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

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.

Conflict of interest statement

Conflict-of-interest disclosure: F. Morschhauser consults for or advises F. Hoffmann-La Roche Ltd.; has received honoraria from Bayer, Bristol Myers Squibb, Celgene, Epizyme, F. Hoffmann-La Roche Ltd., Gilead Sciences, and Janssen Pharmaceuticals; and is a member of advisory boards for F. Hoffmann-La Roche Ltd., Celgene, Bristol Myers Squibb, Gilead Sciences, Bayer. and Epizyme. I.W.F. consults or advises for AbbVie, AstraZeneca, BeiGene, F. Hoffmann-La Roche Ltd., Gilead Sciences, Janssen Pharmaceuticals, Juno Therapeutics, Kite Pharma, MorphoSys, Nurix Therapeutics, Seattle Genetics, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, and Yingli Pharmaceutical and has received research funding from AbbVie, Acerta Pharma, Agios, ArQule, Astra Zeneca, BeiGene, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, F. Hoffmann-La Roche Ltd., FORMA Therapeutics, Forty Seven, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen Pharmaceuticals, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Merck, MorphoSys, Novartis, Pharmacyclics, Pfizer, Portola Pharmaceuticals, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Unum Therapeutics, and Verastem. R. Gasiorowski has received honoraria from AbbVie, MSD, Novartis, and Takeda. R. Greil consults or advises for AbbVie, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Gilead Sciences, Merck, MSD, Novartis, and Takeda; has received honoraria from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann-La Roche Ltd., Genentech, Gilead Sciences, Janssen-Cilag Pharmaceuticals, Merck, MSD, Mundipharma, Novartis, Pfizer, Sandoz, Sanofi Aventis, and Takeda; has received research funding from AbbVie, Amgen, AstraZeneca, Celgene, F. Hoffmann-La Roche Ltd., Genentech, Gilead Sciences, GSK, Merck, MSD, Mundipharma, Novartis, Pfizer, Ratiopharm, and Takeda; and has received travel support from Amgen, AstraZeneca, Celgene, F. Hoffmann-La Roche Ltd., Gilead Sciences, MSD, and Novartis. Á.I. has received honoraria and is a member of advisory boards for Celgene, F. Hoffmann La-Roche Ltd., Janssen Pharmaceuticals, Novartis, Pfizer, and Takeda and has received research funding from Seattle Genetics and Takeda. N.A.J. is an employee of AbbVie, F. Hoffmann-La Roche Ltd-, and Lundbeck; consults or advises for AbbVie, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd., and Merck; has received honoraria from AbbVie, Bristol Myers Squibb, F. Hoffmann La-Roche Ltd., Lundbeck, Merck, and Seattle Genetics; is a member of advisory boards for AbbVie, F. Hoffmann-La Roche Ltd., and Lundbeck; has received research funding from AbbVie, F. Hoffmann-La Roche Ltd., and Lundbeck; has received travel support from F. Hoffmann-La Roche Ltd. and Lundbeck; and has received a significant proportion of antibodies at no cost from BD Biosciences. J.-F.L. has received honoraria from Janssen Pharmaceuticals and research funding from Bayer, F. Hoffmann-La Roche Ltd., Gilead Sciences. and Merck. P.J.L. has received honoraria from Celgene, F. Hoffmann-La Roche Ltd., Genmab, Janssen-Cilag Pharmaceuticals, Servier, and Takeda; research funding from F. Hoffman-La Roche Ltd., Servier, and Takeda; and participates in the speakers bureau for F. Hoffmann-La Roche Ltd. G.A.S. consults or advises for AbbVie, Autolus, Celgene, Epizyme, F. Hoffmann-La Roche Ltd., Gilead Sciences, Janssen Pharmaceuticals, Karyopharm, Kite Pharma, Merck, MorphoSys, Novartis, Servier, and Takeda; has received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Epizyme, F. Hoffmann La Roche Ltd., Gilead Sciences, Janssen Pharmaceuticals, Karyopharm, Kite Pharma, Merck, MorphoSys, Novartis, Servier, and Takeda; is a member of advisory boards for AbbVie, Autolus, Celgene, F. Hoffmann-La Roche Ltd., Gilead Sciences, Janssen Pharmaceuticals, Karyopharm, Kite Pharma, Merck, MorphoSys, Novartis, Servier, and Takeda; and participates in educational events for AbbVie, Amgen, Celgene, F. Hoffmann-La Roche Ltd., Gilead Sciences, Janssen Pharmaceuticals, Karyopharm, Kite Pharma, Merck, MorphoSys, Novartis, Servier, and Takeda. M.T. consults or advises for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Gilead Sciences, Incyte, Janssen Pharmaceuticals, MorphoSys, Takeda, and F. Hoffmann-La Roche Ltd. and has received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Gilead Sciences, Incyte, Janssen Pharmaceuticals, MorphoSys, Takeda, and F. Hoffmann-La Roche Ltd. S.d.V. consults for or advises Verastem and Bayer and is a member of the advisory board for Portola Pharmaceuticals. F. Mir is a former employee of F. Hoffmann-La Roche Ltd. D.S., Y.J., and E.P. are employees of Genentech and hold Roche stock. S.Y.K. is an employee of AbbVie and holds stock in the company. A.S., E.C., N.S., K.H., and A.B. are employees of F. Hoffmann-La Roche Ltd. E.C. holds patents and receives royalties from F. Hoffmann-La Roche Ltd. A.B. holds stock in F. Hoffmann-La Roche Ltd. A.D.Z. consults or advises for AbbVie, Adaptive Biotechnologies, BeiGene, Biotech, Amgen, AstraZeneca, Celgene, F. Hoffmann-La Roche Ltd., Genentech, Gilead Sciences, Janssen Pharmaceuticals, MorphoSys, and Novartis; has received honoraria from AbbVie, Adaptive Biotech, Amgen, AstraZeneca, Celgene, F. Hoffmann-La Roche Ltd., Genentech, Gilead Sciences, Janssen Pharmaceuticals, MorphoSys, and Novartis; has received research funding from BeiGene, Gilead Sciences, MEI Pharma, and F. Hoffmann-La Roche Ltd., and is a chair for a BeiGene Data Monitoring Committee. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Investigator-assessed PFS in CAVALLI vs GOYA IPI 2 to 5. Kaplan-Meier curves for the overall population (A) and the Bcl-2 IHC+ (B), Bcl-2 IHC− (C), and DEL (D) subgroups. The following covariates were adjusted: age, sex, ECOG PS, bone marrow involvement, IPI (high vs nonhigh), bulky disease (>7.5 cm), disease stage (IV vs I-III), LDH, and COO.

Figure 2.

OS in CAVALLI vs GOYA IPI 2-5. Kaplan-Meier curvesfor the overall population (A) and the Bcl-2 IHC+ (B), Bcl-2 IHC− (C), and DEL (D) subgroups. The following covariates were adjusted: age, sex, ECOG PS, bone marrow involvement, IPI (high vs nonhigh), bulky disease (>7.5 cm), disease stage (IV vs I-III), LDH, and COO.