First-generation covalent Bruton tyrosine kinase inhibitors (cBTKi; ie, ibrutinib) and second-generation cBTKis, acalabrutinib and zanubrutinib, disrupt aberrant B-cell receptor (BCR)-signaling via inhibition of BTK. BTKis, along with idelalisib, a phosphatidylinositol 3-kinase delta inhibitor that also inhibits BCR signaling, have transformed outcomes for patients with chronic lymphocytic leukemia (CLL) 1. However, despite being in second-generation, these agents are not curative and adverse effects (albeit to a less extent) and susceptibility to resistance mechanisms remain 2, 3. Venetoclax (ABT-199) is an oral selective small molecule BCL-2 inhibitor (BCL-2) approved as monotherapy or, in combination with an anti-CD20 antibody, as a fixed-duration regimen for adults with CLL, with high response rates observed in key pivotal trials in patients with relapsed or refractory CLL 4-6. Unlike BTK or PI3K inhibitors, venetoclax acts independent of the BCR pathway 7. In prior studies, objective response rates (ORR) with venetoclax following BTKi progression and/or intolerance ranged from 54%–65% with ibrutinib and 28%–67% with idelalisib 8, 9; estimated 1-year progression-free survival (PFS) and overall survival (OS) ranged from 75%–79% and 91%–94%, respectively 8, 9. This long-term follow-up report aims to better understand resistance mechanisms to these therapies, which may facilitate better treatment decisions for patients with CLL. To that end, this report provides updated data, with extended follow-up, on venetoclax monotherapy in patients with relapsed/refractory (R/R) CLL after prior BCRi treatment, including exploratory analyses looking at gene expression changes and mutational data. This was a Phase 2, open-label, single-agent, multicenter trial (NCT02141282) in adults previously treated with ibrutinib and/or idelalisib, whose disease relapsed on treatment or progressed after discontinuation due to toxicity of either agent. Patients with R/R CLL defined as per 2008 International Workshop for CLL National Cancer Institute–sponsored Working Group criteria were enrolled in two study arms based on most recent BCRi received (prior ibrutinib or prior idelalisib; Figure S1). Eligible patients received venetoclax 20 mg daily for 1 week, followed by weekly ramp-up to 400 mg target dose from Week 1 to Week 5 8, 9. Full study design was previously published 8, 9. The trial was institutional review board approved and conducted in accordance with relevant ethical research standards. Patients provided written informed consent. The primary endpoint was ORR. Secondary endpoints included duration of response (DOR), time to progression (TTP), PFS, and OS. Undetectable minimal residual disease (uMRD) rate (threshold of 10−4, i.e., 90% upregulated post-venetoclax, including MCL1, BCL2L1, and BCL2A1 (Figure 2B,C). Pre- versus post-venetoclax sample comparisons (from patients whose disease did not progress; 27 vs. 18) at time of post-treatment sample collection identified over 10 000 differentially expressed genes, including MCL1, BCL2L1, and BCL2A1 upregulation at end of treatment (Figure 2D). The observation that the BCL-2 family genes change on Ven treatment independently of CLL progression suggests that additional alterations are needed for clinical relapse. In our study, uMRD in peripheral blood (29%) was similar to previous reports 7, 10, with slightly higher rates observed in patients who had prior ibrutinib versus prior idelalisib. There were 34/127 patients who had BTK C481 mutation at study entry; 20 of these had > 20% variant allele frequency (VAF) decrease after initiation of venetoclax, and BTK C481 was undetectable in 5 patients (3 at progression, 2 without progression) at final analysis (limit of quantitation: 0.7%) (Figure S4). Similar treatment efficacy was observed in patients with and without pre-existing BTKi mutations. Responses were early during treatment, indicating BTKi mutations do not impair venetoclax monotherapy efficacy 11, 12. With extended follow-up, venetoclax monotherapy demonstrated deep and durable remissions in patients with CLL disease that progressed on BCRis, including achieving uMRD and disease stabilization in patients with high disease burden and poor prognostic features. Responses in these patients indicate a meaningful clinical benefit in a difficult-to-treat population. The safety profile of venetoclax monotherapy was similar to previous reports 13, with no new safety signals detected. This study further supports the utility of venetoclax-based therapy for management of R/R CLL post-progression on BCRis, particularly in patients who have discontinued BCRi monotherapy, and provides useful insights into potential mechanisms of resistance that are possibly extrapolatable to the combination-therapy setting. Although fixed-duration venetoclax combination therapy is generally favored for most patients, indefinite-duration monotherapy may yet be beneficial for patients who cannot tolerate anti-CD20 antibodies, those who have restrictive comorbidities, or who are heavily pre-treated. Data from the two study arms were published as two separate manuscripts: AbbVie and the authors wish to thank the participants and their families, as well as the study sites, investigators, coordinators, and support staff who participated in the NCT02141282 clinical trial. Medical writing support was provided by Vasileios Stamou, PhD, and Brandy Menges, PhD, of Avalere Health Ltd., and funded by AbbVie. As a special tribute, AbbVie and the authors would also like to acknowledge the significant contribution of Dr. Steven Coutre (Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA, USA) to the design, conduction, and data interpretation of this study. Venetoclax is being developed in collaboration between AbbVie Inc. and Genentech. AbbVie Inc. is funding this study and participating in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, reviewing for important intellectual content, and approval of this publication. No honoraria or payments were made for authorship. The trial was approved by the institutional review board and conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines and the ethical principles of the Declaration of Helsinki. All patients provided written informed consent. Jennifer A. Woyach provided consultancy for AbbVie, AstraZeneca, Beigene, Genentech, Janssen, Loxo, Newave, Merck, Pharmacyclics, and Schrodinger; and received research funding from AbbVie, Janssen, Morphosys, and Schrodinger. Michelle Boyer is an employee of Genentech Inc. and may hold stock or options. Jeffrey Jones is an employee of Celgene. Received honoraria from Janssen and Acerta has taken an advisory role for Pharmacyclics LLC, an AbbVie Company, Janssen, AbbVie, Morphosys, and Gilead and received research funding from Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, Genentech, Gilead, and Acerta. Richard R. Furman provided consultancy for AbbVie, Alpine Immune Sciences, AstraZeneca, Beigene, Genentech, Ipsen, Janssen, Lilly, Pharmacyclics, Sanofi; has received research funding from Beigene, Janssen; has received speaker fees from Beigene and AstraZeneca. William Wierda received honoraria from Sanofi, Genentech/Roche, Pharmacyclics LLC, an AbbVie Company, Celgene, Gilead, GSK/Novartis, Genzyme, Merck, AbbVie, and Emergent; received research funding from GSK/Novartis, AbbVie, Genentech, Karyopharm, Pharmacyclics LLC, an AbbVie Company, Acerta, Gilead, Janssen, Emergent, Juno, and Kite; and taken an advisory role for Sanofi, Genentech/Roche, Pharmacyclics LLC, an AbbVie Company, Celgene, Gilead, GSK/Novartis, Genzyme, Merck, AbbVie, and Emergent. Jason Gotlib received honoraria from Incyte, Cogent Biosciences, and Blueprint Medicines; taken advisory role for Blueprint Medicines, Incyte, and Cogent Biosciences; received research funding from AbbVie (Inst), Blueprint Medicines (Inst), Incyte (Inst), CTI BioPharma Corp (Inst), Protagonist Therapeutics (Inst), BMS (Inst), Merck (Inst), and Telios (Inst); and received travel and accommodations expenses from Blueprint Medicines. Stephen J. Schuster received research funding from Celgene, Genentech/Roche, Incyte, Novartis, AbbVie, Adaptive Biotechnologies, DTRM, Juno Therapeutics, Merck, Pharmacyclics, TG Therapeutics; provided consultancy for Acerta, Beigene, Celgene, Genentech/Roche, Incyte, Janssen, Legend Biotech, Loxo, Morphosys, MustangBio, Nordic, Nanovector, Novartis, Regeneron; and served as an advisory board member for Regeneron and Caribou Biosciences. Relja Popovic, Emily L. Rossi, Sanjana Singh, Toshihiko Oki, Tanya S. Rosenberg, Chen Qian, Michael Moran, Zihuan Liu, Brenda Chyla are employees of AbbVie and may hold stock or options. Matthew S. Davids received grant support paid to his institution from Ascentage Pharma, MEI Pharma, Novartis; and received consulting fees from AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Eli Lilly, Janssen, Galapagos, Genentech, Genmab, MEI Pharma, Merck, Nuvalent, and Schrödinger. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time after approval in the US and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ then select “Home”. Figure S1: M14-032 trial enrollment scheme Table S1:. Demographic and baseline disease characteristics of all treated patents Table S2: Concordance table for pat ents with TP53 mutation Table S3: Summary of treatment-emergent adverse events and deaths during the study Figure S2: Patent disposition Figure S3: Summary of response rate for all treated pat ents (subgroup analysis) Figure S4: BTK mutations after venetoclax therapy by best responsea Figure S5: VAF of BCL-2 mutations at final visit by CLL progression status Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Woyach et al. (Wed,) studied this question.