Copanlisib population pharmacokinetics from phase I–III studies and exposure–response relationships in combination with rituximab

Copanlisib dose selection was established under the maximum tolerated dose paradigm, and no dedicated dose‐finding studies have investigated copanlisib dose selection when used in combination with rituximab. In CHRONOS‐3, copanlisib plus rituximab demonstrated significantly improved progression‐free survival versus placebo plus rituximab in patients with relapsed indolent non‐Hodgkin lymphoma (iNHL). We conducted a comprehensive investigation of copanlisib population pharmacokinetics (PopPK) from a pooled analysis of 712 patients across nine copanlisib phase I–III studies and exposure–response (ER) relationships for efficacy and safety from the 1‐year follow‐up of CHRONOS‐3. PopPK analyses examined the impact of demographic, laboratory, and comedication covariates on copanlisib between‐patient PK variability. Individual static and time‐varying exposure estimates were derived to investigate exposure–efficacy and exposure–safety relationships. Multivariate Cox proportional hazards and logistic regression analyses examined ER relationships with consideration of predefined potentially prognostic demographic‐, laboratory‐, and/or disease‐related baseline covariates. Copanlisib PK were best described by a three‐compartment model with first‐order elimination. Individual identified covariates had modest effects on copanlisib PK and were generally in line with known copanlisib disposition properties. In CHRONOS‐3, ER analyses showed a significant relationship between time‐varying exposure estimates and progression‐free survival, and no significant exposure–safety relationships. Thus, lower copanlisib doses may result in reduced efficacy but not necessarily improved safety or tolerability. These outcomes substantiate the current intermittent dosing regimen of copanlisib 60 mg on days 1, 8, and 15 of a 28‐day cycle and support the observed clinical results of copanlisib in combination with rituximab in the iNHL population.