The Addition of Bevacizumab to Standard Therapy with R-CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Is Associated with an Increased Rate of Cardiac Adverse Events: Final Analysis of Safety and Efficacy Outcomes From the Placebo-Controlled Phase 3 MAIN Study
Authors: Seymour John F. , Pfreundshuh Michael , Coiffier B. , Trneny Marek , Sehn Laurie H. , Csinady Eva 
Published: October 2019

Abstract
Abstract 58
Vascular endothelial growth factor (VEGF) is involved in lymphoma growth, suggesting a potential therapeutic role for anti-VEGF therapies. This randomized, placebo (PBO)-controlled, double-blind, multicenter, phase 3 trial (MAIN study) evaluated if adding the anti-VEGF antibody bevacizumab (Bev) to standard R-CHOP therapy improves outcomes for patients (pts) with previously untreated CD20+ diffuse large B-cell lymphoma (DLBCL). The study was designed to detect a 27% reduction in the risk of a progression-free survival (PFS) event (Hazard ratio [HR] = 0.73, R-CHOP + Bev vs R-CHOP).
Pts with DLBCL (IPI score ≥2 or bulky disease, ≥7.5 cm irrespective of IPI) and normal cardiac function were randomized (1:1) to receive Bev or PBO + site pre-specified immunochemotherapy (8 cycles R-CHOP-21 or 6 cycles R-CHOP-14 followed by 2 cycles R). R-CHOP-21 & R-CHOP-14 cohorts received Bev at 15 mg/kg q21d & 10 mg/kg q14d, respectively. Response was assessed at the end of induction; pts achieving complete remission continued Bev monotherapy (15 mg/kg q21d, up to 1y from study start, Bev arm) or observation (PBO arm). To observe the required 326 events the planned sample size was 1060 pts followed for 60 mo.
The protocol specified strict cardiac monitoring; left ventricular ejection fraction (LVEF) was measured at baseline (bl), after 4 & 8 cycles of therapy, and at 1y. LVEF adverse events (AEs) were defined as a ≥20% absolute decline from bl and/or a decline of ≥10% from bl to <50%. The term “congestive heart failure” (CHF) encompassed symptomatic AEs consistent with CHF such as decreased ejection fraction, LV dysfunction, and cardiomyopathy as reported by the investigators. Pts with a decrease of LVEF to <50% (grade 2, NCI CTCAE v3.0) were discontinued from Bev/PBO treatment.
As part of ongoing serial safety monitoring, in May 2010 the independent Data and Safety Monitoring Board (DSMB) observed an increased number of LVEF AEs in the Bev arm. Given a low probability of the study meeting the primary efficacy endpoint, the DSMB concluded an unfavorable benefit–risk profile for pts treated with R-CHOP + Bev. Therefore, Bev treatment was immediately discontinued and further enrollment stopped. The study was revised and completed as a safety-oriented follow-up of the enrolled pts.
The final analysis included 787 pts (enrolled 7/07 to 6/10) who were followed until 12 mo after the last pt had received the last dose of chemotherapy. Study arms were balanced for age, gender, planned chest irradiation, history of hypertension, cardiac risk factors, and bl LVEF. Efficacy of R-CHOP was not significantly affected by the addition of Bev; median PFS was 42.9 (PBO) vs 40.2 mo (Bev) (HR = 1.09, P =.49). While survival data are immature, no difference was evident (deaths 83/397 [20.9%] PBO vs 82/390 [21%] Bev).
Pts in the Bev arm vs the PBO arm had higher rates of LVEF (18.0 vs 8.0%; OR 2.51, 95% CI [1.60;3.93], respectively) and CHF AEs (16.2 vs 6.5%; OR 2.79; 95% CI [1.72;4.54], respectively). Further analysis of CHF AEs by treatment and age group indicated that pts ≥65y had a higher rate than younger pts; both in the Bev arm (20.0 vs 14.0%) and PBO (9.3% vs 4.7%). Incidence of CHF AEs varied according to backbone regimen and in the Bev arm was 16.8% (R-CHOP-21) and 13.8% (R-CHOP-14), and in the PBO arm was 4.6% (R-CHOP-21) and 13.8% (R-CHOP-14). As this was an unplanned analysis on a non-randomized pt population an imbalance of relevant bl features was observed (e.g. age and race composition). CHF events began to increase (determined by Kaplan–Meier analysis) at a cumulative doxorubicin dose of 200 mg/m2 and above in both treatment arms, and increased further at a cumulative doxorubicin dose ≥300 mg/m2 in the Bev arm vs. the PBO arm.
Pts in the PBO arm were more likely to resolve their CHF events without sequelae (by investigators reporting, 77.8% in PBO arm vs 63.2% in Bev arm), and also had fewer unresolved CHF events (14.8% vs 20.6%). Fatal CHF AEs were comparable in both arms (1/386 vs 2/395).
In conclusion, this study demonstrates that the addition of Bev to R-CHOP is associated with an increased risk of LVEF/CHF events in pts with DLBCL. Following the DSMB recommendation, recruitment was stopped and Bev was discontinued. Data suggest that, regardless of randomization CHF risk is increased for pts ≥65 y of age, and the addition of Bev increases the cardiac toxicity rate of doxorubicin. The current data do not support further evaluation of Bev with R-CHOP in DLBCL.

Disclosures:
Seymour: Roche/Genetech: Honoraria. Off Label Use: The addition of bevacizumab to standard therapy with R-CHOP in patients with previously untreated diffuse large B-cell lymphoma. Pfreundshuh:Roche: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy; Mundi Pharma: Consultancy; Onyx: Consultancy; Amgen: Research Funding. Coiffier:Roche: Consultancy. Trneny:Roche: Consultancy, Honoraria, Research Funding. Sehn:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Csinady:Roche: Employment.