ATLANTA—No further evaluation of bevacizumab with R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL) is recommended based on data reported during the 54th American Society of Hematology Annual Meeting and Exposition showing the agent increased the cardiac toxicity rate of doxorubicin.
“Data suggest that, regardless of randomization, congestive heart failure (CHF) risk is increased for patients 65 years of age and over,” said John F. Seymour, MBBS, of the Peter MacCallum Cancer Center, East Melbourne, Australia. After an increased risk of left ventricular ejection fraction (LVEF)/CHF events were observed, recruitment in the phase 3 MAIN study was stopped following a recommendation by the Data Safety Monitoring Board (DSMB) and bevacizumab was discontinued.
The randomized, placebo-controlled, double-blind, multicenter trial was evaluating if adding bevacizumab to standard R-CHOP therapy improved outcomes for patients with previously untreated CD20+ DLBCL.
Patients with normal cardiac function were randomized 1:1 to receive bevacizumab (n=395) or placebo (n=386) plus site-prespecified immunochemotherapy, 8 cycles of R-CHOP-21 or 6 cycles of R-CHOP-14 followed by 2 cycles of rituximab. The R-CHOP-21 cohort received bevacizumab 15mg/kg every 21 days and the R-CHOP-14 cohort, bevacizumab 10mg/kg on day 14.
Response was assessed at end of induction; those achieving complete remission continued bevacizumab monotherapy 15mg/kg every 21 days up to 1 year from study start in bevacizumab arm or observation in the placebo arm. To observe the required 326 events, the planned sample size was 1,060 patients followed for 60 months.
“The protocol specified strict cardiac monitoring,” Dr. Seymour noted. LVEF was measured at baseline, after 4 and 8 cycles of therapy, and at 1 year. LVEF adverse events (AEs) were defined as a ≥20% absolute decline from baseline and/or a decline of ≥10% from baseline to <50%.
After observing an increased number of LVEF AEs in the bevacizumab arm, “the DSMB concluded an unfavorable benefit-risk profile for patients treated with R-CHOP + bevacizumab. Therefore, bevacizumab treatment was immediately discontinued and further enrollment stopped. The study was revised and completed as a safety-oriented follow-up of the enrolled patients,” he noted.
Of the 787 patients followed until 12 months after the last patient had received the last dose of chemotherapy, median PFS was 42.9 months in the placebo arm vs 40.2 months in the bevacizumab arm (HR 1.09, 95% CI 0.85-1.40; P=0.49). While survival data are immature, no difference was evident: 20.9% of patients had died in the placebo arm vs 21% in the bevacizumab arm.
Patients in the bevacizumab arm had higher rates of LVEF (18.0%) vs the placebo arm (8.0%; OR 2.51, 95% CI 1.6–3.9) and CHF adverse events (16.2 vs 6.5%; OR 2.8; 95% CI 1.7–4.5, respectively). Those ≥65 years of age had a higher rate of CHF adverse events than younger patients. CHF events began to increase at a cumulative doxorubicin dose of ≥200mg/m2 in both treatment arms, and increased further at a cumulative doxorubicin dose ≥300 mg/m2 in the bevacizumab arm vs the placebo arm.
Patients in the placebo arm were more likely to resolve their CHF events without sequelae and had fewer unresolved CHF events. One patient in the placebo arm and 2 patients in the bevacizumab arm died due to CHF.