Population Pharmacokinetics and Exposure-Response Analyses from Phase I-III Studies Support Copanlisib Dose Selection in Relapsed Indolent Non-Hodgkin Lymphoma

Introduction: Copanlisib is a novel PI3K inhibitor that is approved for single-agent treatment of relapsed follicular lymphoma in patients (pts) who have received ≥2 systemic therapies. In the pivotal Phase III CHRONOS-3 study, pts with relapsed iNHL were randomized to copanlisib at the approved maximum tolerated dosing regimen of 60 mg administered on days 1, 8, and 15 of a 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). No dedicated dose-finding studies have been undertaken to investigate copanlisib dose selection when used in combination with rituximab; however, initial safety assessments demonstrated acceptable tolerability. We investigated popPK and ER relationships for copanlisib efficacy and safety from a pooled analysis, with particular focus on the 1-year follow-up of CHRONOS-3 to confirm copanlisib dose selection.

Methods: A copanlisib comprehensive popPK model was developed from 712 pts across 9 copanlisib clinical Phase I-III studies. Demographic, laboratory, and co-medication 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) and key treatment-emergent safety events using Cox proportional hazards (CPH) and multivariate 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 following intravenous infusion. Copanlisib PK was dose proportional and time independent, with no accumulation with the approved dosing regimen. Statistically selected covariates influencing copanlisib PK included rifampin (strong CYP3A inducer) and itraconazole (strong CYP3A inhibitor) co-administration and mild or worse hepatic impairment, confirming the results of dedicated clinical pharmacology studies. Additional covariates influencing copanlisib PK included female sex, residence in Japan, and a CHRONOS-3 study effect, with the majority of covariates or subpopulations defined by sex, age, body weight, renal function, and geographic region showing exposure variations not exceeding traditional bioequivalence ranges (80-125%). In CHRONOS-3, CPH analyses demonstrated a statistically significant, positive ER relationship for PFS for all 3 time-varying copanlisib exposure estimates (average concentration [Cavg] over 2 weeks [Cavg_2wk]: p=0.002; 4 weeks [Cavg_4wk]: p=0.004; and 8 weeks [Cavg_8wk]: p=0.002), along with a near-significant relationship for area under the curve from 0 to 168 hours (AUC_(0-168)nd) [p=0.023] (Figure 1). Therefore, greater copanlisib exposure was associated with prolonged PFS, while lower copanlisib doses may result in reduced efficacy in relapsed iNHL. CPH and/or logistic regression analyses demonstrated no significant ER relationship for investigated safety events (serious adverse events [AEs], grade ≥3 treatment-emergent AEs, hyperglycemia, hypertension, diarrhea, nausea, fatigue, lung infections, and neutropenia of any grade). Thus, lower starting doses of copanlisib are not anticipated to improve safety and tolerability. ER analyses support the overall positive benefit/risk assessment of copanlisib reported from the clinical efficacy and results of CHRONOS-3 in iNHL.

Conclusion: PopPK and ER analyses substantiate administration of a dosing regimen of copanlisib 60 mg on days 1, 8, and 15 of a 28-day cycle in the relapsed iNHL population.

Moss:Bayer: Consultancy. Garmann:Bayer Pharma AG: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Austin:Bayer: Consultancy, Research Funding. Hiemeyer:Bayer Pharma AG: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Matasar:TG Therapeutics: Consultancy; IGM Biosciences: Research Funding; ADC Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Karyopharm: Consultancy; Epizyme: Consultancy, Honoraria; AstraZeneca: Consultancy; Janssen: Honoraria, Research Funding; ImmunoVaccine Technologies: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; IMV Therapeutics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Teva: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Merck: Consultancy, Current equity holder in private company; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Zinzani:Secura Bio: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Beckert:Bayer Pharma AG: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Mongay Soler:Bayer HealthCare Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Childs:Bayer HealthCare Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Morcos:Bayer HealthCare Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company.