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
Year: 2024
Type: conference-abstract
Abstract: 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.
Source: Blood
Authors: Mahesh Swaminathan, Philip A. Thompson, Jan A. Burger, Musa Yilmaz, Nitin Jain, Tapan M. Kadia, Lucia Masarova, Yesid Alvarado Valero, Prithviraj Bose, Alessandra Ferrajoli, Ghayas C. Issa, Steven M. Kornblau, Farhad Ravandi, Koji Sasaki, Gautam Borthakur, Kelly S. Chien, Courtney D. DiNardo, Danielle Hammond, Elias Jabbour, Guillermo Montalban-Bravo, Naveen Pemmaraju, Nicholas J. Short, Koichi Takahashi, Francesco Paolo Tambaro, Wei Qiao, Naveen Garg, Michael J. Keating, William G. Wierda
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Amgen, Bristol-Myers Squibb, Eli Lilly and Company, AstraZeneca, Gilead Sciences, American Society of Clinical Oncology, Celgene, F. Hoffmann-La Roche, PTC Therapeutics, National Comprehensive Cancer Network, Astex Pharmaceuticals, Foghorn Therapeutics, CareDx, Adaptive Biotechnologies, BeiGene, CTI Biopharma, Incyte, Ascentage Pharma, Daiichi-Sankyo, Astellas Pharma, Servier, Medac, Plexxikon, Aptitude Health, National Institutes of Health, Genentech, Chugai Pharmaceutical, Takeda Oncology, Pharmacyclics, Juno Therapeutics, Loxo Oncology, National Cancer Institute, Daiichi Sankyo Europe
OpenAlex ID: W4405034648