A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma

F Morschhauser, P Feugier, IW Flinn, R Gasiorowski, R Greil, Á Illés, NA Johnson, JF Larouche, Elly Lugtenburg, C Patti, GA Salles, M Trn?ný, S de Vos, F Mir, D Samineni, SY Kim, Y Jiang, E Punnoose, A Sinha, E ClarkN Spielewoy, K Humphrey, A Bazeos, AD Zelenetz

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Abstract

The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups. Key Points: • The phase 2 CAVALLI study assessed efficacy and safety of venetoclax + R-CHOP in patients with DLBCL, including Bcl-2+ subpopulations. • Venetoclax + R-CHOP showed potential for improved efficacy vs R-CHOP alone, supporting further investigation of venetoclax in Bcl-2+ DLBCL.

Original languageEnglish
Pages (from-to)600-609
Number of pages10
JournalBlood
Volume137
Issue number5
DOIs
Publication statusPublished - 4 Feb 2021

Bibliographical note

Funding Information:
The authors thank the patients and study investigators who participated in the CAVALLI study. Special thanks are also given to Jeremy Ross (AbbVie), who supported the CAVALLI study from concept (biological rationale, biomarker hypotheses, and study design) to input on data interpretation at study readout; Joe Paulson (Genentech; Principal Statistical Scientist Primary Health Care, Early Development Oncology Biostatistics group), who provided statistical analysis and data interpretation at study readout; and Jill Ray (Genentech; Senior Companion Diagnostic Project Leader), who supported the biomarker hypothesis and analysis of data. Venetoclax is being developed as a collaboration between Genentech Inc. and AbbVie. Genentech Inc. and AbbVie provided financial support for the CAVALLI phase 2 study and participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. A.D.Z. was supported by National Institutes of Health National Cancer Institute Core Grant P30 CA008748 and Memorial Sloan Kettering Cancer Center Specialized Program of Research Excellence (SPORE) in Lymphoma Grant P50 CA192937. Under the direction of the authors, third-party medical writing assistance was provided by Rachel Dobb (Gardiner-Caldwell Communications), which was funded by F. Hoffmann-La Roche Ltd.

Funding Information:
Venetoclax is being developed as a collaboration between Genentech Inc. and AbbVie. Genentech Inc. and AbbVie provided financial support for the CAVALLI phase 2 study and participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. A.D.Z. was supported by National Institutes of Health National Cancer Institute Core Grant P30 CA008748 and Memorial Sloan Kettering Cancer Center Specialized Program of Research Excellence (SPORE) in Lymphoma Grant P50 CA192937. Under the direction of the authors, third-party medical writing assistance was provided by Rachel Dobb (Gardiner-Caldwell Communications), which was funded by F. Hoffmann-La Roche Ltd.

Publisher Copyright:
© 2021 American Society of Hematology

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