A phase 2 study presented at the 2024 ASCO Annual Meeting reveals that prophylactic use of tocilizumab, an IL-6 inhibitor, alongside ipilimumab and nivolumab, enhances efficacy and reduces immune-related toxicities in patients with unresectable melanoma. The findings suggest a promising strategy to improve outcomes and manage adverse effects associated with immune checkpoint inhibitors.
Study Design and Key Findings
The phase 2 trial (NCT03999749) evaluated the impact of IL-6 blockade with tocilizumab on immune-related toxicities following treatment with ipilimumab (Yervoy) and nivolumab (Opdivo) in patients with unresectable melanoma. Seventy patients received prophylactic tocilizumab in combination with ipilimumab and nivolumab, followed by nivolumab maintenance. After a median follow-up of 23 months, the best overall response (BOR) rate was 57% per RECIST 1.1 criteria. The median progression-free survival was 9.1 months, and the estimated 2-year overall survival rate was 75%.
Matthew Hadfield, DO, an assistant professor of medicine at the Warren Alpert Medical School of Brown University, noted the significance of IL-6 as a therapeutic target. "IL-6 is an important cytokine that’s been shown in preclinical models to contribute to therapeutic resistance to immune checkpoint inhibitors, particularly in melanoma. It is also an important cytokine that is upregulated during the development of toxicities," he said.
Reduced Immune-Related Adverse Events
The safety population (n = 71) experienced grade 1 or 2 immune-related adverse effects (irAEs) at a rate of 71%, while grade 3 or 4 irAEs were reported in 22% of patients. Common grade 1 or 2 irAEs included pruritus (n = 23), skin/rash toxicities (n = 21), and elevated AST/ALT levels (n = 20). Grade 3 or 4 irAEs included elevated AST/ALT levels (n = 4), diarrhea (n = 4), colitis (n = 2), and lipase/amylase level elevation (n = 2). Compared to the expected rate of approximately 34% for grade 3 or 4 adverse effects with nivolumab plus ipilimumab, as seen in the CheckMate 511 trial, the study showed a comparatively decreased rate of toxicity.
Clinical Implications and Future Directions
The findings suggest a twofold effect: potentially increased efficacy in patients with primary resistance to immunotherapy and prophylactic protection against toxicities. "As we begin to learn more about [which patients are] at higher risk for developing these toxicities, we can possibly start adding these prophylactic regimens early [in the treatment course]," Hadfield explained. The goal is to keep patients receiving therapies for as long as possible and avoid treatment discontinuation due to grade 3 or 4 AEs.
Future research will focus on understanding the causes of therapeutic resistance and expanding the benefits of checkpoint inhibitors to more solid tumor types. The study serves as a platform to show that treatment efficacy can be preserved while reducing toxicity, which is crucial for improving patient outcomes in immunotherapy.
