Introduction: CHRONOS-3 randomized patients (pts) with relapsed iNHL to the PI3K inhibitor copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle in combination with standard rituximab (C+R) or placebo plus rituximab (P+R) and demonstrated superior progression-free survival (PFS) of C+R vs. P+R (hazard ratio[HR]: 0.52; Matasar et al. Lancet Oncol 2021). In an updated 1-year follow-up analysis, the benefit of C+R was confirmed in the overall relapsed iNHL population (Zinzani et al., EHA 2022) and in the subset of pts with FL (see Capra et al. AACR Lymphoma 2022 abstract). We investigated popPK and ER relationships for copanlisib efficacy and safety from a pooled analysis, with a particular focus on the 1-year follow-up of CHRONOS-3 to confirm copanlisib dose selection. Methods: A comprehensive popPK model for copanlisib was developed using plasma concentrations from 712 pts across 9 copanlisib clinical Phase 1-3 studies. Demographic, laboratory, and comedication covariates were investigated for their influence on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates for pts enrolled in CHRONOS-3 were derived to investigate relationships to efficacy (PFS, overall response rate [ORR], complete response [CR]) and key treatment-emergent safety events using multivariate cox proportional hazards (CPH) and logistic regression analyses, after accounting for predefined potentially prognostic demographic, laboratory, and/or disease related baseline covariates. Results: Copanlisib PK was best described by a 3-compartment PK model with first-order elimination from the central compartment following intravenous infusion. Copanlisib PK was dose proportional and time independent with no accumulation. Covariates statistically selected as influencing copanlisib PK included rifampin (strong CYP3A inducer) and itraconazole (strong CYP3A inhibitor) co-administration, female sex, Japanese pts, mild or worse hepatic impairment, and a CHRONOS-3 study effect, however all identified covariates, aside from rifampin/itraconazole, had no clinically relevant effect (≤ 35%) on copanlisib AUC. In CHRONOS-3, CPH analyses demonstrated a statistically significant positive ER relationship for PFS where greater copanlisib exposure was associated with prolonged PFS. Relative to P+R, the HR for C+R at the 5th and 95th percentile of copanlisib time-varying exposure was 0.875 and 0.217, respectively. Thus, lower copanlisib doses may result in reduced efficacy in relapsed iNHL. CPH and/or logistic regression analyses demonstrated no significant ER relationship for ORR and investigated adverse events. Based on the modelling, lower starting doses of copanlisib are not anticipated to improve safety and tolerability. The ER analyses support the overall positive benefit/risk assessment of copanlisib reported from the clinical efficacy and results of CHRONOS-3 in iNHL. Conclusions: PopPK and ER analyses support copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle dose selection in the relapsed iNHL population.

Citation Format: Jonathan Moss, Dirk Garmann, Rupert Austin, Florian Hiemeyer, Patricia DeLora, Matthew J Matasar, Pier Luigi Zinzani, Vita Beckert, Lidia Mongay Soler, Barrett H Childs, Peter N Morcos. Copanlisib population pharmacokinetics (popPK) and exposure-response (ER) in relapsed indolent non-Hodgkin lymphoma (iNHL): Analysis from the 1-year follow-up of the phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A25.