Dr Mehnert on Next Steps for the Evaluation of Quadruplet Therapy in Advanced Melanoma

"Putting everything together in context, we’re seeing an interesting signal that by adding IL-6 inhibition [to an ICI backbone], we don’t sacrifice response; if anything, we gain a little there. However, we [also] gain an advantage on the toxicity front, and that’s important."

Janice M. Mehnert, MD, a professor in the Department of Medicine at NYU Grossman School of Medicine, director of the Melanoma Medical Oncology Program, and associate director of Clinical Research at Perlmutter Cancer Center, discussed next steps for the investigation of sarilumab (Kevzara) plus ipilimumab (Yervoy), nivolumab and relatlimab-rmbw (Opdualag) in unresectable stage III or IV melanoma and contextualizes the regimen's efficacy and safety profile with that of other combination regimens for this patient population.

Findings from a phase 2 study (NCT05428007) presented at the 2025 ASCO Annual Meeting showed a 24-week overall response rate (ORR) of 63.6% (n = 21/33) with the combination. In contrast, the ORR was 45.6% (n = 82/180) in the phase 3 Checkmate-511 trial (NCT02714218) and 58.7% (n = 27/46) in the phase 1/2 Relativity-048 trial (NCT03459222). Additionally, at a median follow-up of 9.8 months, the 24-week clinical benefit rate in the phase 2 study was 78.8% (95% CI, 61.1%-91%).

Mehnert discussed the "interesting signal" observed in the phase 2 study, which suggests that adding IL-6 inhibition to an immune checkpoint inhibitor backbone potentially enhances rather than diminish responses. Crucially, Mehnert highlighted that this addition also offers an advantage in terms of toxicity, which she considers to be an important benefit.

The next steps to verify these initial findings involve a randomized phase 2 cohort study, she stated. This study will compare 30 patients receiving the quadruplet regimen against 30 patients treated solely with ipilimumab, nivolumab, and relatlimab. This randomized comparison is designed to help researchers understand the contribution of IL-6 inhibition to the overall efficacy and safety profile of the treatment, Mehnert said. Readout of data from this study is anticipated in June, 2026.