Indirect Comparisons Shows Relatlimab/Nivolumab Has Comparable Outcomes to Ipilimumab/Nivolumab in Advanced Melanoma

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Findings from an updated 4-year indirect treatment comparison (ITC) analysis between the phase 2/3 RELATIVITY-047 trial (NCT03470922) and the phase 3 CheckMate-067 trial (NCT01844505) showed that the combination of nivolumab and relatlimab (Opdualag) produced similar efficacy outcomes to nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with advanced melanoma.

Findings presented in a poster presentation at the 2025 ASCO Annual Meeting showed that after balancing key baseline characteristics for the nivolumab/relatlimab (n = 339) and nivolumab/ipilimumab groups (n = 297), investigator-assessed progression-free survival (PFS; HR, 1.08; 95% CI, 0.89-1.33) and overall survival (OS; HR, 0.95; 95% CI, 0.76-1.19) outcomes after weighting were similar between both groups. The median PFS in each arm, respectively, was 12.0 months (95% CI, 8.2-17.1) vs 11.2 months (95% CI, 8.5-18.1). Additionally, the median OS was 64.5 months (95% CI, 38.6-not reached [NR]) with relatlimab vs NR (95% CI, 37.1-NR) with ipilimumab.

Additional efficacy data revealed that the investigator-assessed confirmed objective response rate (ORR) was 48% with relatlimab vs 50% with ipilimumab after weighting, with an HR of 0.91 (95% CI, 0.73-1.14). The complete response rates were 16% vs 20%, with 31% vs 30% attaining partial responses. The median duration of response (DOR) in each arm was 67.4 months (95% CI, 59.8-NR) vs NR (95% CI, NR-NR; HR, 0.90; 95% CI, 0.62-1.29). Furthermore, the median melanoma-specific survival in both groups was NR (HR, 0.87; 95% CI, 0.68-1.12).

Subgroup analysis revealed that efficacy appeared to be similar between groups; however, a trend favoring ipilimumab emerged for ORR among patients with BRAF-mutant disease, as well as those with serum lactate dehydrogenase levels twice the upper limit of normal. Additionally, untruncated follow-up analyses were consistent with truncated analyses.

“In the absence of a head-to-head [randomized controlled trial], this updated adjusted ITC with longer follow-up from RELATIVITY-047 and CheckMate-067 continues to show that first-line treatment with [nivolumab/relatlimab] may have comparable efficacy to and lower toxicity than [nivolumab/ipilimumab] in patients with advanced melanoma,” Dirk Schadendorf, MD, director of the Clinic for Dermatology at the University of Essen and the German Cancer Consortium, wrote in the poster with study coinvestigators. “Across most subgroups, PFS, OS, and confirmed ORR were similar between [nivolumab/relatlimab] and [nivolumab/ipilimumab].”

Patients in the phase 2/3 RELATIVITY-047 trial were randomly assigned to receive relatlimab/nivolumab at a fixed dose combination or nivolumab alone. A long-term analysis revealed that nivolumab/relatlimab elicited enhanced PFS per blinded independent central review (HR, 0.78; 95% CI, 0.65-0.93) and OS outcomes (HR, 0.77; 95% CI, 0.64-0.94) vs nivolumab alone.

Those in the phase 3 CheckMate-067 trial were randomly assigned to receive nivolumab/ipilimumab, nivolumab, or ipilimumab. Nivolumab/ipilimumab showed superior investigator-assessed PFS and OS outcomes vs ipilimumab, but the study was not powered for comparison between the nivolumab/ipilimumab and nivolumab groups.

In the RELATIVITY-047 and CheckMate-067 trials, 61.05% vs 62.17% of patients were male, 13.84% vs 15.37% were treated in the US, and the mean time from advanced melanoma diagnosis to index date was 3.20 years (SD, 5.44) vs 3.36 years (SD, 4.17). A total of 85.80% vs 82.97% did not receive prior adjuvant therapy, 66.25% vs 65.85% had an AJCC stage of M0/M1 and a lactate dehydrogenase at or under the upper limit of normal, and 92.09% vs 92.93% had AJCC stage IV disease. Furthermore, 73.89% vs 76.36% of each trial population had cutaneous non-acral melanoma, 69.60% vs 70.95% had an ECOG performance status of 0, and 63.43% vs 63.83% had BRAF wild-type disease.

The end points of the 4-year ITC update were PFS, MSS, confirmed ORR, and DOR by investigator assessment, as well as OS.

After weighting, the any-grade treatment-related adverse effect (TRAE) incidence in the relatlimab and ipilimumab arms were 85% vs 96%. Additionally, grade 3 or 4 TRAEs occurred in 23% vs 62% of each respective arm.

TRAEs leading to treatment discontinuation occurred in 18% vs 41%, respectively. The most common TRAEs by category were skin (47% vs 62%), endocrine (28% vs 36%), gastrointestinal (19% vs 48%), and hepatic (15% vs 33%).

Reference

Schadendorf D, Tawbi H, Lipson EJ, et al. Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: an updated indirect treatment comparison (ITC) with 4-year follow-up data. J Clin Oncol. 2025;43(suppl 16):9554. doi:10.1200/JCO.2025.43.16_suppl.9554