Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data
Authors: Zinzani Pier Luigi , Topp Max S , Yuen Sam LS , Rusconi Chiara , Fleury Isabelle , Pro Barbara , Gritti Giuseppe , Crump Michael , Hsu Wanling , Punnoose Elizabeth A. , Hilger James , Mobasher Mehrdad , Hiddermann Wolfgang 
Published: October 2019

Abstract
Introduction
Despite improved response and survival for patients (pts) with follicular lymphoma (FL) receiving rituximab (R) plus chemotherapy, new options are needed. FL is typically characterized by the presence of chromosomal translocation t(14;18), which results in overexpression of the anti-apoptotic protein BCL-2. BCL-2 may also contribute to resistance to chemoimmunotherapy such as bendamustine+R (BR), a regimen commonly used in FL. Venetoclax (VEN), a selective, potent oral BCL-2 inhibitor, is in development for the treatment of B-cell malignancies. Preclinical and early clinical data suggest VEN+R or VEN+BR may improve response over R or chemotherapy alone and is feasible. This open-label study will assess efficacy and toxicity of VEN+R as well as VEN+BR vs BR alone, in pts with relapsed/refractory (R/R) FL (NCT02187861).
Methods
R/R pts (age ≥18 yrs, confirmed Gr 1-3a FL, ECOG PS 0-2, adequate hematologic function) were assigned (at investigators' discretion) to chemotherapy-free (chemo-free) or randomized to chemotherapy-containing (chemo) arms. Those in the chemo-free Arm (Arm A) received VEN 800mg daily for 1 yr + R (cycles [C] 1, 4, 6, 8, 10 and 12). After a safety run-in (9 pts at 600mg VEN daily + 6 cycles BR), those in the chemo Arm were randomized 1:1 to Arm B (VEN 800mg + 6 cycles BR) or C (BR only). The primary endpoint was complete response (CR) rate by PET-CT. Secondary endpoints include CR rate by CT and overall response rate. Response assessment was per Lugano non-Hodgkin lymphoma assessment (Cheson et al. 2014) 6-8 wks after D1 of C6 (or the cycle non-VEN agents were permanently discontinued: whichever came first).
Results
One hundred sixty-four pts were enrolled as of May 13, 2016 (Table 1); 53 chemo-free (Arm A) and 111 chemo (9 run-in; 51 Arm B; 51 Arm C). 61% were refractory to prior treatment: 79% Arm A; 56% safety run-in; 43% Arm B; 62% Arm C.
One hundred fifty-three of 160 safety evaluable pts (94%) experienced any AE (Table 2). Common AEs (all grades): diarrhea (37%), neutropenia (29%), nausea (25%), fatigue (25%), and IRR (25%). Common AEs for Arm B vs Arm C: nausea (61% vs 38%), neutropenia (51% vs 26%), diarrhea (41% vs 12%), thrombocytopenia (39% vs 20%) and fatigue (37% vs 24%). Neutropenia and thrombocytopenia were the most common Gr 3-4 AEs among all groups. 40 pts had serious AE (SAEs): 14 (27%) Arm A; 4 (44%) run-in; 15 (31%) Arm B; 7 (14%) Arm C. SAEs in >1 pt in any arm: febrile neutropenia (2 run-in; 5 Arm B; 1 Arm C), pneumonia (2 Arm A; 1 Arm B), and LDH increase (2 Arm A). Laboratory tumor lysis syndrome (TLS) events occurred in 2 pts (1 Arm A; 1 Arm B): both manageable and resolved with no clinical complications.
Five deaths occurred on study: 3 Arm A (colitis, pulmonary hemorrhage, PD), 1 Arm B (pneumonia), 1 Arm C (PD). Pts with AEs leading to dose interruptions or modification: 28 (54%) Arm A; 7 (78%) run-in; 37 (76%) Arm B; 12 (24%) Arm C. Pts with early drug discontinuations of VEN: 29 (56%) Arm A; 5 (56%) run-in; 11 (22%) Arm B. Early R discontinuations: 28 (54%) Arm A; 3 (33%) run-in; 7 (14%) Arm B; 5 (10%) Arm C. Early B discontinuations: 3 (33%) run-in; 7 (14%) Arm B; 4 (8%) Arm C.
Efficacy by PET+CT for safety evaluable patients who reached an assessment event is shown in Table 3. Arm A had 17 (33%) responders with 14% CR. Arm A was predominantly refractory to last treatment (79%): among non-refractory pts (21%), ORR was 64% with 27% CR. There was 68% ORR in Arm B with 50% CR compared with 64% ORR with 41% CR in Arm C. 55 (51%) of chemo pts have yet to reach a response-relevant event. Correlation with expression of BCL-2 family members is pending.
Conclusion
Early results from the first study evaluating VEN+R and VEN+BR in pts with FL show that daily VEN 800mg has an acceptable benefit/risk ratio. As expected with the known VEN safety profile, both VEN+R and VEN+BR are associated with hematologic and GI toxicity, which appears manageable. Laboratory TLS was rare (<2%) and manageable with no clinical sequelae. Objective response with VEN+R is 33% even in a highly refractory pt population and 64% among non-refractory pts, providing a potential chemotherapy-free option for both groups. While early data shows VEN+BR is associated with more toxicity and some early treatment discontinuations compared with BR alone, data suggest it may be a tradeoff for increased CR and decreased PD. Future data will help determine whether continued VEN treatment beyond initial chemotherapy deepens response.

Disclosures
Zinzani: Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Topp:Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Roche: Honoraria, Other: travel; Pfizer: Consultancy, Other: Travel; Boehringer: Consultancy, Other: Travel, Research Funding; Jazz: Consultancy. Rusconi:Janssen: Consultancy, Other: Congress attendance; Takeda: Consultancy; Teva: Consultancy, Other: Congress attendance. Fleury:Novartis: Consultancy, Speakers Bureau; Lundbeck: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau. Pro:Celegene: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Hsu:Genetech, Inc.: Employment. Punnoose:Genetech, Inc.: Employment. Hilger:Genetech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Hiddermann:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.