic and clinical factors that may influence treatment benefit.

About the RELATIVITY-098 Trial

In this global, randomized, double-blind phase 3 trial, a total of 1093 patients who had undergone complete resection of stage III/IV melanoma were randomized 1:1 to receive adjuvant treatment consisting of either 480 mg of nivolumab plus 160 mg of relatlimab (n = 547) or 480 mg of nivolumab monotherapy (n = 546). Treatments were administered intravenously for every 4 weeks up to a maximum of 1 year.⁴

Translational Evidence: Reflecting on the RELATIVITY Trials

When considering the differences in outcomes between the RELATIVITY-098 and RELATIVITY-047 trials, findings from an exploratory analysis may offer some insight as to why the combination was efficacious in the advanced melanoma setting of RELATIVITY-047 but not in the resected setting of RELATIVITY-098.

Comparative analyses of immune checkpoint expression in tumor and blood samples from patients across both studies suggest that presence of the tumor may be required for the benefit to hold. In patients with advanced melanoma (RELATIVITY-047), LAG-3⁺ and LAG-3⁺ PD-1⁺ CD8 T cells were found to be substantially higher in the tumor vs blood. Comparing baseline blood levels of LAG-3–expressing T cells in advanced melanoma and resected melanoma (RELATIVITY-098), those with resected melanoma had fewer circulating LAG-3⁺ T cells than those with advanced melanoma.

Analyses were also performed to investigate associations of tumor expression with clinical outcomes. In resected melanoma, higher LAG-3 and CD8 expression were associated with RFS benefit in both treatment arms; there was also a trend toward RFS benefit favoring the combination arm in CD8-low inflamed tumors.

“The absence of macroscopic tumor and reduced peripheral LAG-3⁺ T cells may explain the lack of added benefit of [the combination] over nivolumab in resected vs metastatic melanoma,” Long et al, study authors, wrote in the publication abstract.¹ Despite the disappointing outcomes of RELATIVITY-098, these findings highlight an opportunity to leverage biomarker insights for development and refinement of alternate adjuvant strategies for resected melanoma.

REFERENCES

1. Long GV, Garnett-Benson C, Dolfi S, et al. Adjuvant nivolumab and relatlimab in stage III/IV melanoma: the randomized phase 3 RELATIVITY-098 trial. Nature Med. 2025;31(12):4301-4309. doi:10.1038/s41591-025-04032-8

2. Bristol Myers Squibb provides update on phase 3 RELATIVITY-098 trial. News release. Bristol Myers Squibb. February 13, 2025. Accessed December 17, 2025. https://tinyurl.com/ms2cbxsa

3. U.S. Food and Drug Administration approves first LAG-3-blocking antibody combination, Opdualag™ (nivolumab and relatlimab-rmbw), as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb. March 18, 2022. Accessed December 18, 2025. https://tinyurl.com/nmz9xtah

4. A study to assess adjuvant immunotherapy with nivolumab plus relatlimab versus nivolumab alone after complete resection of stage III-IV melanoma (RELATIVITY-098). ClinicalTrials.gov. Updated May 18, 2025. Accessed December 17, 2025. https://clinicaltrials.gov/study/NCT05002569