Venetoclax (ABT-199/GDC-0199) Monotherapy in Patients with Relapsed/Refractory NHL

Venetoclax is a selective, potent, oral inhibitor of antiapoptotic protein BCL-2 that showed single-agent activity in a phase 1, open-label, multicenter, dose-escalation study of patients with relapsed/refractory non-Hodgkin lymphoma (NHL). Gerecitano and colleagues reported the updated safety and efficacy results of this trial.¹ In the dose-escalation phase in patients with NHL other than mantle-cell lymphoma (MCL), venetoclax was administered once daily at a starting dose of 200 mg to reach a maximum dose level of 1200 mg after 3 weeks stepwise intrapatient dose ramp-up (dose ramp-up was longer for patients with MCL); in the safety expansion cohort, stepwise escalation was from 400 mg to 800 mg to 1200 mg. A total of 106 patients were enrolled in the trial. In the dose-escalation phase (200-1200 mg/day) of 70 patients, there were 20 patients with a diagnosis of diffuse large B-cell lymphoma (DLBCL), 14 with follicular lymphoma (FL), 28 with MCL, and 3 with marginal zone lymphoma. In the safety expansion cohort (1200 mg/day), 21 patients with DLBCL and 15 with FL were enrolled.

Of the total 160 patients on the trial, 82 patients discontinued treatment, mainly due to progressive disease (n = 69), 7 due to adverse events. Treatment-emergent grade 3/4 adverse events including anemia (16%), neutropenia (12%), fatigue (6%), and thrombocytopenia (9%) were reported. Serious adverse events (SAEs) reported included hyponatremia, diarrhea, and influenza (each 3%). Overall, an overall response rate (ORR) of 44% was achieved including 14 complete responses (CRs) and 33 partial responses (PRs), median progression-free survival (PFS) of 17 months and 12-month overall survival (OS) of 72% was achieved in the total cohort. Among 29 patients with FL, an ORR of 38% was achieved, including 4 CRs and 7 PRs, a a median PFS of 11 months and a 12-month OS of 100%. Among 28 patients with MCL, an ORR of 75% was achieved, including 6 CRs and 15 PRs, a median PFS of 14 months and a 12-month OS of 82%. Among 34 patients with DLBCL, the ORR was 18%, including 4 CRs and 2 PRs, a median PFS of 1 month, and a 12-month OS of 34%. Based on these results, the authors concluded that venetoclax monotherapy showed a tolerable safety profile in patients with relapsed/refractory NHL, and hypothesized that the optimal role of venetoclax might be as combination therapy.

1. Gerecitano JF, et al. ASH 2015. Abstract 254.