Exposure–response analysis of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia: pooled results from a phase 1b study and the phase 3 MURANO study

Abstract

Exposure–response relationships from a phase 1b (M13-365) and phase 3 (MURANO) study were investigated to assess benefit/risk of venetoclax 400 mg daily plus rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Dose intensities were summarized by tertiles of predicted venetoclax steady-state average concentrations based on nominal venetoclax dose (C_{meanSS,nominal}) for tolerability; exposure–safety analyses used logistic regression. Exposure–progression-free survival (PFS) relationships were assessed using MURANO data, with C_{meanSS,nominal} as a grouping factor. Covariates were demographics, geographic region, study, baseline disease characteristics, ECOG performance status, responsiveness to prior therapy, and chromosomal abnormalities. There was no significant effect of covariates on grade ≥3 neutropenia/infection or PFS, and no relationship between venetoclax exposure and these endpoints, or venetoclax or rituximab dose intensity. These results support the recommended venetoclax 400 mg daily dose in combination with rituximab in patients with R/R CLL or small lymphocytic leukemia.

Keywords:

• Venetoclax
• rituximab
• exposure–response analysis
• chronic lymphocytic leukemia

Acknowledgments

The authors thank the patients, enrolling physicians, site staff, and venetoclax study teams. The authors also thank Dr Mehrdad Mobasher for his valuable contributions to the manuscript. Third-party medical writing assistance was provided by Christopher Dunn and Andrew Sutton of Gardiner-Caldwell Communications, and was funded by F. Hoffmann – La Roche Ltd.

Disclosure statement

Rong Deng, Tong Lu, Dan Lu, Chunze Li, Sandhya Girish, Jue Wang, Noopur Shankar, and Dale Miles are employees of Genentech and have equity in Genentech/F. Hoffmann-La Roche Ltd. Leonid Gibiansky received consultancy fees from Genentech. Xiaobin Li is an employee of Genentech. Michelle Boyer is an employee of F. Hoffmann-La Roche Ltd and has equity in the company. Kathryn Humphrey is an employee of F. Hoffmann-La Roche Ltd. Kevin J. Freise and Ahmed Hamed Salem are employees of AbbVie and have equity in the company. John F. Seymour received grants from AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd; consultancy fees from AbbVie, Acerta, Celgene, Janssen, F. Hoffmann-La Roche Ltd, and Takeda; travel support from AbbVie; advisory board fees from Celgene; lecture/speakers’ bureaus fees from AbbVie and F. Hoffmann-La Roche Ltd; and expert testimony fees from F. Hoffmann-La Roche Ltd. Arnon P. Kater received grants from F. Hoffmann-La Roche Ltd, Genentech, and AbbVie; consultancy fees from AbbVie; travel support from F. Hoffmann-La Roche Ltd; and lecture/speakers’ bureaus fees from AbbVie.

Data availability

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Additional information

Funding

Venetoclax is being developed in collaboration between Genentech Inc. and AbbVie. Genentech and AbbVie provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data as well as the writing, review, and approval of the manuscript.