Itacitinib for the Prevention of IEC Therapy-Associated CRS: Results From the Two-Part Phase 2 INCB 39110-211 Study

Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common complications following IEC therapy for hematologic malignancies. This two-part, phase 2 study (INCB 39110-211) investigated safety and efficacy of itacitinib, a potent, highly selective Janus kinase 1 inhibitor with broad anti-inflammatory activity, for prevention of CRS and ICANS in patients receiving commercial CD19-directed IEC therapy. Patients in part 1 received once-daily itacitinib 200 mg 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 twice-daily (bid) itacitinib 200 mg or placebo 3 days before IEC therapy with axi-cel. The primary endpoint was proportion of patients with CRS grade ≥2 by Day 14 using ASTCT consensus grading system. Overall, 111 patients were enrolled (63 in part 1; 48 in part 2), with 109 patients analyzed for efficacy and 110 for safety. Itacitinib 200 mg bid resulted in a significantly lower proportion of patients with grade ≥2 CRS by Day 14 versus placebo (17.4% vs 56.5%; P=0.003). 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 the most common TEAE (itacitinib 200 mg bid: 43.5%; placebo: 50.0%) and itacitinib-related cytopenias manageable. Importantly, itacitinib did not impact IEC therapy efficacy (objective response rate at 6 months: 39.1% for itacitinib 200 mg bid vs 26.1% for placebo). Trial registration: clinicaltrials.gov; #NCT04071366.