Population Pharmacokinetics and Exposure–Response Analyses for Venetoclax in Combination with R-CHOP in Relapsed/Refractory and Previously Untreated Patients with Diffuse Large B?Cell Lymphoma

摘要

Abstract Introduction Outcomes remain poor in patients with diffuse large B?cell lymphoma (DLBCL) who overexpress BCL-2 protein. We present population pharmacokinetics (PopPK) and exposure–response (ER) analyses for venetoclax (a selective BCL-2 inhibitor) administered with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed/refractory (R/R) and previously untreated (1L) non-Hodgkin lymphoma (NHL) from the phase?1b/2 CAVALLI study, to confirm dose selection for future studies.Methods Analyses included 216 patients with R/R or 1L NHL treated for eight 21-day cycles with 400–800?mg venetoclax (cycle?1: days?4–10; cycles?2–8: days?1–10) in combination with R for eight cycles and CHOP for 6–8 cycles. A legacy PopPK model for venetoclax was used to describe the observed data and provide post hoc PK parameters. Venetoclax steady-state exposure (AUCss) was used to predict clinical efficacy, safety, or tolerability. To isolate the effect of venetoclax, ER analyses referenced data from the R-CHOP arm of a historical control study, GOYA, in 1L DLBCL.Results There was no significant association between venetoclax AUCss and progression-free survival or complete response either for all-comers or the BCL-2-immunohistochemistry-positive subpopulation. No statistically significant trends were observed with venetoclax AUCss and the key grade?≥?3 adverse events and serious adverse events. Similar dose intensities were observed for venetoclax and R-CHOP components across venetoclax exposures, suggesting venetoclax did not impact delivery of the R-CHOP backbone.Conclusions The PopPK and ER analyses, in addition to the positive benefit–risk observed in the clinical data, support the selection of 800?mg venetoclax given with R-CHOP for future studies in BCL-2-immunohistochemistry-positive patients with 1L DLBCL.Trial Registration ClinicalTrials.gov Identifier NCT02055820.