Early Obinutuzumab Significantly Increases Bone Marrow Undetectable MRD (10^-4 sensitivity) (uMRD4) Rate When Combined with Acalabrutinib and Venetoclax in a Randomized Phase II Trial for Treatment Naïve CLL

Background

Combined, time-limited BTK- plus BCL2-inhibitor (BTKi, BCL2i) therapy for CLL achieves deep remissions with high uMRD4 rate for treatment-naïve (TN) and relapsed/refractory (RR) patients (pts) with CLL and is associated with durable remissions. Ibrutinib (IBR)+venetoclax (VEN) demonstrated high uMRD4 rates, long remissions, and was well-tolerated, finite-duration treatment in multiple clinical trials. There are multiple considerations for optimizing combined targeted therapy, such as use of second-generation BTKi, potential utility and contribution of including CD20 mAb, duration of treatment, and expectations for outcomes with subsequent therapy for relapsed patients.

Methods

To gain insights into the utility of second-generation BTKi and potential contribution of obinutuzumab (OBIN), we performed a randomized phase II trial of acalabrutinib (ACA) plus VEN with and without early OBIN for TN and RR pts with CLL (NCT04169737). We report results for the TN cohort, which enrolled high risk patients, defined as: age >65 or unmutated (UM) IGHV or TP53 abnormality (del(17p)/TP53-mutated) or del(11q). The primary endpoint was bone marrow (BM) uMRD4 status at end of cycle (C) 9, aiming to increase this from 40% (expectation based on historic IBR+VEN) to 70% with addition of early OBIN. Enrollment began July 2020, pts were randomized to receive 6 cycles standard dose early OBIN starting C1, where ACA started in C2 vs. no early OBIN, where ACA started in C1. Standard VEN ramp up started in C3 for both arms. All pts received a total of 24 cycles of ACA+VEN. Formal IWCLL response assessments (CT and BM with MRD4 by flow) were performed at the end of C9, C14, C20, and C26. Pts with detectable MRD4 or in PR at C14 assessment could receive 6 cycles of OBIN starting C15, independent of prior OBIN.

Results

83 pts with TN CLL were enrolled: 42 pts in the ACA+VEN (AV) arm (no early OBIN) and 41 pts in the ACA+VEN+OBIN (AVO early OBIN) arm. Current median follow up is 29 months. All TN pts were evaluable for the primary endpoint at C9 and at C15 assessment; 20 pts remain on treatment and 58 are in follow up. 78 pts are alive and there were 5 deaths. Pt characteristics are similar in each arm. Medians (range) for pts in the AV vs. AVO arm were: age: 60 yrs (42-78) vs. 63 (30-79); WBC: 68.4K/uL (3.1-255) vs. 60.4 (4.6-212); ALC: 60K/uL (1.1-250) vs. 49.6 (1.1-199); HGB: 11.6g/dL (8.4-15) vs. 11.2 (8.2-15); PLT: 159K/uL (73-310) vs. 145 (46-310). Proportion of pts in the AV vs. AVO arm were similar: male: 52% vs. 66%; Rai III-IV: 38% vs. 39%; UM-IGHV: 86% vs. 73%; del(11q): 26% vs. 15%; TP53 abnormality: 19% vs. 27%; complex karyotype: 31% vs. 32%. For the primary endpoint, the C9 BM uMRD4 rate for AV vs. AVO was 14% vs. 63%. The C14 BM uMRD4 rate for AV vs. AVO was 24% vs. 73%. Based on trial design, 33 of 42 pts in the AV arm received late OBIN, 30 for detectable BM MRD4 and 8 of 41 pts in the AVO arm received late OBIN, 6 for detectable BM MRD4. Of 41 pts who received late OBIN: 17-UM-IGHV (no TP53 abnormality or del 11q); 9-UM-IGHV+TP53 abnormality; 8-UM-IGHV+del(11q); 7- M-IGHV (without TP53 abnormality). Updated C21 BM MRD4 data will be presented. There are 10 pts in each arm currently on treatment; 32 and 26 pts completed treatment and are in follow up in the AV and AVO arms, respectively. The most common Grade ³3 AEs in AV vs. AVO arms were: neutropenia (14% vs. 34%), non-melanoma skin cancers (7% vs. 15%), and infections (5% vs. 32%). The common grade ³3 infections in AVO arm were: 8-COVID19 infection, 4-pneumonia due to unknown organism, and 1 due to influenza A infection. The most common AEs of all grades in AV vs. AVO were diarrhea (60% vs. 54%), headache (57% vs. 37%), infections (38% vs. 54%), and neutropenia (17% vs. 41%). There have been 5 deaths, all in the AVO arm, 3 due to COVID19 in C3, C8, and C12;1 due to sepsis related to myelosuppressive chemotherapy for another malignancy; and 1 due to progressive Richter transformation. Additional analyses of benefit and AEs of late OBIN administration starting in C15 in improving BM uMRD4 rate are ongoing.

Conclusions

The primary endpoint of this randomized phase II trial demonstrated significantly improved BM uMRD4 rate at end of C9 with administration of early OBIN to ACA+VEN, which persisted at end of C14 in TN pts with CLL. AV was well-tolerated; the addition of OBIN added toxicity of increased neutropenia and infection, with 3 COVID19-related deaths among the pts treated with AVO.

Swaminathan:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thompson:Abbvie: Consultancy, Honoraria; Adaptive biotechnologies: Honoraria, Research Funding; Ascentage: Consultancy, Honoraria; AstraZeneca: Honoraria; Beigene: Consultancy, Honoraria; Eli Lilly and Company: Consultancy, Honoraria; Genentech: Honoraria; Janssen: Consultancy, Honoraria; Merck: Honoraria; Roche: Consultancy. Burger:Novartis: Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AstraZeneca: Research Funding; Janssen: Consultancy; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; BeiGene: Consultancy, Research Funding, Speakers Bureau. Yilmaz:daiichi sankyo: Honoraria, Research Funding. Jain:Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; Janssen: Consultancy, Honoraria, Other: Travel Support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; ADC Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Dialectic Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; Medisix: Research Funding; MingSight: Honoraria, Research Funding; Newave: Research Funding; NovalGen: Research Funding; Pfizer: Research Funding; Servier: Research Funding; Takeda: Research Funding; TransThera Sciences: Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Kadia:Cellenkos: Research Funding; Regeneron: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; DrenBio: Consultancy, Research Funding; JAZZ: Research Funding; Sellas: Consultancy, Research Funding; Rigel: Honoraria; Servier: Consultancy; Pfizer: Research Funding; Ascentage: Research Funding; Incyte: Research Funding; ASTEX: Research Funding; Novartis: Honoraria; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Masarova:Cogent: Other: Advisory Board Participant; GSK: Consultancy, Other: Travel support; PharmaEssentia: Other: Advisory Board Participant; MorphoSys: Other: Advisory Board Participant. Bose:CTI Biopharma Corp: Honoraria, Research Funding; GSK: Honoraria; BMS: Honoraria, Research Funding; Disc Medicine: Research Funding; Cogent: Honoraria, Research Funding; Astellas: Research Funding; Telios: Research Funding; Pfizer: Research Funding; Incyte: Honoraria, Research Funding; Ionis Pharmaceuticals: Research Funding; Kartos: Honoraria, Research Funding; Karyopharm: Honoraria; Novartis: Honoraria; MorphSys: Honoraria, Research Funding; PharmaEssentia: Honoraria; AbbVie: Honoraria; Blueprint: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Ferrajoli:BeiGene: Membership on an entity's Board of Directors or advisory committees. Issa:Celgene: Research Funding; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Merck: Research Funding. Ravandi:Astellas: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Xencor: Research Funding; Amgen: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Astyex/Taiho: Research Funding. Sasaki:Daiichi-Sankyo: Consultancy; Enliven: Research Funding; Otsuka: Other: Lecture fees; Chugai: Other: Lecture fees; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Borthakur:Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees. Chien:AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. DiNardo:Genetech: Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Amgen: Consultancy; Immunogen: Honoraria; Notable Labs: Honoraria; Riegel: Honoraria; Rigel: Research Funding; Schrodinger: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Loxo: Research Funding; Astex: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Foghorn: Research Funding; Cleave: Research Funding; ImmuneOnc: Research Funding; AstraZeneca: Honoraria; GSK: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Gilead: Consultancy; Jazz: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Pemmaraju:Triptych Health Partners: Consultancy; Immunogen: Consultancy; Blueprint Medicines: Consultancy, Honoraria; DAVA Oncology: Honoraria, Other: Travel Expenses; Aptitude Health: Honoraria; Bristol-Myers Squibb: Consultancy; Celgene: Honoraria, Other: Travel Expenses; ClearView Healthcare Partners: Consultancy; Neopharm: Honoraria; Protagonist Therapeutics: Consultancy; Incyte: Honoraria; LFB Biotechnologies: Honoraria; Roche Molecular Diagnostics: Honoraria; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; Cellectis: Research Funding; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Research Funding; Affymetrix/Thermo Fisher Scientific: Research Funding; CTI BioPharma: Consultancy; Novartis: Honoraria, Research Funding; Pacylex: Consultancy; CareDx: Honoraria; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Short:Novartis: Honoraria; Amgen: Honoraria; Xencor: Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; Stemline Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria; NextCure: Research Funding; Takeda Oncology: Honoraria, Research Funding; Sanofi: Honoraria; Autolus: Honoraria; GSK: Consultancy, Research Funding; Pfizer Inc.: Honoraria; BeiGene: Honoraria. Tambaro:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees, Other: travel expense; Amgen: Other: travel expense, Speakers Bureau; Novartis: Other: travel support; Neovii: Other: travel support ; Gilead: Membership on an entity's Board of Directors or advisory committees; Medac: Other: travel support , Speakers Bureau. Wierda:Novartis: Research Funding; Oncternal Therapeutics: Research Funding; Juno Therapeutics: Research Funding; Accutar Biotechnology: Research Funding; Genentech, Inc.: Research Funding; AbbVie: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; Loxo Oncology: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Nurix Therapeutics: Research Funding; Eli Lilly: Research Funding; Numab Therapeutics: Research Funding; Kite: Research Funding; GSK: Research Funding; Gilead Sciences: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Oncternal Therapeutics: Research Funding; National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL).