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4614 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

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphoid Leukemias, Combination therapy, Adult, CLL, Clinical Research, Drug-drug interactions, Diseases, Treatment Considerations, Lymphoid Malignancies, Study Population, Human
Monday, December 9, 2024, 6:00 PM-8:00 PM

Matthew S. Davids, MD, MMSc1, Sikander Ailawadhi, MD2, Asher A. Chanan-Khan, MD3, Boyd Mudenda, MD4*, Larysa Nogaieva, MD5*, Iryna Kryachok, MD6*, Ganna Usenko, MD7*, Vladimir Ivanov, MD8*, Olena Kyselova, MD, PhD9*, Tetiana Perekhrestenko, MD, PhD10*, Ivan Muzhychuk, MD11*, Alexander Myasnikov, MD12*, Les Lukavetsky, MD13*, Andrei Proydakov, MD14*, Olga Uspenskaya, MD15*, Elena Borisenkova, MD16*, Paula Marlton, MBBS17, Tanya Siddiqi, MD, MBBS18*, Allison M. Winter, MD19, Tamila Lysa, MD20*, Bulat Akhatovich Bakirov21*, Tommy Fu, PhD4*, Mingyu Li, PhD4*, Mohammad Ahmad, MD4*, Zi Chen, MD, PhD22*, Zhiyan Liang, PhD4*, Divya J. Mekala, PhD4*, Olena Karpenko, MD9*, Iurii Osipov, MD23*, Asit De, PhD4*, Hengbang Wang, PhD22*, Nashat Gabrail, MD24*, Vinod Ganju, MD25*, Tatiana Konstantinova, MD, PhD26*, Olga Samoilova, MD, PhD27*, Dajun Yang, MD, PhD4,22* and Yifan Zhai, MD, PhD4,22

1Department of Medical Oncology, Dana-Farber Cancer Institute, Inc., Boston, MA
2Mayo Clinic, Jacksonville, FL
3Division of Hematology-Oncology, Mayo Clinic-Florida, Jacksonville, FL
4Ascentage Pharma Group Inc., Rockville, MD
5Communal Nonprofit Enterprise, Clinical Center of Oncology, Hematology, Transplantology and Palliative Care of Сherkasy Oblast Council, Hematology and Bone Marrow Transplantation Division with Chemotherapy Rooms, Cherkasy, Ukraine
6Oncohematology, National Cancer Institute, Ukraine Hemoblastoses of Division of Conservative Methods of Treatment, Kyiv, Ukraine
7Dnipropetrovsk Regional Hematology Center, Dnipro, Ukraine
8Almazov National Medical Research Centre, Saint-Petersburg, Russian Federation
9Medical Center “Ok!Clinic+”, Kyiv, Ukraine
10Medical Center Named by Academician Yuriy Spizhenko (ARENSIA Exploratory Medicine Unit), Kyiv, Ukraine
11SI SP Grygoriev Institute of Radiology of the NAoMS of Ukraine, Kharkiv, Ukraine
12Republican Hospital n.a. V.A. Baranov, St. Petersburg, Russian Federation
13SI “Institute of Blood Pathology and Transfusion Medicine of NAoMS of Ukraine,” Hematology Department, Lviv, Ukraine
14State Institution Komi, Krasnozatonsky, Russian Federation
15Leningrad Regional Clinical Hospital, St. Petersburg, Russian Federation
16Kaluga Regional Clinical Hospital, Kaluga, Russian Federation
17Princess Alexandria Hospital and University of Queensland, Brisbane, Australia
18City of Hope National Medical Center, Duarte, CA
19Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
20Regional Clinical Hospital n. a. O. F. Herbachevskyi, Zhytomyr, Ukraine
21Bashkir State Medical University, Ufa, Russian Federation
22Ascentage Pharma (Suzhou) Co., Ltd., Suzhou, China
23Almazov National Medical Research Center, St. Petersburg, Russian Federation
24Gabrail Cancer Center, Canton, OH
25PASO Medical, Frankston, Australia
26Regional Clinical Hospital No 1, Ekaterinburg, Russian Federation
27Nizhny Novgorod Regional Clinical Hospital named after N A Semashko, Nizhniy Novgorod, Russian Federation

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.

Disclosures: 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: BTG Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; BeiGene: 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.

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