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.

9510 Background: Combination immune checkpoint inhibitor regimens, especially those utilizing anti-CTLA-4 blockade, demonstrate higher response rates compared with single agent anti-PD-1 therapy but also increased rates of immune related adverse events (irAEs). IL-6, a key cytokine in driving inflammatory and autoimmune responses, is a compelling target to reduce irAEs through the use of IL-6 receptor (IL-6R) inhibitors. We conducted a clinical trial of 1L Nivo, Rela, and Ipi combined with the IL-6R inhibitor Sari in patients with advanced melanoma. Methods: 33 patients with advanced stage III/IV melanoma were treated in a single arm phase II trial. Patients received Nivo/Rela 480 mg/160 mg Q4W, Ipi 1 mg/kg Q8W and Sari 200mg q2 weeks for 12 doses over 24 weeks followed by maintenance Nivo/Rela 480 mg/160 mg Q4W and Ipi 1 mg/kg Q8W. Prior adjuvant immunotherapy was allowed if > 6 months before enrollment. Patients with controlled brain metastases could enroll. The co-primary endpoints were rate of grade (gr) 3-5 irAEs and antitumor activity defined by RECIST best overall response rate at 24 weeks. With 33 patients, a difference of ≥ 22% from the known irAE rate of Nivo, Rela, and Ipi could be detected using a binomial test (2-sided alpha = 0.05, 80% power). BORR was estimated with an exact 95% Clopper Pearson confidence interval. Circulating IL-6 signaling mediators were measured over time in 14 patients using Luminex assays. Results: 33 patients (40% F, 60% M, PS 0-1, median age 63) were treated. Median follow-up was 9.8 months (95% CI: 8.5, 12.6 months; data lock, 12/12/24). 3% had acral and 9% mucosal melanoma. 24% had > M1c disease and 39% elevated LDH. BRAF status, known for 81% of patients, was positive in 26%. BORR at 24 weeks was 63.6% (95% CI: 45.1%, 79.6%). Median PFS and OS were not reached (25 th percentile for PFS = 8.3 (95% CI: 2.77, NA) months). Median treatment duration was 28 weeks and 9% discontinued therapy for toxicity. At 24 weeks 12.1% (n = 4) experienced > gr 3/4 irAEs, significantly lower than the expected known irAE rate (2-sided p = 0.0007, 95% CI: 12.1%-28.2%). 27% (n = 9) had gr 3/4 toxicity over study duration; 93.9% (n = 31) had any grade irAE. Circulating IL-6Ra and IL-4 were significantly reduced at Cycle 2 (P < 0.05). Conclusions: Nivo, Rela, Ipi, + Sari demonstrated encouraging efficacy and tolerability. At 24 weeks, 63.6% BORR and 12.1% gr 3/4 irAE rate were observed. 2 patients had gr 4 toxicity; no gr 5 events were reported. These results compare favorably with published combination regimens including CTLA-4 blockade. Decreases in lL-6Ra and the inflammatory marker IL-4 observed post-treatment will be evaluted in a larger cohort of samples. An ongoing randomized cohort of Nivo + Rela + Ipi +/- Sari will further define the impact of IL-6R blockade on clinical outcomes in metastatic melanoma. Clinical trial information: NCT05428007 .