Dr Mehnert on the Rationale for Adding IL-6 Blockade to Checkpoint Inhibition in Melanoma

"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."

Janice Mehnert, MD, 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, explained the clinical rationale for combining IL-6 receptor blockade with checkpoint inhibitors to potentially enhance antitumor efficacy and reduce immune-related toxicity in advanced melanoma.

Although current checkpoint blockade regimens have transformed treatment outcomes, a substantial percentage of patients either fail to respond or develop significant immune-mediated adverse effects. Preclinical and translational evidence indicates that elevated IL-6 signaling contributes to both treatment resistance and immunotoxicity by promoting a suppressive tumor microenvironment and enhancing inflammatory pathways. Based on this rationale, IL-6 receptor inhibition may dampen detrimental inflammation while simultaneously improving responsiveness to immune checkpoint blockade.

In a phase 2 trial (NCT05428007), investigators evaluated an IL-6 receptor antagonist plus checkpoint inhibitors in 33 patients with unresectable stage III or IV melanoma. Findings presented at the 2025 ASCO Annual Meeting demonstrated favorable antitumor activity, with an overall response rate of 63.6% at 24 weeks—including one complete response and 20 partial responses. Importantly, toxicity was manageable: grade 3/4 adverse effects occurred in 48.4% of patients, treatment-related events in 21.2%, and immune-related effects in 12.1%. No grade 5 toxicities were observed.

Mehnert noted that the dual goal of the regimen is to improve outcomes for those unlikely to benefit from standard immunotherapies while mitigating toxicities that can limit their use. By targeting IL-6 signaling, the approach seeks to reprogram the tumor microenvironment to restore sensitivity to checkpoint blockade and lessen excessive immune activation. If efficacy and safety are confirmed in larger trials, IL-6 receptor blockade could offer a new combination backbone for patients with advanced melanoma—particularly those at higher risk for resistance or immune-related toxicity with current treatment options.