Early Results Indicate Acceptable Safety and Promising Efficacy of Venetoclax in Combination with Pola-R-CHP for Untreated High-Risk BCL-2-Positive B-Cell Lymphoma Including Double/Triple Hit Lymphoma

Background: The Phase II CAVALLI study assessed the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Ven; 800mg for 10 days [Ds]) + rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisolone (P; R-CHOP), for first line treatment of diffuse large B-cell lymphoma (DLBCL). The end of treatment (EOT) complete response (CR) rate was 64% in patients (pts) with BCL-2 overexpression by immunohistochemistry (BCL-2 IHC+); there was a 2-year progression-free survival (PFS) benefit compared with R-CHOP (GOYA trial; 78% vs 62%); but a higher incidence of Grade (Gr) 3/4 adverse events (AEs; 86% vs 66%, respectively; Morschhauser et al. Blood 2021). In the Phase III POLARIX study, polatuzumab vedotin (Pola)-R-CHP had a prolonged PFS vs R-CHOP, establishing Pola-R-CHP as standard of care for untreated DLBCL (Tilly et al. N Engl J Med 2022; Morschhauser et al. EHA 2022). Thus, we explored whether adding Ven to Pola-R-CHP could further improve outcomes in BCL-2 IHC+ DLBCL. Here, we report early safety and efficacy results from a Phase Ib study (BO42203; NCT04790903), evaluating the optimal dose/schedule of Ven+Pola-R-CHP. Methods: BO42203 is an ongoing open-label, multicenter study of pts with untreated BCL-2 IHC+ DLBCL (including Grade 3b follicular lymphoma). Pts enrolled had an International Prognostic Index (IPI) of 2-5, and BCL-2 IHC+ defined as ≥50% expression (by local pathology). The primary endpoint is to determine the recommended Phase II dose (RP2D) for Ven+Pola R-CHP based on the rate of dose-limiting toxicity (DLT) during the first 2 cycles (42 Ds), with tolerability assessed by dose modifications/delays and discontinuation. Secondary endpoints include percentage of pts with AEs, and PET-based response rates/duration. Pts are enrolled in 5 cohorts (n=10 pts each). Safety data are reviewed by an internal monitoring committee (IMC) who can alter the Ven dose/schedule for the next cohort. Pts receive 6 21-D cycles of treatment. Pola-R-CHP is administered on D1 of each cycle at the following doses: Pola 1.8mg/kg, R 375mg/m 2, C 750mg/m 2, H 50mg/m 2, and P 100mg/D for 5 Ds. All pts in Cohort 1 were assigned to Ven 800mg/D for 5 Ds/cycle; doses start on D4 of Cycle 1 and D1 of subsequent cycles (Schedule A) with optional escalation to 10 Ds/cycle from Cohort 2 onwards (Schedule B), depending on IMC assessment. Results: At the time of analysis (data cutoff: May 2, 2023), 4 cohorts were enrolled (n=40). At baseline, the median age was 64.0 y