The efficacy and safety of add-on ruxolitinib for patients with severe checkpoint inhibitor pneumonitis management with corticosteroids: A multicenter, open-label, randomised phase 2 trial.

Abstract

12016 Background: Checkpoint inhibitor pneumonitis (CIP) stands out as a remarkable complication during ICIs therapy. Severe CIP represents a potentially life-threaten immune-related adverse event (irAE) with limited evidence from clinical trials that guides therapeutic interventions. Ruxolitinib, a selective JAK1/2 inhibitor, effectively attenuates cytokine-release syndrome and show significant anti-fibrotic in mouse lung with BLM model. We conducted a multicenter, investigator-initiated, open-label, phase 2 randomized controlled trial to evaluate the efficacy and safety of add-on ruxolitinib for patients with severe CIP management with corticosteroids. Methods: Patients with malignant who were suffered from CTCAE grade (G) 3 or G4 CIP after ICIs therapy were screened. Enrolled CIP patients were randomly assigned 1:1 to control group (only glucocorticoids) or ruxolitinib group (glucocorticoids plus ruxolitinib). Initiated dosage of glucocorticoids was no less than prednisone 1 mg/kg/day (or same steroid equivalent dose) with subsequent tapering off. In ruxolitinib group, enrolled patients were add-on ruxolitinib (5 mg twice daily for 2 weeks, followed with 5 mg daily for 2 weeks). The primary end point was the proportion of patients with a prednisone daily dosage of no more than 10mg and improvement to G1 CIP at week 8. Continuous variables were analyzed using a mixed-effects model for repeated measures with treatment group, study visit and treatment-by-visit interaction. Results: From April 2023 to November 2025, a total of 60 eligible patients were recruited and randomly assigned to control group and ruxolitinib group. There were 52 cases of G3 CIP and 8 cases of G4 CIP. There were more patients in the ruxolitinib group improved to G1 CIP and received ≤prednisone 10mg daily at 8 th week than in the controlled group (20cases/66.7% vs 11cases/36.7%, p = 0.0379 ). This effect was more significant in the 2 nd and 4 th week. Two patients in ruxolitinib group and 4 patients in the control group died within eight weeks. The repeated measures analysis using a generalized linear mixed model demonstrated a significant overall treatment effect, ie. add-on ruxolitinib was associated with significantly higher odds of clinical improvement (adjusted OR = 5.12, 95% CI 1.06 - 24.64; p = 0.04). A total of 13 G3 or higher treatment-related AEs (TRAEs) occurred (7 cases in control group and 6 cases in ruxolitinib group), including 9 cases of infectious diseases. Conclusions: Add-on ruxolitinib for malignant patients with severe CIP management with glucocorticoids show with higher resolution rates and earlier response trends than only glucocorticoids treatment. And there were no different adverse events between them. Add-on ruxolitinib with glucocorticoids might be a promising proposed treatment for patients with severe CIP. Clinical trial information: NCT05899725 .