Background/Purpose: Immune checkpoint inhibitors (ICIs) led to impressive survival benefits in treatment of cancers. However, immune-related adverse events (irAEs) can cause treatment discontinuation and sometimes fatalities, more often seen with combination ICIs. Through nanostring gene expression profiling of colitis-irAE, normal colon, and tumor biopsies, we found that the interleukin-6 (IL-6)/T helper 17 (Th17) pathway may be implicated in ICI-related autoimmunity and resistance. In mouse model of experimental autoimmune encephalomyelitis transplanted with tumors, we found that adding IL-6 blockade mitigated the ICI induced exacerbation of encephalitis and enhanced tumor shrinkage. In a single-center retrospective study of melanoma patients who received IL-6 receptor (IL-6R) blockade for ICI-induced irAEs [inflammatory arthritis (77%), myositis overlap with myasthenia gravis and/or myocarditis (6.5%), hepatitis (6.5%), 3% each with CNS vasculitis, encephalitis, and systemic sclerosis] at MD Anderson Cancer Center, we observed a 74% improvement rate of irAEs after a median of 2 months of IL-6R blockade therapy and found that the best overall response rate (ORR) to ICI was 57.7% before versus 65.4% after therapy (p = 0.500). Overall, our data suggested that IL-6 blockade could be an effective targeted therapy for irAEs without dampening the tumor response to ICIs.

Methods: We conducted a phase II, open-label, single center study (NCT04940299) to evaluate the upfront use of tocilizumab (Toci) and ipilimumab (Ipi) plus nivolumab (Nivo) for patients with treatment-naïve advanced cutaneous melanoma (n=35). Key inclusion criteria: age ≥18 years, and histologically confirmed locally advanced or metastatic disease including patients with stable asymptomatic brain metastases. Patients with autoimmune diseases, interstitial lung diseases, infection, or diseases requiring immunosuppressive therapies are excluded. Patients receive intravenously Ipi 3 mg/kg + Nivo 1 mg/kg/3 wks for up to 4 doses plus subcutaneous Toci 162 mg/2wks for up to 12 wks (induction phase) and then continue Nivo 480 mg/4 wks up to 2 yrs (maintenance phase). Blood, inflamed tissues, and tumor biopsies are collected for longitudinal immune analysis. Imaging is every 12 wks up to 2 yrs or until dose-limiting toxicities or progression. The primary objective is to assess rate of grade 3 or higher irAEs. The secondary objective is to estimate ORR and overall survival. Exploratory objective is to assess predictive biomarkers of toxicity and tumor response/resistance.

Results: The trial opened in October 2021 and is actively enrolling. As of June 8^th, 2022, 21 patients were enrolled; duration of follow-up ranged from 3 to 32 wks. Six pts (29%) had grade 3 irAEs including diarrhea in 5 pts (24%), elevated lipase in 2 pts (10%) and elevated transaminases in 1 pt (5%). The overall response rate was 58% (1 CR and 6 PR out of 12 evaluable patients) and disease control date was 75%. One patient discontinued treatment due to toxicity and there was no treatment-related death.

Conclusion: Our preliminary data showed that adding Toci to the combination of Ipi and Nivo is safe and well tolerated and had no negative impact on tumor immunity. Biomarker analysis are still ongoing.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-ii-clinical-trial-to-assess-the-safety-and-efficacy-of-tocilizumab-in-combination-with-ipilimumab-and-nivolumab-for-treatment-naive-metastatic-melanoma/