Résumé
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.
Zelenetz:Janssen Pharmaceuticals: Consultancy, Honoraria; None other than mutual funds (401K): Current equity holder in publicly-traded company; Pharmacyclics: Consultancy, Honoraria; SAB: Membership on an entity's Board of Directors or advisory committees; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; MEI Pharma Inc: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Gilead: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Diefenbach:Gillead: Current equity holder in publicly-traded company; OverT Therapeutics: Current equity holder in private company; F. Hoffmann-La Roche Ltd/Genentech, Inc., BMS, Merck, Abbvie, Novartis, Celgene, Cargo, Nekktar: Research Funding; Genmab, Abbvie, Regeneron, F. Hoffmann-La Roche Ltd/Genentech, Inc., Seattle Genetics, Merck: Membership on an entity's Board of Directors or advisory committees. Herbaux:AbbVie, F. Hoffmann-La Roche Ltd, AstraZeneca, Janssen: Honoraria; AbbVie, Takeda: Research Funding; AbbVie, F. Hoffmann-La Roche Ltd, AstraZeneca, Janssen: Consultancy; Physician and professor of Hematology at academic center (CHU Montpellier France): Current Employment. Tani:Abbvie, Jansen-Cilag, Incyte: Membership on an entity's Board of Directors or advisory committees. Houot:Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte, Miltenyi: Consultancy; Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, F. Hoffmann-La Roche Ltd: Honoraria. Bastos-Oreiro:SEHH, AMHH: Membership on an entity's Board of Directors or advisory committees; BMS, Kite, Novartis, F. Hoffmann-La Roche Ltd, Incyte, Abbvie: Honoraria, Speakers Bureau; Incyte, Kite: Consultancy; F. Hoffmann-La Roche Ltd, Kite, SEHH, AMHH: Research Funding; Gregorio Maranon Hospital: Current Employment, Membership on an entity's Board of Directors or advisory committees. Tilly:F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; BMS, F. Hoffmann-La Roche Ltd, ADC therapeutics: Membership on an entity's Board of Directors or advisory committees. Thieblemont:Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Kyte, Gilead, Novartis, BMS, Abbvie, F. Hoffmann-La Roche Ltd, Amgen: Honoraria; Janssen: Honoraria, Other: Travel Expenses; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Hospira: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Paris University, Assistance Publique, hopitaux de Paris (APHP): Current Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Troy-Barnes:F. Hoffmann-La Roche Products Ltd: Current Employment; University College London Hospitals NHS Foundation Trust, North Middlesex University Hospital NHS Trust: Ended employment in the past 24 months; Whittington Health NHS Trust (honorary contract): Honoraria. Olivieri:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in private company. Kesavan:F. Hoffmann-La Roche Ltd: Current Employment; Oxford university hospitals NHS Trust: Ended employment in the past 24 months. Kanwar:Viatris: Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd: Current Employment. Barlera:Member of the DSMB for an independent (not sponsored) study conducted at the Mario Negri Institute, no fees: Other. Hatzi:Genentech, Inc., F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Jiang:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Boyer:F. Hoffmann-La Roche Ltd: Current Employment. Morschhauser:F. Hoffmann-La Roche Ltd, Gilead, AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd, AbbVie, BMS, Genmab, Gilead, Novartis: Consultancy.
Venetoclax plus Pola-R-CHP is an investigational combination. Venetoclax (Venclexta) is a BCL-2 inhibitor indicated: for the treatment of adult pts with CLL or SLL; in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemo. Polatuzumab vedotin (Pola) is a CD79b-directed antibody-drug conjugate indicated: in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatmen