RELATIVITY-048: Triplet Immunotherapy Shows Activity in Untreated Advanced Melanoma

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As a first-line treatment of advanced melanoma, the triplet immunotherapy regimen of nivolumab, relatlimab-rmbw, and ipilimumab produced high response rates and promising progression-free and overall survival in the nonrandomized phase I/II RELATIVITY-048 trial, as reported by Paolo Antonio Ascierto, MD, of the Istituto Nazionale dei Tumori IRCCS in Naples, Italy, at the 2024 ASCO Annual Meeting.1

“Preliminary efficacy data from 46 patients compare favorably with historical published data from nivolumab plus ipilimumab2 and nivolumab plus relatlimab,3 though cross-trial comparisons should be interpreted with caution,” Dr. Ascierto said. He cited the overall survival rate in RELATIVITY-048 (an exploratory endpoint) as 72% at 4 years, compared with approximately 20% with the doublets.

Paolo Antonio Ascierto, MD

Paolo Antonio Ascierto, MD

Background for the Triplet

Lymphocyte-activation gene 3 (LAG3) and PD-1 are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG3-blocking antibody, and nivolumab, a PD-1–blocking antibody, previously showed benefit in RELATIVITY-047. In an updated 2-year analysis presented at the 2023 ASCO Annual Meeting, median progression-free survival was 10.2 months with the doublet vs 4.6 months with nivolumab alone (hazard ratio [HR] = 0.81; 95% confidence interval [CI] = 0.67–0.97).3 Median overall survival was not reached and was 33.2 months with nivolumab alone (HR = 0.82; 95% CI = 0.67–1.02). At 4 years 52% and 42% of the respective cohorts were alive. However, the study was not powered for an overall survival difference.


The nonrandomized phase I/II RELATIVITY-048 study evaluated whether the addition of a third immunotherapy drug might further improve outcomes in previously untreated advanced melanoma. The study’s 46 patients received nivolumab at 480 mg every 4 weeks plus relatlimab at 160 mg every 4 weeks plus ipilimumab at 1 mg/kg every 8 weeks. The primary endpoints were safety, objective response rate, disease control rate, and duration of response. Median duration of therapy was 5 months.

Objective response rate per investigator review was 59% (17% complete responses), with a clinical benefit rate of 76%. Rates by blinded independent central review were 52% (22%) and 72%, respectively. Median duration of response was not reached. Target tumor reductions were observed in 82% of patients.

Patients with cutaneous nonacral melanoma had an objective response rate of 64%, compared with 33% in those with mucosal melanoma and 25% in those with acral melanoma. Although those with noncutaneous types of melanoma had lower responses, Dr. Ascierto indicated he has observed long-term benefit in some such patients. Higher response rates were also observed in patients who had LAG3-positive vs -negative (68% vs 33%) and PD-L1–positive vs –negative (67% vs 59%).

Median progression-free survival was not reached, and at 2 years, 57% were progression-free, as were 52% at 3 years and 52% at 4 years. In an exploratory analysis, median overall survival was also not reached. Survival rates were 80% at 2 years, 72% at 3 years, and 72% at 4 years, Dr. Ascierto reported, pointing to an “interesting flat tail” emerging that may signal long-term overall survival for many patients.

Safety Profile

“There were no new safety signals with nivolumab, relatlimab, and ipilimumab compared with other immunotherapy combinations,” Dr. Ascierto said. “Surprisingly, the toxicity was similar to that with ipilimumab plus nivolumab.” The use of ipilimumab at 1 mg/kg rather than 3 mg/kg may have ameliorated toxicity, he suggested.

Almost all patients had treatment-related adverse events; they were grade 3 or 4 in 39% and led to treatment discontinuation in 41%. The most common grade 2 or 3 toxicities were lipase increase (13%), diarrhea/colitis (11%), and hepatitis (11%). There were two treatment-related deaths within 100 days of the last treatment dose, one from rectal hemorrhage and dyspnea and one from immune-mediated myositis. Cardiac events were found to be rare with the triplet.

In the 23 patients who discontinued treatment because of toxicity, median progression-free survival was not reached. At 3 and 4 years, 67% remained progression-free, added Dr. Ascierto. 

Expert Point of View

The invited discussant of RELATIVITY-048, Sunandana Chandra, MD, MS, Associate Professor of Medicine at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, agreed that the triplet has strong potential and has a reassuring safety profile. However, more work is needed for this regimen, as for other experimental approaches moving into the front-line setting.

“We see a flattening of the [Kaplan-Meier] curves for progression-free as well as overall survival. And the response rate with nivolumab, relatlimab, and ipilimumab in the front-line setting is quite significant,” Dr. Chandra said. “The overall survival data at 48 months (72%) and the progression-free survival at 36 months (52%) are significantly higher with the triplet regimen [than with doublets].... This is not surprising, given the nonredundant mechanisms of action of these three monoclonal antibodies…, but we do need larger confirmatory phase III trials with appropriate control arms.” 

DISCLOSURE: Dr. Ascierto has served as a consultant or advisor to 4SC, Anaveon, AstraZeneca, Bayer, Bio-AI Health, BioNTech SE, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Erasca, Idera, Immunocore, Italfarmaco, ITeos Therapeutics, Lunaphore Technologies, Medicenna, Merck Serono, Merck Sharp & Dohme, Nektar, Nouscom, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Regeneron, Replimune, Roche/Genentech, Sandoz, Sanofi, Seagen, Sun Pharma, Ultimovacs, and ValoTx; has received institutional research funding from Bristol Myers Squibb, Pfizer, Roche/Genentech, and Sanofi; and has received reimbursement for travel, accommodations, and expenses from Bio-AI Health, MSD Oncology, Pfizer, Pierre Fabre, and Replimune. Dr. Chandra reported financial relationships with Array BioPharma, Bristol Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Sanofi/Regeneron, and Alkermes.


1. Ascierto PA, Dummer R, Gaudy-Marqueste C, et al: Efficacy and safety of triplet nivolumab, relatlimab, and ipilimumab in advanced melanoma. 2024 ASCO Annual Meeting. Abstract 9504. Presented May 31, 2024.

2. Hodi FS, Chiarion-Sileni V, Lewis KD, et al: Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067. 2022 ASCO Annual Meeting. Abstract 9522.

3. Tawbi HA, Hodi FS, Lipson EJ, et al: Nivolumab plus relatlimab vs nivolumab in previously untreated metastatic or unresectable melanoma. 2023 ASCO Annual Meeting. Abstract 9502.