LONG‐TERM FOLLOW‐UP OF MULTICENTER PHASE II TRIAL OF ZANUBRUTINIB, OBINUTUZUMAB, AND VENETOCLAX (BOVEN) IN PREVIOUSLY UNTREATED PATIENTS WITH CLL/SLL

Abstract

Background: Venetoclax-obinutuzumab induces durable undetectable MRD (median time to MRD ≥10-4 of 21 mo) in CLL (Al-Sawaf JCO, 2021) and zanubrutinib is a second-generation BTKi with a favorable safety profile (Brown NEJM 2023). BOVen appeared well-tolerated and achieved frequent uMRD in CLL (Soumerai Lancet Haem 2021), but longer follow-up was needed to evaluate the MRD-driven treatment strategy. Herein, we present the initial report on long-term follow-up of BOVen in CLL. Methods: In this multicenter phase 2 trial (NCT03824483), eligible pts had CLL/SLL requiring first-line treatment (iwCLL), ECOG PS ≤2, ANC ≥1000, PLT ≥75,000 (ANC ≥0/PLT ≥20,000 if due to CLL). Informed consent was obtained from all pts. BOVen was administered in 28-day (D) cycles (C): Zanubrutinib 160 mg PO twice daily starting D1; Obinutuzumab 1000 mg IV D1 (split D1–2 if ALC ≥25,000 / LN ≥5 cm), D8, D15 of C1, and D1 of C2–8; Venetoclax ramp up initiated C3D1 (target 400 mg PO daily). MRD was evaluated by flow cytometry (MRD-FC) with uMRD defined as ≤10-4 for the primary endpoint. ΔMRD400 was evaluated by immunosequencing (Adaptive ClonoSEQ) in 35/39 (13 pending) and defined as ≥400-fold reduction in peripheral blood (PB) MRD level at C5D1. Treatment consisted of 8–24 cycles (duration determined by prespecified MRD-FC criteria). Beginning C7D1 then q2 cycles, PB uMRD-FC prompted bone marrow (BM) <14 days. If BM uMRD-FC, PB MRD-FC was repeated after 2 additional cycles. Pts with confirmed uMRD-FC in PB and BM discontinued therapy. All-cause adverse events (AE) were assessed (CTCAE v5). Median time to PB MRD-FC ≥10-4 was calculated from end-of-treatment (EOT; Kaplan–Meier method). Results: The study accrued 52 pts (3–10/2019; 7–4/2021): median age 61, 75% male, 75% IGHV unmutated, 18.4% del17p/TP53M. All evaluable for safety with 50 evaluable for efficacy. With median follow up of 40 mo (4.1–47.4) and treatment duration of 10 cycles (IQR 8–14), 96% (48/50) were uMRD-FC in PB; 92% (46/50) were uMRD in PB and BM after a median 8 mo (IQR 6–11.5). The most common AEs were thrombocytopenia (55.8%), fatigue (55.8%), neutropenia (53.8%), diarrhea (46.2%), bruising (44.2%), infusion related reaction (36.5%). The most common grade ≥3 AE were neutropenia (23.1%), thrombocytopenia (7.7%), lung infection (5.8%). No lab/clinical TLS occurred (Howard). Of 46 pts meeting MRD-FC criteria to end treatment, MRD-FC free survival was 29.8 mo (3.6–35.1; A). Of pts who were PB uMRD-FC and evaluable for ΔMRD400, MRD-FC free survival was longer in ΔMRD400 achievers (NR vs. 18.1 mo, log-rank p = 0.003; B) despite fewer median cycles of therapy (8 vs. 13, p < 0.001). The research was funded by: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute. Keywords: chronic lymphocytic leukemia (CLL), molecular targeted therapies Conflicts of interests pertinent to the abstract J. D. Soumerai Consultant or advisory role: Abbvie, AstraZeneca, Beigene, Bristol Myers Squibb, Roche, Seattle Genetics, TG Therapeutics Research funding: Adaptive Biotechnologies, Beigene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics. A. Dogan Consultant or advisory role: Incyte, EUSA Pharma, LOXO Research funding: Roche, Takeda E. Hochberg Stock ownership: Leuko J. S. Abramson Consultant or advisory role: AbbVie, Astra-Zeneca, BeiGene, BMS, Caribou Biosciences, Cellectar, Century Therapeutics, Epizyme, Genentech, Genmab, Incyte, Interius, Janssen, Kite Pharma, Kymera, Lilly, Morphosys, Mustang Bio, Ono Pharma, Regeneron, Takeda A. Noy Consultant or advisory role: Janssen, Morphosys, Cornerstone, Epizyme, EUSA, Recordati, TG Therapeutics, ADC Therapeutics, AstraZeneca, Kite/Gilead Research funding: Pharmacyclics/Abbvie, Kite/Gilead, Cornerstone. Honoraria from Pharmacyclics/Abbvie M. L. Palomba Consultant or advisory role: Synthekine, Cellectar, Beigene, Kite, BMS A. Kumar Consultant or advisory role: Genentech Honoraria: AstraZeneca, Kite Pharmaceuticals, Janssen, Genentech, Loxo/Lily Pharmaceuticals Research funding: AbbVie, Adaptive Biotechnologies, Celgene, Pharmacyclics, Loxo/Lily Pharmaceuticals, Seattle Genetics L. E. Roeker Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, Beigene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, TG Therapeutics Stock ownership: Abbott Laboratories Honoraria: DAVA, Curio, Medscape, PeerView Research funding: Adaptive Biotechnologies, AstraZeneca, Genentech, AbbVie, Pfizer, Loxo Oncology, Aptose Biosciences, Dren Bio, Qilu Puget Sound Biotherapeutics Educational grants: LOXO oncology M. Thompson Consultant or advisory role: LOXO Oncology at Lilly, AstraZeneca Honoraria: MJH Life Sciences, Intellisphere LLC, Brazilian Association of Hematology, Hemotherapy and Cellular Therapy, Dava Oncology, Curio Science, Massachusetts Medical Society, VJHemOnc Research funding: Beigene, Nurix Therapeutics, Abbvie, Genentech, AstraZeneca, Genmab Z. Epstein-Peterson Honoraria: OncLive Research funding: Amgen, Kymera M. Geyer Consultant or advisory role: Allogene, Novartis, Sanofi Research funding: Sanofi, Amgen, Actinium A. Cohen Employment or leadership position: Beigene Stock ownership: Beigene J. Biondo Employment or leadership position: Genentech Research funding: Genentech A. Jacob Employment or leadership position: Adaptive Biotechnologies O. Abdel-Wahab Consultant or advisory role: H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, Janssen Research funding: H3B Biomedicine, Nurix Therapeutics, Minovia Therapeutics, LOXO Oncology Other remuneration: Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., Pfizer Boulder A. D. Zelenetz Consultant or advisory role: Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis, Adaptive Biotechnology, MorphoSys, Abbvie, AstraZeneca, MEI Pharma Research funding: MEI Pharmaceuticals, Genentech/Roche, Beigene Other remuneration: DMC Chair for Beigene and DMC Member for BMS/Celgene/Juno

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