JAK inhibitor for the treatment of steroid refractory and life-threatening immune-related adverse events secondary to immune checkpoint inhibitors.

Abstract

2643 Background: Immune checkpoint inhibitors (ICIs) boost anti-tumor immune responses but carry the risk of off-target effects, manifesting as immune-related adverse events (irAEs). Approximately 20% of irAEs are refractory to steroids, requiring subsequent immunosuppressive therapies, while a smaller subset presents with fulminant reactions requiring multiple agents simultaneously. Although biologics like TNF and IL-6 inhibitors are often used, their targeting of single inflammatory pathways may be insufficient to resolve irAEs in these critical scenarios. We conducted a prospective study to assess the safety and efficacy of oral JAK inhibitors, molecules capable of rapidly modulating multiple inflammatory cytokine signals, in managing steroid-refractory or life-threatening irAEs. Methods: The MIRAE Biobank is a prospective cohort study of cancer patients treated with ICI at the Jewish General Hospital in Montreal, Canada. Patients with steroid refractory subjects with grade > 3 irAE or persistent grade 2 toxicity despite optimal therapy, as well as life-threatening irAEs in the first-line setting treated with JAK inhibitors were extracted from the database and their clinical data was summarized. Among those who survived at least 30 days post-JAK inhibitor, we compared characteristics of responders and non-responders. Responders were defined as resolution of the irAE to grade < 1 and < 10mg prednisone equivalents without any relapses during a 30-day period. Results: In this series, 29 patients were treated with JAK inhibitors for refractory or life-threatening irAEs. Mean age was 69 years, 34.5% were women, 82.8% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 13.8% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (10, 34.5%) and lung cancer (6, 20.7%). Primary irAEs for which JAK inhibitors were initiated included myocarditis (n=11), colitis (n=4), arthritis (n=4), hepatitis (n=4), encephalitis (n=2), pneumonitis (n=2), myasthenia gravis (n=1) and sicca (n=1). JAK inhibitors were used as second- (refractory to steroids alone), third- or fourth- or more line in 9, 11 and 9 patients, respectively. Median duration of JAK inhibitor exposure was 30.5 days. Among the 24 patients who survived at least 30 days, 17 (71%) responded after a median of 11 days from initiation of the JAK inhibitor. Interestingly, this included 6/8 patients with myocarditis, 4/4 with arthritis and 2/3 with colitis. Of those who responded to JAK inhibitor, 11/18 were steroid refractory and 6/6 were life-threatening cases requiring simultaneous treatment with steroids. Conclusions: This preliminary data suggests that JAK inhibitors may be effective at treating various types of steroid-refractory and life-threatening irAEs.