Polatuzumab Vedotin Plus Venetoclax with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Primary Efficacy Analysis of a Phase Ib/II Study

Introduction: Polatuzumab vedotin (Pola) combined with rituximab (R) demonstrated activity and tolerability in a Phase (Ph) II trial of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (Morschhauser et al. Lancet 2019). The pro-survival MCL-1 protein has been identified as a mechanism of resistance to venetoclax (Ven), a potent inhibitor of BCL-2, in non-Hodgkin lymphoma cell lines. 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 (Amin et al. AACR 2020). We sought to determine whether the combination of Pola-Ven-R might further enhance anti-tumor response. Here, we present the primary efficacy and safety analysis from a Ph Ib/II study of Pola-Ven-R in pts with R/R DLBCL (GO29833; NCT02611323).

Methods: GO29833 is an open-label, multicenter study of pts with R/R DLBCL who had received ≥1 prior anti-CD20 chemo-immunotherapy regimen. The recommended Ph II dose (RP2D) combination for Pola-Ven-R was initially defined in a 3+3 dose escalation phase and was then expanded into Ph II. Pts in the expansion cohort received induction therapy with six 21-day cycles of: intravenous (IV) Pola 1.8mg/kg (Cycle [C] 1–6: Day [D]1), Ven 800mg by mouth daily and R 375mg/m² IV (C1–6: D1). Responders received consolidation therapy for 8 months (Ven 800mg daily and R 375mg/m² on D1 every 2 months). The primary safety objectives were to determine the RP2D for Pola and Ven when given in combination with R and to evaluate the safety and tolerability of the Pola-Ven-R combination. The primary efficacy endpoint was complete response (CR) at end of induction (EOI), as determined by the Independent Review Committee (IRC) based on positron emission tomography-computed tomography (PET-CT) scans using modified Lugano 2014 response criteria. Secondary objectives included CR-rate at EOI and best overall response (BOR) determined by the investigator (INV). Exploratory objectives included INV-assessed progression-free survival (PFS) and overall survival (OS).

Results: At the primary analysis (January 30, 2020), 57 pts from the Ph Ib/II populations were enrolled and received at least one study drug; the median duration of follow-up was 7.0 (range 0.2–30.4) months. Baseline characteristics of the safety-evaluable pts are shown in Table 1: median age, 65 years; male, 49%; Ann Arbor Stage III–IV, 84%; International Prognostic Index (IPI) ≥3, 54%; median prior lines of therapy, 3; refractory to last line, 83%; primary refractory, 65%. Dose limiting toxicity was not observed in Ph I and the maximum dose level was chosen as RP2D. All except two pts experienced at least one adverse event (AE), 21 (37%) had a serious AE, and 45 (79%) had a Grade 3–4 AE. The most common Grade 3–4 AEs were neutropenia (30 pts, 53%), infections (9 pts, 16%), and anemia (6 pts, 11%). AEs leading to dose reduction or interruption of any drug occurred in 10 (18%) and 35 (61%) pts, respectively; the majority of dose modifications were changes to Ven dosing. Seven (12%) pts had an AE that led to the discontinuation of any study drug (Pola [n=5]; Ven [n=7]; R [n=6]). One grade 5 AE was reported (pneumonia); however, it was not considered related to study treatment as the pt had received new anti-lymphoma therapy following disease progression. In the primary efficacy-evaluable population (n=48), the IRC-assessed modified Lugano CR rate at EOI was 29% (Table 2). The INV-assessed CR rate at EOI and BOR were 31% and 65%, respectively, with a median duration of response of 5.8 months (95% confidence interval [CI]: 3.4–6.7). The median PFS and OS were 4.4 months (95% CI: 3.0–7.1) and 11.0 months (95% CI: 6.7–not evaluable), respectively.

Conclusions: 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 pts with R/R DLBCL. 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.