Lisaftoclax (APG-2575) Demonstrates Activity and Safety When Given with Accelerated Ramp-up and then Combined with Acalabrutinib or Rituximab in Patients (pts) with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Including Those with Prior Exposure to Venetoclax

Introduction

BCL-2 inhibition with venetoclax (ven) was a major advance in CLL treatment, but the 5-week dose ramp-up to mitigate the risk of tumor lysis syndrome and drug-drug interactions (DDIs) challenge treatment optimization. Lisaftoclax is an investigational, oral BCL-2i with a short half-life, allowing it to be ramped-up on a daily schedule. We present updated results of a phase 1b/2 study of lisaftoclax alone or combined with acalabrutinib or rituximab in pts with treatment-naïve (TN; lisaftoclax-acalabrutinib arm), relapsed/refractory, or prior ven-treated CLL/SLL (NCT04215809).

Methods

Pts were treated with a rapid 4- to 6-day daily ramp-up of lisaftoclax from 20 mg to a target dose of 400, 600, or 800 mg, receiving daily oral lisaftoclax alone or, plus continuous acalabrutinib or 6 cycles of rituximab in 28-day cycles, starting on Cycle 1 Day 8 (C1D8) until disease progression, complete response by C24, or unacceptable toxicity. Intensive blood samples were collected for pharmacokinetic (PK) and exposure-response (E-R) analyses.

Results

From March 20, 2020, to June 27, 2024, 176 pts were enrolled: 46 in monotherapy and 39 and 91 in rituximab and acalabrutinib combination cohorts, respectively; 154/176 (87.5%) were R/R and 22/176 (12.5%) TN. The median (range) age was 63 (34-80) years; 67% were male; 25.6% had del(17p) and/or TP53 mutation; and 70.6% had unmutated IGHV. Median (range) duration of treatment with lisaftoclax was 16.5 (1-54; monotherapy), 24 (3-39; rituximab), and 27 (1-43; acalabrutinib) months. In R/R pts, the median (range) number of prior lines of therapy was 2 (1-15), and 14 (9%) pts had been treated with ven. Prior ven pts had a median (range) age of 65 (51-78); 79% were male; of evaluable pts, 50% had del(17p), 36% TP53 mut, 64% del(11q), 38% complex karyotype (≥ 3 abnormalities), and 92% unmutated IGHV; 57% were BTKi naïve; and the median (range) number of prior therapies was 3 (1-6). Incidence and severity of TEAEs were similar across cohorts. Common (>10%) any-grade TEAEs in all cohorts combined were neutropenia (59 [33.5%]), diarrhea (38 [21.6%]), anemia (27 [15.3%]), and thrombocytopenia (26 [14.8%]). Grade ≥ 3 TEAEs were neutropenia in 15 (32.6%), 10 (25.6%), and 22 (24%) pts and anemia in 10 (21.7%), 5 (12.8%), and 12 (13.2%) pts in monotherapy, rituximab, and acalabrutinib combination cohorts, respectively. Comprehensive E-R analyses indicated that lisaftoclax had similar systemic exposure as monotherapy or when combined with acalabrutinib or rituximab; lisaftoclax had no DDI when combined with acalabrutinib or rituximab.

No discontinuations were attributed to lisaftoclax TRAEs. Forty-four (95.7%) pts in monotherapy discontinued treatment. Most discontinuations were due to progressive disease (n = 41 [23.3%]) and 13 (7.4%), AEs; 9 (5.1%) pts withdrew consent; 7 (4%) achieved complete response or MRD negativity after ≥ 24 cycles; 5 (2.8%) died; and 18 (10.2%) discontinued for other reasons. Clinical (n = 2) and laboratory (n = 3) TLS was observed in 5 (2.8%) pts on lisaftoclax (by Howard/Cairo-Bishop criteria), with cases rapidly resolving to resume lisaftoclax safely.

ORR for lisaftoclax plus acalabrutinib in 87 pts was 96.6%, and the median DOR (95% CI, 23-NR) and median PFS (95% CI, 34-NR) were not reached. The 12- and 18-month PFS rates were 89% and 86%, respectively. Fourteen R/R CLL ven-exposed pts received lisaftoclax plus acalabrutinib, of whom 9 had progressed on ven, 3 relapsed after completing ven, and 2 discontinued due to ven intolerance. Median (range) duration of treatment was 16 (3-25) months. Safety profile was similar to that of other study cohorts. ORR was 85.7% (12/14), 100% (8/8), and 66.7% (4/6) in the ven-exposed, ven-exposed but BTKi-naïve, and ven- and BTKi-exposed pts, respectively. The median duration of response (DOR) and progression-free survival (PFS) were not reached. The 12- and 18-month PFS rates were 84% and 73%, respectively.

Conclusions

Our data suggest that lisaftoclax combined with acalabrutinib is effective for pts with prior ven exposure, including those with progression on ven. In this updated analysis with longer follow-up, no DDIs or new safety findings were observed in TN or R/R CLL/SLL pts treated with lisaftoclax monotherapy/combinations. We continue to accrue pts with prior ven exposure to further evaluate this promising signal. A global registrational phase 3 study GLORA (NCT06104566) is recruiting.

Davids:AbbVie: Consultancy, Research Funding; Merck: Consultancy; Surface Technology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Eli Lilly: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Janssen: Consultancy; BeiGene: Consultancy; Novartis: Research Funding; Adaptive Biosciences: Consultancy; BMS: Consultancy; MEI Pharma: Research Funding; AstraZeneca: Consultancy, Research Funding; Genmab: Consultancy; Genentech: Consultancy, Research Funding. Ailawadhi:Johnson and Johnson: Consultancy, Research Funding; Sanofi: Consultancy; GSK: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Ascentage: Research Funding; Regeneron: Consultancy; Cellectar: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Beigene: Consultancy; Xencor: Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Pharmacuclics: Consultancy, Research Funding. Chanan-Khan:Starton Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mudenda:Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Kryachok:AstraZeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Biopharma: Consultancy, Speakers Bureau; Bayer: Research Funding; MSD: Research Funding; GlaxoSmithKline: Research Funding; InnoCare Pharma: Research Funding; AcertaPharma: Research Funding; MorphoSys AG: Research Funding; CromosPharma: Research Funding; Pharmacyclics: Research Funding. Ivanov:MSD: Research Funding. Marlton:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Gilead: Other: Ad board; Abbvie: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Speakers Bureau. Winter:AstraZeneca: Consultancy; BeiGene: Consultancy; BTG Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy. Fu:Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Li:Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Ahmad:Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Chen:Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Liang:Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Mekala:Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Osipov:Novartis: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Biocad: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Dr.Reddy'S: Speakers Bureau; MSD: Speakers Bureau; GSK: Speakers Bureau. De:Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Wang:Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Yang:Ascentage Pharma Group Inc.: Current Employment, Other: Leadership and fiduciary officer roles, Patents & Royalties; Ascentage Pharma Group International: Current holder of stock options in a privately-held company, Other: Leadership and fiduciary officer roles; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Other: Leadership and fiduciary officer roles, Patents & Royalties. Zhai:Ascentage Pharma Group Inc.: Current Employment, Other: Leadership role, Patents & Royalties; Guangzhou Healthquest Pharma Co. Ltd.: Current Employment, Other: Leadership role, Patents & Royalties; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Other: Leadership role, Patents & Royalties; Ascentage Pharma Group International: Current holder of stock options in a privately-held company.