Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma

Abstract

This open-label phase 2 study (CONTRALTO) assessed the safety and efficacy of BCL-2 inhibitor venetoclax (VEN) plus rituximab (R), and VEN plus bendamustine (B) and R, vs B + R (BR) alone in relapsed/refractory (R/R) follicular lymphoma. Patients in the chemotherapy-free arm (arm A: VEN + R) received VEN 800 mg/d plus R 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, 10, and 12. After a safety run-in with VEN 600 mg, patients in the chemotherapy-containing cohort were randomized to either VEN + BR (arm B; VEN 800 mg/d for 1 year + 6 cycles of BR [B 90 mg/m2 on days 1 and 2 and R 375 mg/m2 on day 1]) or 6 cycles of BR (arm C). Overall, 163 patients were analyzed (9 in the safety run-in and 52, 51, and 51 in arms A, B, and C, respectively). Complete metabolic/complete response rates were 17% (arm A), 75% (arm B), and 69% (arm C). Of patients in arm B, only 61% received ≥90% of the planned B dose vs 96% of patients in arm C. More frequent hematologic toxicity resulted in more reduced dosing/treatment discontinuation in arm B vs arm C. Rates of grade 3/4 adverse events were 51.9%, 93.9%, and 60.0% in arms A, B, and C, respectively. VEN + BR led to increased toxicity and lower dose intensity of BR than in arm C, but efficacy was similar. Optimizing dose and schedule to maintain BR dose intensity may improve efficacy and tolerability of VEN + BR, while VEN + R data warrant further study. This study was registered at www.clinicaltrials.gov as #NCT02187861.

Conflict of interest statement

Conflict-of-interest disclosure: P.L.Z. received honoraria, consulting/advisory, and speakers’ bureau compensation from Servier, MSD, Gilead, BMS, Janssen, Verastem, and F. Hoffmann-La Roche. I.W.F. received consulting/advisory compensation from AbbVie, Seattle Genetics, TG Therapeutics, and Verastem and research funding from Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kile Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, F. Hoffmann-La Roche, TG Therapeutics, Trillium Therapeutics, AbbVie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead sciences, Astra Zeneca, Juno Therapeutics, Unum Therapeutics, and MorphoSys, AG. S.L.S.Y. received travel assistance from Seattle Genetics. M.S.T. received honoraria from Amgen and Regeneron Pharmaceuticals; is on the board of directors or advisory committee of Amgen and F. Hoffmann-La Roche; received research funding from Amgen, Boehringer Ingelheim, Regeneron Pharmaceuticals, and F. Hoffmann-La Roche; and received travel assistance from Amgen. C.R. received honoraria from Celgene, Takeda, Janssen, and F. Hoffmann-La Roche; research funding from Celgene; and travel, accommodation, and expenses assistance from Takeda, F. Hoffmann-La Roche, and Celgene. I.F. received consultancy payments from Novartis, Janssen, Seattle Genetics, Gilead, AbbVie, F. Hoffmann-La Roche, and Celgene and travel, accommodation, and expenses assistance from Gilead, Novartis, and Janssen. C.A. received honoraria and consulting/advisory compensation from Novartis) and travel, accommodation, and expenses assistance from F. Hoffmann-La Roche. G.G. had a consultancy and advisory role at Autolus, Biovista, Takeda, and Italfarmaco; received speakers’ bureau compensation from Amgen; received research funding from Gilead; and received travel, accommodation, and expenses assistance from F. Hoffmann-La Roche, Beckton Dickinson, Takeda, and Kite. M.C. received honoraria and consultancy and advisory compensation from F. Hoffmann-La Roche, Servier, Kite, and Gilead. A.P. received employment, travel, accommodation, and expenses compensation from and has ownership interests in AbbVie. D.S. and E.A.P. are employed by Genentech. D.S. has ownership interests in Genentech. E.A.P. has equity ownership in F. Hoffmann-La Roche and received travel, accommodation, and expenses assistance from F. Hoffmann-La Roche. M.M. has ownership interests and is a former employee of F. Hoffmann-La Roche; has ownership interests in and leadership and employment roles at Corvus Pharmaceuticals. A.S., N.S., M.K., and K.H. are employed by F. Hoffmann-La Roche. E.S.-G. is employed by Genentech and has ownership interests in Genentech/F. Hoffmann-La Roche. M.K. has ownership interests in F. Hoffmann-La Roche, Bayer AG, and Johnson & Johnson. K.H. has equity ownership at F. Hoffmann-La Roche. W.H. received honoraria from F. Hoffmann-La Roche, Gilead, Janssen, and Helsinn Pharmaceuticals; received consultancy payments from F. Hoffmann-La Roche, Gilead, Janssen; is on the speakers’ bureau of F. Hoffmann-La Roche, Gilead, Janssen, and Vector; and research funding from F. Hoffmann-La Roche, Janssen, and Amgen. The remaining authors have no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Dosing schedule by arm and time on study. Arm A (chemotherapy-free): VEN (800 mg daily) + R (375 mg/m2). Arm B (chemotherapy containing): VEN (800 mg daily) + B (90 mg/m2) + R (375 mg/m2). Arm C (chemotherapy containing): B (90 mg/m2) + R (375 mg/m2). *R administered on days 1, 8, 15, and 22. Safety run-in arm (not displayed above) consisted of 9 patients that received VEN (600 mg daily for 1 year) + B (90 mg/m2 on days 1 and 2 of each 28-day cycle) + R (375 mg/m2 on day 1 of each cycle). D, day.

Figure 2.

Patient flow. Rand, randomization.

Figure 3.

Kaplan-Meier plot of DOR and PFS. DOR (A) and PFS (B) *Stratified by DOR to prior therapy (≤12 months/>12 months) and disease burden (high/low), according to modified Groupe d’Etude des Lymphomes Folliculaires criteria.