Polatuzumab vedotin plus venetoclax with rituximab (Pola-Ven-R) shows promise in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), according to findings from an open-label, multi-center, phase 1b/2 study being presented by Giuseppe Gritti, MD, PhD, ASST Papa Giovanni XXIII, Bergamo, Italy, at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition. 

Dr Gritti and colleagues conducted this study to determine if the combination of Pola-Ven-R might enhance anti-tumor response in patients with R/R DLBCL. 

“Preclinical studies have demonstrated that concurrent treatment with Pola promotes MCL-1 degradation and enhances anti-tumor efficacy in vivo, thus providing a strong rationale for the combination with Ven,” they explained.

A total of 57 patients (median age, 65 years) who had received ≥1 prior anti-CD20 chemo-immunotherapy regimen, were included in the study. The phase II dose for Pola-Ven-R was in a 3+3 dose-escalation phase, and patients in the expansion cohort received induction therapy with six 21-day cycles of: intravenous (IV) Pola 1.8mg/kg (cycles 1-6, day 1), Ven 800 mg daily and R 375 mg/m² IV (cycles 1-6, day 1). Furthermore, responders received consolidation therapy of 800 mg of Ven daily and R 375 mg/m² on day 1 every 2 months. 

The primary safety objectives were to determine the recommended dose for the phase 2 combination of Pola-Ven-R and to evaluate the safety and tolerability of Pola-Ven-R. Primary efficacy endpoints included complete response (CR) at end of induction (EOI), which was determined by the Independent Review Committee (IRC) based on positron emission tomography-computed tomography scans using modified Lugano 2014 response criteria. The secondary objectives were CR-rate at EOI and best overall response (BOR), while the exploratory objectives included progression-free survival (PFS) and overall survival (OS).

The median follow-up duration was 7.0 (range, 0.2-30.4) months, the INV-assessed CR rate at EOI and BOR was 31% and 65%, respectively, with a median duration of response of 5.8 months (95% CI, 3.4-6.7). Among the primary efficacy-evaluable population (n = 48), 29% were identified as the IRC-assessed modified Lugano CR rate at EOI. The median PFS was 4.4 months (95% CI, 3.0-7.1), and the median OS was 11.0 months (95% CI, 6.7 to not evaluable).

Almost every patient experienced at least one adverse event (AE), except for two. 21 (37%) patients had a serious AE, while 45 (79%) had AEs of grade 3 or higher. The most common grade 3-4 AEs included neutropenia (30 patients, 53%), infections (9 patients,16%), and anemia (6 patients,11%). Dose reduction or interruption of any drug due to AEs occurred in 10 (18%) and 35 (61%) patients, respectively; changes to venetoclax dosing were the most prevalent. 

Seven (12%) patients had to discontinue any study drug due to AE 9 (Pola [n=5]; Ven [n=7]; R [n=6]). One grade 5 AE (pneumonia) was reported, but it was not considered to be related to the study treatment.

“Our study of the novel triplet combination, Pola-Ven-R, demonstrates a safety profile consistent with the known profiles of the individual drugs. This first report of the full efficacy population showed promising activity in a heavily pre-treated and refractory population of patients with R/R DLBCL,” wrote Gritti et al. 

“Further evaluation of Pola-Ven-R and the impact of consolidation therapy is warranted to address the significant unmet medical need in this patient population,” they concluded. —Alexandra Graziano

Gritti G, Marlton P, Phillips TJ, et al. Polatuzumab Vedotin Plus Venetoclax with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Primary Efficacy Analysis of a Phase Ib/II Study. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 599.