Itacitinib for the prevention of IEC therapy–associated CRS: results from the 2-part phase 2 INCB 39110-211 study
Matthew J. Frigault, Richard T. Maziarz, Jae H. Park, Aleksandr Lazaryan, Nirav N. Shah, Jakub Svoboda, Lazaros J. Lekakis, Ran Reshef, Christine L. Phillips, Lea Burke, Jing Lei, Michael A. Pratta, Rodica Morariu-Zamfir, John F. DiPersio
Abstract
ABSTRACT: Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common complications after IEC therapy for hematologic malignancies. This 2-part phase 2 study (INCB 39110-211) investigated the safety and efficacy of itacitinib, a potent, highly selective Janus kinase 1 inhibitor with broad anti-inflammatory activity, for the prevention of CRS and ICANS in patients who received commercial CD19-directed IEC therapy. Patients in part 1 received 200 mg itacitinib once daily 3 days before IEC therapy (axicabtagene ciloleucel [axi-cel], brexucabtagene autoleucel, or tisagenlecleucel) through day 26 with guidelines for use of other CRS/ICANS interventions. In part 2 (double-blind), patients were randomized to receive 200 mg itacitinib twice daily or placebo 3 days before IEC therapy with axi-cel. The primary end point was the proportion of patients with CRS grade ≥2 by day 14 using the American Society for Transplantation and Cellular Therapy consensus grading system. Overall, 111 patients were enrolled (63 in part 1; 48 in part 2); 109 patients were analyzed for efficacy and 110 for safety. By day 14, grade ≥2 CRS occurred in fewer patients on 200 mg twice daily itacitinib (17.4%) than on placebo (56.5%; P = .003). The proportion of patients with grade ≥2 ICANS by day 28 was lower than with placebo (8.7% vs 21.7%). Itacitinib was well tolerated, with pyrexia being the most common treatment-emergent adverse event (200 mg itacitinib twice daily, 43.5%; placebo, 50.0%), and itacitinib-related cytopenias were manageable. Itacitinib did not affect IEC therapy efficacy (objective response rate at 6 months, 39.1% [200 mg itacitinib twice daily] vs 26.1% [placebo]). This study was registered at www.clinicaltrials.gov as #NCT04071366.