Results of a registrational Phase 2 study of lisaftoclax monotherapy for treatment of patients (pts) with Relapsed/Refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who had failed Bruton's tyrosine kinase inhibitors (BTKis)

Abstract Introduction BCL-2 inhibitors play an important role in the treatment of CLL/SLL. Although venetoclax monotherapy is approved (ex-China) to treat pts with CLL/SLL who have a 17p deletion [del(17p)] (Davids MS et al, Clin Lym Mye Leuk. 2017), there is no effective treatment available for pts with CLL/SLL that has failed prior BTKi therapies, especially those who previously received CD20-based immunochemotherapy (ICT) or had high-risk (HR) factors. This issue remains a highly unmet medical need in China. Methods In this pivotal phase 2 study (APG2575CC201; NCT05147467), eligible pts with R/R CLL/SLL met dual criteria: (A) documented progression on ≥ 1 prior BTKi, and (B) either previous ICT failure or had HR factors (e.g., del(17p)/TP53 mutation, unmutated IGHV, chromosomal complex karyotype [CK]). Pts were treated with daily oral doses of lisaftoclax (a novel investigational BCL-2 inhibitor) using a rapid 5-day ramp-up from 20 to 600 mg (target dose), in repeated 28-day cycles, until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Efficacy was assessed by the investigators and by an independent review committee (IRC) based on hematology, imaging examinations, and bone marrow (BM) examinations, in accordance with the NCI-WG-CLL criteria and the 2014 Lugano criteria for NHL, including complete response (CR), CR with incomplete marrow recovery (CRi), and partial response (PR). Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS), minimal residual disease (MRD), and adverse events (AEs). Results As of July 25, 2025, 77 pts had been enrolled, and the last enrolled pt completed ≥18 cycles of treatment. The median follow-up was 22.01 months (mo.); median age was 63 years; 59.7% were male; and 31.2% had an ECOG PS of 2. Sixty-eight pts (88.3%) were diagnosed with CLL, 66 (85.7%) had Binet stage B/C, and 45 (58.4%) had Rai stage II-IV. Nine pts (11.7%) had SLL with Rai stage III/IV. Thirty-five pts (45.5%) had disease that had relapsed or was refractory or intolerant to both BTKis and ICT. The remaining 42 pts (54.5%) disease that had previously failed on BTKis and had HR factors. Thirty pts (39.0%) had del(17p) and/or TP53 mutations; 33 (42.9%) had CK; 21 (27.3%) had high CK (abnormal chromosome number ≥ 5); and 41 (53.2%) had unmutated IGHV. Among the 33 pts with CK, 21 cases (63.6%) also had del(17p) or TP53 mutation. Among 72 evaluable pts, the ORR was 62.5% (per IRC), and 58.3% (per investigators). The median PFS (mPFS) was 23.89 mo.; median time-to-response (TTR) was 3.68 mo.; and median DOR was 18.53 mo. Median OS was not reached. Almost all pts were resistant to prior BTKis (and not BTKi intolerant); 14 (18.2%) pts experienced rotation between different BTKis, and only 5 achieved PR. Univariate analysis showed that mPFS of pts with del(17p)/TP53 mutation plus CK was 11.2 months vs 29.6 months in pts without del(17p)/TP53 mutation or CK. In pts with high CK versus those without high CK, the mPFS was 12.9 months vs 29.6 months, respectively. These two groups accounted for nearly 30% of the total population, which is much higher than observed in historical studies and represents true BTKi failure and a pt population with very HR refractory disease. In 55 MRD-evaluable pts, 12 cases (21.8%) were MRD-negative. Of 11 evaluable cases with BM MRD, 6 (54.5%) were MRD-negative. In 11 cases where peripheral blood and BM MRD could be evaluated, 6 cases (54.5%) were MRD-negative. Of note, because study enrollment occurred during the COVID-19 epidemic, many pts were unable to adhere to treatment and achieve satisfactory efficacy due to COVID-19 infections. Fifty-five (74%) pts experienced grade ≥ 3 TEAEs during treatment; frequent TEAEs (≥ 10%) included decreased neutrophil (28.6%) and platelet (23.4%) counts; anemia (15.6%), and infectious pneumonia (11.7%). Forty (53.2%) pts experienced grade ≥ 3 AEs related to the study drug (TRAEs), including decreased neutrophil (27.3%), decreased platelet (16.9%), and white blood cell (7.8%) counts; anemia (9.1%), and infectious pneumonitis (3.9%). No tumor lysis syndrome was reported, and no lisaftoclax-related deaths occurred. Conclusion In this study, we show that lisaftoclax monotherapy achieved significant ORR and long-lasting PFS with an acceptable safety profile in pts with heavily-treated R/R CLL/SLL refractory to BTKis.