The addition of the interleukin-6 (IL-6) inhibitor sarilumab (Kevzara) to the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) and relatlimab-rmbw (Opdualag) generated preliminary efficacy signals and had a tolerable safety profile in patients with unresectable advanced melanoma, according to Janice Mehnert, MD.
A phase 2 trial (NCT05428007) investigated the combination in patients with unresectable, advanced, stage III or IV melanoma (n = 33). Findings presented at the 2025 ASCO Annual Meeting showed that at 24 weeks, the rates of grade 3/4 adverse effects (AEs), serious AEs, treatment-related AEs, and immune-related (irAEs) were 48.4%, 27.2%, 21.2%, and 12.1%, respectively. Notably, no grade 5 toxicities were reported. Additionally, at 24 weeks, the overall response rate (ORR) was 63.6%, including 1 complete response and 20 partial responses.
“Importantly, if our paradigm is successful, this [study will have] implications for melanoma and for tumors beyond melanoma,” Mehnert said in an interview with OncLive®. “We use checkpoint inhibitor therapy in multiple different tumor types, and we [may] be able to start to explore whether adding IL-6 inhibition can similarly improve outcomes in those patients.”
In the interview, Mehnert discussed the rationale for adding IL-6 inhibition to an immune checkpoint inhibitor (ICI) backbone in patients with advanced melanoma, top efficacy and safety findings from part 1 of the phase 2 trial, and next steps for this research.
Mehnert is a professor in the Department of Medicine at the New York University Grossman School of Medicine, director of the Melanoma Medical Oncology Program, and associate director of Clinical Research at the Perlmutter Cancer Center.
OncLive: What was the clinical rationale for incorporating IL-6 receptor blockade into a combination with checkpoint inhibition for patients with advanced melanoma?
Mehnert: We have good standards of care to manage melanoma these days, but we’re still faced with the fact that over 40% of patients do not respond to therapy, and the development of serious immunotoxicity plagues several of our patients as well. Our idea in designing this trial was to try to inhibit the signaling of IL-6, since this is known to be a pathway that drives both resistance to therapy, as well as toxicity from therapy, with the hope that we could both improve response rates and decrease toxicity.
What was the design of this trial?
The trial was designed in 2 parts. At ASCO 2025, I presented [findings from both parts] of the study, which enrolled 33 patients [who received] a regimen of ipilimumab, nivolumab, relatlimab, and the IL-6 receptor inhibitor sarilumab. Importantly, [ipilimumab plus nivolumab and relatlimab] is a backbone of multiple ICIs that, on its own, [can] promote AEs. We wanted to see if by adding the IL-6 inhibitor, we could bring that toxicity rate down and the response rate up. [Those were the] coprimary end points for which the trial was designed to test.
What efficacy data were presented from part 1?
We observed a best ORR of 63.6%. That’s exciting because it is one of the highest response rates we’ve seen in studies of immune checkpoint inhibition in melanoma to date.
What safety findings are important to note?
No untoward or unexpected toxicities were noted. We measured our coprimary end point of grade 3 to 5 irAEs at 24 weeks. We picked that 24-week time point because that’s how long we gave the sarilumab during the trial. The rate [of grade 3/4 irAEs] came in at 12.1%, which is much lower than what we’ve seen in other studies to date that use CTLA-4 inhibition as part of the regimen.
How do these efficacy findings place this regimen in the context of previously established combination regimens for patients with 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.
What are the next steps for this research?
We’ll be verifying these [part 1] findings in a randomized phase 2 cohort that I’m hoping to have ready for [readout in June 2026]. The next steps of this phase 2 trial will be to evaluate 30 patients who are treated with this quadruplet regimen vs 30 patients who are treated with just ipilimumab, nivolumab, and relatlimab. [This will be a] randomized comparison, which will help us understand the contribution of the IL-6 inhibition.
Reference
Mehnert J, Mehni I, Goldberg J, et al. A phase II study of the interleukin-6 (IL-6) receptor blocking antibody sarilumab (Sari) in combination with ipilimumab (Ipi), nivolumab (Nivo) and relatlimab (Rela) in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2025;43(suppl 16):9510. doi:10.1200/JCO.2025.43.16_suppl.9510