-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

577 Final Analysis of the Safety and Efficacy of Venetoclax in Combination with Pola-R-CHP for Untreated High-Risk BCL-2-Positive B-Cell Lymphoma Including Double/Triple Hit Lymphoma

Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphomas: Pharmacologic Therapies: New R-CHOP Combinations for Treatment Naïve DLBCL
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Lymphomas, Assays, Clinical Research, Diseases, Aggressive lymphoma, Treatment Considerations, Lymphoid Malignancies, Technology and Procedures
Sunday, December 8, 2024: 12:00 PM

Catherine S. Diefenbach1, Andrew D. Zelenetz2*, Charles Herbaux, MD, PhD3*, Monica Tani4*, Roch Houot, MD, PhD5*, Mariana Bastos-Oreiro6*, Hervé Tilly7, Thomas Gastinne, MD8*, Catherine Thieblemont, MD9, Wilfred Leung10*, Katerina Hatzi10*, Murali Kesavan11*, Simona Barlera12*, Michelle Boyer10* and Franck Morschhauser, MD, PhD13

1Perlmutter Cancer Center, NYU Langone Health, New York, NY
2Memorial Sloan Kettering Cancer Center, New York, NY
3Centre Hospitalier Universitaire de Montpellier, Montpellier, France
4Ospedale Santa Maria delle Croci, Ravenna, Italy
5Centre Hospitalier Universitaire de Rennes - Hôpital Pontchaillou, Rennes, France
6Hematology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
7Department of Hematology, Centre Henri Becquerel, Rouen, France
8Centre Hospitalier Universitaire de Nantes, Nantes, France
9Hospital Saint-Louis, Paris, France
10Genentech, Inc., South San Francisco, CA
11F. Hoffmann-La Roche Ltd, London, United Kingdom
12Parexel International, Milan, Italy
13Centre Hospitalier Régional Universitaire de Lille, Lille, France

Background: Venetoclax (Ven) is an oral B-cell lymphoma 2 (BCL-2) inhibitor which has shown activity combined with rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O), and prednisolone (P; R-CHOP) in first line diffuse large B-cell lymphoma (DLBCL; Morschhauser et al. Blood 2021).

In the Phase III POLARIX study, polatuzumab vedotin (Pola)-R-CHP had a longer progression-free survival (PFS) versus R-CHOP, establishing Pola-R-CHP as standard of care for untreated patients (pts) with DLBCL and BCL-2 overexpression by immunohistochemistry (BCL-2 IHC+; Morschhauser et al. EHA 2022). The BO42203 trial (NCT04790903) explored whether Ven+Pola-R-CHP could further improve outcomes in this population; early results showed acceptable safety and promising efficacy (Zelenetz et al. ASH 2023). Here, we report the final analysis of the BO42203 trial.

Methods: BO42203 was a Phase Ib, open-label, multicenter trial of pts with untreated BCL-2 IHC+ DLBCL (including Grade 3b follicular lymphoma). Pts enrolled had an International Prognostic Index (IPI) score of 2–5, and BCL-2 IHC+ defined as ≥50% expression (by local pathology).

The primary endpoint was 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 days [D]). Secondary endpoints included safety/tolerability, PET-CT based objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and PFS.

Pts were enrolled in 5 cohorts (n=10 pts each). Safety data were reviewed by an internal monitoring committee (IMC) who could alter the Ven dose/schedule for the next cohort. Pts received 6 21-D treatment cycles. Pola-R-CHP was administered on D1 of each cycle at the following doses: Pola 1.8mg/kg, R 375mg/m2, C 750mg/m2, H 50mg/m2, and P 100mg/D for 5 Ds. All pts in Cohort 1 were assigned to Ven 800mg/D for 5 Ds/cycle; doses started 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 review.

Results: At data cut-off (May 21, 2024), 5 cohorts were enrolled (n=50). At baseline, the median age was 64.5 years, 20 (40.0%) pts were female, and 5 (10.0%) had an Eastern Cooperative Oncology Group performance status of 2. High-risk features were prevalent: 45 (90.0%) pts had Ann Arbor Stage III–IV; 38 (76.0%) had an IPI score of ≥3; and 7 (14.0%) had high-risk cytogenetics (double/triple hit lymphoma [DHL/THL]). Median duration of follow-up was 15.5 months (range: 1.7–34.0).

Forty-two pts completed study treatment. Reasons for discontinuation included death (n=7: 5 due to progressive disease [PD], 2 due to adverse events [AEs]) and withdrawal by patient (n=1). Forty-eight pts completed the DLT period; 2 pts withdrew prior to this due to meningitis and a COVID-related AE. No DLTs were observed. Grade ≥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, Schedule A was maintained/administered for all future pts.

All pts had ≥1 AE; 37 (74.0%) and 24 (48.0%) pts had ≥1 Grade ≥3 AE and serious AE (SAE), respectively. The most common (≥15%) Grade ≥3 AEs included: neutropenia (46.0%) and febrile neutropenia (18.0%). Two (4.0%) pts died due to treatment-related SAEs (investigator-assessed; arrhythmia/cardiac arrest [related to Ven] and sepsis [related to Ven+Pola-R-CHP]). AEs leading to dose modification/delay of any drug occurred in 20 (40.0%) pts (Ven: 19 [38.0%]; R: 17 [34.0%]; Pola: 16 [32.0%]; C and H: 15 [30.0%] each; P: 6 [12.0%]); 7 (14.0%) pts had an AE that led to discontinuation of any study drug.

The end of treatment PET-CT based ORR and CR were 86.0% and 82.0% (n=50), respectively (including all pts with DHL/THL [n=7; CR: 100%]). Two (4.0%) pts had PD, and 5 were not assessed (2 pts died before PD assessment; 3 pts had discontinued treatment). The median DOR was not estimable (NE; 95% confidence interval [CI]: NE). The 1-year PFS and overall survival rates were 75.5% (95% CI: 61.1, 90.0) and 91.7% (95% CI: 83.9, 99.5), respectively.

Conclusions: Ven 800mg/D for 5 Ds/cycle plus Pola-R-CHP was determined as the RP2D for untreated BCL-2 IHC+ DLBCL. In this final analysis, no new safety signals were observed. In this high-risk group of pts, high CR rates were seen across all cohorts, including pts with DHL/THL.

Disclosures: Diefenbach: MorphoSys: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millenium: Research Funding; Merck: Consultancy, Research Funding; MEI Pharma: Research Funding; Incyte: Consultancy, Research Funding; I MAB: Consultancy; Genmab: Consultancy; Genentech/Roche: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; OverT Therapeutics: Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company; NYU Grossman School of Medicine/Perlmutter Cancer Center at NYU Langone Health: Current Employment. Zelenetz: Memorial Sloan Kettering Cancer Center: Current Employment; BMS, Celgene, JUNO, Genentech/Roche, Gilead/Kite; BeiGene; Pharmacyclics, Janssen, Amgen, AstraZeneca, Novartis, MEI Pharma, Ipsen: Consultancy, Honoraria; Genentech/Roche, MEI Pharma, AbbVie; BeiGene, Pharmacyclics, Janssen: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees. Herbaux: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; Abbvie: Consultancy, Honoraria, Other: Travel support; Roche/Genentech: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Tani: Roche, Abbvie, Jansen-Cilag, Incyte, BeiGene, Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca SpA: Membership on an entity's Board of Directors or advisory committees. Houot: Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, Incyte, Miltenyi, Roche, Abbvie: Consultancy; Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, Roche, Abbvie: Honoraria. Bastos-Oreiro: Spanish Society of haematology, Madrid association of haematology, GELTAMO: Membership on an entity's Board of Directors or advisory committees; AbbVie, BMS, Incyte, Janssen, Kite, Lilly, Novartis, Roche: Honoraria, Speakers Bureau; Kite, Roche: Research Funding; Hospital Gregorio Maranon: Current Employment. Tilly: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Gastinne: Roche: Other; Gilead/Kite, BMS: Membership on an entity's Board of Directors or advisory committees; Gilead/Kite: Honoraria. Thieblemont: Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodation, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Honoraria; ADC Therapeutics: Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel and accommodation, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel and Accommodation, Speakers Bureau; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Other: Travel and accommodation, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel and accommodation, Speakers Bureau; Cellectis: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel and accommodation, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Other: Travel and accommodation, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel and accommodation, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria; University of Paris: Current Employment, Ended employment in the past 24 months. Leung: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Hatzi: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Kesavan: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company; Oxford University Hospitals NHS Trust: Ended employment in the past 24 months. Barlera: Parexel: Current Employment; DSMB member as Statistician for a non-profit study in Neurology: Membership on an entity's Board of Directors or advisory committees. Boyer: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Morschhauser: Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Eisai: Honoraria; Chugai: Honoraria; Roche/Genentech: Consultancy, Honoraria, Other: Payment for Expert Testimony, Honoraria for Scientific Lectures; Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: Venetoclax plus Pola-R-CHP is an investigational combination. Venetoclax (Venclexta) is a BCL-2 inhibitor indicated: for the treatment of adult patients 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 treatment of adult patients who have previously untreated DLBCL, NOS or HGBL and who have an IPI score of 2 or greater; and in combination with bendamustine and a rituximab product for the treatment of adult patients with relapsed or refractory DLBCL, NOS after at least two prior therapies.

Previous Abstract | Next Abstract >>
*signifies non-member of ASH