Itacitinib Population Pharmacokinetics (PopPK) and Exposure-Response for Prevention of Cytokine Release Syndrome Induced by Immune Effector Cell Therapy: Results From Phase 2 Study NCT04071366
Authors: Ivanova Olga , Yang Hong , Chen Xuejun , McGee Ryan , Sheng Jennifer 
Published: February 2025

Objectives: The PopPK model of itacitinib monotherapy for prevention of cytokine release syndrome (CRS) with immune effector cell (IEC) therapy was used primarily to evaluate the impact of pharmacokinetic (PK) exposure levels on efficacy, with endpoints of CRS grade and severity and incidence and severity of IEC-associated neurotoxicity syndrome (ICANS). Additionally, an exposure-safety (E-S) analysis was performed to evaluate the potential hematotoxicity of itacitinib and its effect on treatment-emergent adverse events (TEAEs). Methods: Itacitinib (INCB039110) is a potent and selective inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases with selectivity for JAK1. JAKs play an important role in signal transduction following cytokine and growth factor binding to their receptors. CRS has been identified as a significant on-target off-tumor side effect of IEC therapies. CRS can lead to pulmonary edema, hypoxia, dyspnea, and pneumonitis, requiring mechanical ventilation. To describe PK in participants receiving itacitinib for prevention of IEC-induced CRS, a total of 224 subjects from studies INCB 39110-211 part 1 (QD dosing) and part 2 (BID dosing), INCB 39110-105 for bioequivalence and food effect, INCB 39110-122 (renal impairment), and INCB 39110-113 (hepatic impairment) were included in the modeling dataset. PopPK modeling was performed using MONOLIX (v2022R1 or higher; Lixoft, Antony, France). Exposure-response (E-R) analyses were conducted using R (v4.0.1). Results: The PK of itacitinib was well described using a dual-absorption mechanism: first-order absorption after a lag time in parallel with a zero-order release followed by a first-order absorption and a 2-compartment model with linear elimination. E-R analyses suggested that reduction in all-grade CRS by Day 14 (grade ≥1) was significantly (P=0.008) correlated to increasing itacitinib steady-state trough concentration in axi-cel-only. It was predicted that 200 mg BID can decrease the odds of all-grade CRS response by Day 14 by 2.86-fold compared to 200 mg QD. No treatment effect was identified for ICANS by Day 28. When compared with placebo, itacitinib 200 mg BID significantly reduced the rate of CRS. CRS-free survival at Day 28 was 70% in itacitinib arm vs 26% in placebo arm.1 According to the PopPK-based E-R evaluation, there was no relationship between PK exposure metrics and ICANS grade by Day 28. E-S analysis suggested that although itacitinib treatment (200 mg QD or 200 mg BID) increased the incidence rate of cytopenias by Day 28, as manifested by decreases in platelets (grade ≥3) and neutrophils (grade ≥3) by 2.64-fold and 1.59-fold, respectively, compared to placebo, no PK exposure was identified as a significant predictor. No treatment effect was identified for TEAEs by Day 28; no relationship has been identified between PK exposure and TEAEs. Conclusion: Cumulatively, PopPK-based E-R and E-S findings may be used for evaluation of an optimal dosing regimen.Citations: Frigault M, et al. American Society of Hematology Annual Meeting, San Diego, CA, December 9–12, 2023.