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

Abstract

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 years, 14 (35.0%) pts were female, and 5 (12.5%) had an Eastern Cooperative Oncology Group performance status of 2. Thirty-six (90.0%) pts had Ann Arbor Stage III-IV; 30 (75.0%) had an IPI score of ≥3; and 10 (25.0%) had poor risk cytogenetics (double/triple hit lymphoma [DHL/THL]). Thirty-eight pts have completed the DLT period; 2 pts withdrew prior to this due to meningitis and a COVID-related AE. No DLTs have been observed. Gr ≥3 myelosuppression was observed in Cohort 1 after the DLT period: neutropenia (n=5 pts [50.0%]), neutrophil count decreased (n=2 [20.0%]), and febrile neutropenia (n=1 [10.0%]). Hence, after IMC review of Cohorts 1-3 it was decided that Schedule A will be maintained/received by all future pts, as the benefit-risk of increasing the Ven schedule may not be favorable. Safety and efficacy analyses were performed on Cohorts 1-3 (n=30) as they have reached the EOT. All pts had ≥1 AE; 21 (70.0%) and 11 (36.7%) pts had at least one Gr ≥3 AE ( Table) and serious AE (SAE), respectively; 2 (6.7%) pts died due to treatment-related SAEs (investigator-assessed; sudden cardiac death [related to Ven] and sepsis [related to Ven+Pola-R-CHP]). AEs leading to dose modification/delay of any drug occurred in 11 (36.7%; 23 events) pts; 21 (91.3%) AEs led to Ven modification in 10 pts (33.3%); and 3 (10.0%) pts had an AE that led to discontinuation of any study drug. Response was evaluated in 30 pts, with an EOT PET-CT based objective response rate and CR of 86.7% (n=26; including all pts with DHL/THL [n=8; CR: 100%]); 1 pt had progressive disease [PD], and 3 were not assessed due to death (n=2) and early discontinuation (n=1; Figure). Three (10.0%) pts died due to PD. Conclusions: Ven 800mg/D for 5 Ds/cycle + Pola-R-CHP has been determined as the RP2D; early results show acceptable safety and promising efficacy for untreated BCL-2 IHC+ DLBCL. High CR rates were observed across all cohorts at EOT, including pts with DHL/THL. Updated results, including circulating tumor DNA, will be presented.