Itacitinib for the prevention of IEC therapy–associated CRS: results from the 2-part phase 2 INCB 39110-211 study

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.