A novel combination therapy incorporating the IL-6 receptor blocking antibody sarilumab with established checkpoint inhibitors has demonstrated remarkable efficacy in patients with advanced melanoma, achieving one of the highest response rates reported in melanoma immunotherapy studies to date.
The phase 2 study (NCT05428007) evaluated sarilumab (Kevzara) in combination with ipilimumab (Yervoy), nivolumab (Opdivo), and relatlimab in 33 patients with unresectable stage III or IV melanoma. At a median follow-up of 9.8 months, the combination achieved a 24-week overall response rate of 63.6%, including one complete response.
Superior Efficacy Compared to Standard Regimens
The 63.6% response rate represents a significant improvement over existing checkpoint inhibitor combinations. For comparison, the phase 3 Checkmate-511 trial reported a 45.6% overall response rate, while the phase 1/2 Relativity-048 trial achieved 58.7%. The 24-week clinical benefit rate reached 78.8% (95% CI, 61.1%-91%) in the current study.
"We were able to observe a best overall response rate of 63.6% and 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," said Janice M. Mehnert, MD, professor in the Department of Medicine at NYU Grossman School of Medicine and director of the Melanoma Medical Oncology Program at Perlmutter Cancer Center.
Improved Safety Profile
The combination demonstrated a notably favorable safety profile compared to other anti-CTLA-4 containing regimens. Grade 3/4 immune-related adverse events occurred in only 12.1% of patients at 24 weeks, substantially lower than the 34% rate observed in Checkmate-511 and the 43% rate in Relativity-048. Any-grade immune-related adverse events occurred in 93.9% of patients, with no grade 5 toxicities reported.
The most common immune-related adverse events included elevated liver enzymes (33%), diarrhea/colitis (27%), and hypothyroidism (15%). These events occurred at grade 3 or 4 severity at rates of 3%, 6%, and 3%, respectively.
Treatment Protocol and Patient Characteristics
The open-label trial enrolled patients with unresectable stage III or IV melanoma, excluding those with ocular/uveal melanoma. Prior anticancer treatment for metastatic disease was not permitted, though previous adjuvant immunotherapy was allowed if completed over 6 months before enrollment.
During the induction phase, patients received intravenous ipilimumab at 1 mg/kg on day 1, nivolumab at 480 mg and relatlimab at 160 mg on days 1 and 29, and subcutaneous sarilumab at 150 mg on days 0, 15, 29, and 43. Maintenance therapy continued with 8-week cycles for a total of 24 weeks, with cycles 3 and beyond excluding sarilumab.
The study population had a median age of 63 years, with 60.6% male patients and 75.8% presenting with stage IV disease. At baseline, 39.4% of patients had elevated lactate dehydrogenase levels and 21.2% had liver metastases.
Survival Outcomes and Treatment Duration
At the data cutoff, median progression-free survival was not reached, with 68% of patients alive without disease progression. Only two deaths were reported at days 57 and 80. The median treatment duration was 28 weeks, with patients receiving median percentages of planned doses of 50% for ipilimumab, 53% for nivolumab/relatlimab, and 92% for sarilumab.
Broader Implications for Cancer Treatment
The success of IL-6 inhibition in enhancing checkpoint inhibitor efficacy while reducing toxicity may have implications beyond melanoma. "If our paradigm is in fact successful, this research has implications not just for melanoma, but for tumors beyond melanoma," Mehnert noted. "We use checkpoint inhibitor therapy in multiple tumor types, and we'll be able to start to explore whether adding IL-6 inhibition can similarly improve outcomes in those patients."
The findings suggest that targeting the IL-6 pathway alongside established checkpoint inhibitors represents a promising strategy for improving outcomes in advanced melanoma while maintaining an acceptable safety profile.
