BRAVE: A Phase 2 Trial Evaluating the Efficacy and Safety of Venetoclax in Combination with Bruton’s Tyrosine Kinase Inhibitors in Patients with First-Line Chronic Lymphocytic Leukemia

Background and Significance: Covalent Bruton tyrosine kinase inhibitors (cBTKis) are highly effective and generally well tolerated by patients (pts) with previously untreated chronic lymphocytic leukemia (CLL), but standard single-agent treatment (Tx) is unlikely to lead to deep remission, including undetectable minimal residual disease (uMRD), thus they are given as continuous Tx. Continuous Tx increases the risk for adverse events (AEs) and acquired resistance, and poses additional challenges (e.g. long-term adherence issues and ongoing financial toxicity). Emerging long-term data from the cBTKi pivotal trials demonstrated that only a minority of pts can remain on Tx long-term (e.g. 42% of pts were still on ibrutinib [Ibr] at 89-months follow-up [FU] in the RESONATE-2 trial, with 24% having discontinued due to an AE; Barr et al. Blood Adv 2022). Discontinuation rates are even higher in real-world retrospective studies (Huntington et al. Cancer Med 2024).

The B-cell lymphoma 2 inhibitor (BCL-2i) venetoclax (Ven), when given as fixed-duration Tx in combination with other agents, was shown to drive deep, durable responses with high rates of uMRD in both first-line (1L) and relapsed/refractory settings, offering pts the benefits of being off Tx. cBTKi plus a BCL-2i was shown to be synergistic preclinically; several Phase II and III trials demonstrated that this combination is highly effective and well tolerated for most pts with CLL. This raised the question of whether pts already on a cBTKi might benefit from the addition of a BCL-2i to deepen response and thereby facilitate discontinuation of both drugs for pts who achieve uMRD. Recently, an investigator-initiated Phase II study examining this strategy by adding Ven for pts already on Ibr demonstrated that 71% of pts were able to achieve uMRD and discontinue both drugs (Thompson et al. Leukemia 2023).

The BRAVE (cBTKi Responders to Achieve deep remission [or off-Tx periods] with VEn) study investigates whether adding Ven for pts with CLL on 1L cBTKi initiated with a treat-to-progression intent can achieve deep, durable remissions, thereby facilitating time-limited Tx.

Study Design and Methods: BRAVE (NCT06524375) is a Phase II, open-label, non-randomized, multicenter trial in the United States (US) to evaluate the proportion of pts who achieve uMRD4 (defined as <1 CLL cell per 10,000 by Next Generation Sequencing [clonoSEQ^R]) through the addition of Ven. Pts (aged ≥18 years) are eligible to enroll if they have received ≥6 months of a cBTKi (Ibr, acalabrutinib [Acala], or zanubrutinib [Zanu]) for 1L Tx of CLL and are on a stable dose with a partial response (PR) or complete response (CR), per International Workshop on CLL criteria. Other key inclusion criteria are an Eastern Cooperative Oncology Group performance status ≤2, and adequate organ function including creatinine clearance ≥30mL/min. Pts are excluded if they had a prior BCL2i, anti-CD20 monoclonal antibodies within the past month, uMRD on cBTKi, or transformation of CLL to aggressive non-Hodgkin lymphoma.

Pts will be enrolled into 1 of 3 cBTKi cohorts depending upon which drug they are receiving at study entry: Ibr, Acala or Zanu (which will continue on commercial supply). Ven (provided by the study) will then be added to the cBTKi for 12 cycles. Each cycle (C) is 28 days in length. Tx with Ven (administered orally) will begin on C1 Day (D) 1 with a 5-week ramp-up per US prescribing information; thereafter, Tx will continue at the target dose (400mg daily) for up to 11 additional cycles concurrent with the cBTKi. At the end of combination Tx (EOCT), defined as C12 D28, pts will enter a FU period for up to 1 year; if the patient has uMRD4 in the peripheral blood (PB), they will discontinue both Ven and the cBTKi. Pts with detectable MRD may continue the cBTKi as monotherapy, at investigator discretion.

The primary endpoint, uMRD4 in PB by clonoSEQ^R, will be assessed at EOCT. Secondary endpoints: objective response rate, CR/CR with incomplete recovery (CRi) rate, PR rate, progression-free survival, event-free survival, overall survival, duration of response, time to next Tx and safety, including rates of tumor lysis syndrome. Exploratory endpoints: MRD kinetics, association between genetic biomarkers and patient outcomes, pharmacokinetics of Ven and each of the 3 cBTKis, and biomarkers of resistance.

Approximately 100 pts are planned for enrollment at around 28 sites in the US. The study is actively recruiting.