Sustained Treatment-Free Survival With Relatlimab/Nivolumab in Advanced Melanoma

The combination of relatlimab (Opdualag) and nivolumab (Opdivo) provided a sustained increase in treatment-free survival (TFS) compared with nivolumab monotherapy in patients with previously untreated advanced melanoma, according to a new analysis of the phase 2/3 RELATIVITY-047 trial (NCT03470922).¹ At 48 months, the mean TFS was 9.7 months for the combination arm vs 6.8 months for the monotherapy arm, a difference of 2.9 months (95% CI, 1.0-4.9). Investigators reported that the Kaplan-Meier estimates of overall survival were 52% in the combination arm and 43% in the monotherapy arm.

This TFS analysis included all 714 patients from the phase 2/3 RELATIVITY-047 trial (NCT03470922) who were randomly assigned to receive either a fixed-dose combination of 160 mg relatlimab plus 480 mg nivolumab (n = 355) or 480 mg nivolumab alone (n = 359) every 4 weeks.¹

The Kaplan-Meier estimates of overall survival at 48 months were 52% in the combination arm and 43% in the monotherapy arm. A greater proportion of patients in the combination arm were free of subsequent systemic therapy or death (38% vs 33%), and overall, patients receiving the combination were treatment-free for 20% of the 4-year follow-up time, compared with 14% for those receiving nivolumab alone.¹

Thirty-eight percent of patients in the combination arm and 33% of patients in the monotherapy arm were free of subsequent systemic anticancer therapy or death, while 13% and 11% of the total patients continued to receive protocol-assigned study medication at 48 months.¹

The TFS analysis included all 714 patients who initiated therapy in the trial. For this analysis, follow-up was restricted at 48 months, at which time there were approximately 30% of patients still in follow-up (117 in the nivolumab plus relatlimab group and 90 in the nivolumab group). Patients in the nivolumab plus relatlimab group were treatment-free for 20% of the 4-year follow-up time since randomization, compared with 14% in the nivolumab group.

The longer mean TFS resulted from a longer mean time to subsequent anticancer systemic therapy in the nivolumab plus relatlimab group than in the nivolumab group (25.2 and 22.5 months, respectively; difference, 2.7 months (95% CI −0.2 to 5.6).

Investigators led by Meredith M. Regan, wrote that mean time on protocol treatment was similar between the treatment groups (15.4 and 15.7 months for nivolumab plus relatlimab and nivolumab, respectively) during the 48-month period. They noted that the observed TFS differences can be attributed mainly to the differences in time to subsequent systemic anticancer therapy initiation or death.

Because adverse events associated with immune checkpoint inhibitors can persist beyond or emerge after treatment continuation, investigators evaluated TFS periods with or without toxicity. As a result, toxicity was defined as follows: grade ≥3 treatment-related adverse events (TRAEs) that occurred before the discontinuation of study drug or reported after the discontinuation of study drug but before the initiation of subsequent systemic anticancer therapy.

Further, relevant AEs reported from randomization to the initiation of subsequent systemic anticancer therapy—including those newly reported after the end of protocol therapy—were considered in the analysis.

TFS with toxicity was also longer in the nivolumab plus relatlimab group than in the nivolumab group. Nivolumab plus relatlimab is associated with more toxicity than nivolumab monotherapy, and increased toxicity for the combination compared with nivolumab alone may lead to longer total TFS and TFS with toxicity.

These results are consistent with those from the phase 3 Check-Mate 067 trial in which patients with advanced melanoma receiving combination nivolumab plus ipilimumab demonstrated longer total TFS and TFS with toxicity than those receiving nivolumab alone.²

The authors demonstrated the sustained benefits in treatment outcomes and highlighted the potential for improved quality of life in patients with advanced melanoma with nivolumab plus relatlimab. Regan MM, et al, wrote that next steps should involve a direct comparison between nivolumab plus relatlimab and nivolumab plus ipilimumab to determine the differences between the regimens in TFS and those in traditional end points.

REFERENCES:

1. Regan MM, Ascierto PA, Lipson EJ, et al. Analysis of treatment-free survival of patients with advanced melanoma receiving nivolumab as monotherapy or in combination with relatlimab in RELATIVITY-047. J Immunother Cancer. 2025;13:e012747. doi:10.1136/jitc-2025-012747

2. Regan MM, Mantia CM, Werner L, et al. Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in CheckMate 067. J Immunother Cancer. 2021;9(11):e003743. doi:10.1136/jitc-2021-003743.