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3151 Olverembatinib (HQP1351) Overcomes Resistance/Intolerance to Asciminib and Ponatinib in Patients (pts) with Heavily Pretreated Chronic-Phase Chronic Myeloid Leukemia (CP‑CML): A 1.5-Year Follow-up Update with Comprehensive Exposure-Response (E-R) Analyses

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Clinical trials, Research, Adult, Clinical Research, CML, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies, Study Population, Human
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Elias Jabbour, MD1,2, Omer Jamy, MD3, Paul B. Koller, MD4, Vivian G. Oehler, MD5*, Maria R. Baer, MD6, Elza Lomaia, MD, PhD7*, Anthony M. Hunter, MD8, Olga Uspenskaya, MD9*, Svetlana Samarina, MD10*, Jorge E. Cortes, MD11, Sudipto Mukherjee, MD, PhD, MPH12, Dennis Dong Hwan Kim, MD, PhD13, Vera Zherebtsova, MD, PhD14*, Vasily Shuvaev, MD15*, Anna Turkina, MD16*, Igor Davydkin, MD, PhD17*, Huanshan Guo, MD18*, Zi Chen, MD, PhD19*, Hengbang Wang, PhD19*, Tommy Fu, PhD20*, Lixin Jiang, MD20*, Zhihong Yang, PhD20*, Cunlin Wang, MD, PhD20*, Dajun Yang, MD, PhD19,20,21*, Yifan Zhai, MD, PhD18,19,20 and Hagop Kantarjian, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
3O'Neal Comprehensive Cancer Center at University of Alabama at Birmingham, Birmingham, AL
4Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
5Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA
6University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
7Scientific and Advisory Department of Hemotherapy of Myeloproliferative Disorders, National Research Center for Hematology, Moscow, Russian Federation
8Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
9Leningrad Regional Clinical Hospital, St. Petersburg, Russian Federation
10Kirov Scientific Research Institute of Hematology and Blood Transfusion of the FMBA, Kirov, Russian Federation
11Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
12Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
13Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
14S.P. Botkin City Clinical Hospital, Moscow, Russian Federation
15Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russian Federation
16National Medical Research Center for Hematology, Moscow, Russian Federation
17Samara State Medical University, Samara, Russian Federation
18Guangzhou Healthquest Pharma Co., Ltd., Guangzhou, China
19Ascentage Pharma (Suzhou) Co., Ltd., Suzhou, China
20Ascentage Pharma Group Inc., Rockville, MD
21Department of Experimental Research, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

Introduction

New treatment options are needed for pts with CP-CML resistant/intolerant to third-generation (3G) TKI ponatinib and/or asciminib, a specifically targeting the ABL myristoyl pocket (STAMP) inhibitor. Olverembatinib is a well-tolerated TKI with potential to overcome resistance. This update presents efficacy and safety data from a phase 1b study of olverembatinib in pts with heavily pretreated CP-CML.

Methods

Adults with CP-CML previously treated with ≥2 TKIs and/or a STAMP inhibitor, adequate organ function, and no major molecular response (MMR) were eligible. Pts were randomly allocated to receive olverembatinib at doses of 30, 40, or 50 mg orally every other day (QOD) in 28-day cycles, with stratification based on T315I mutation status. Comprehensive E-R analyses were performed.

Results

As of July 28, 2024, 67 pts with CP-CML were enrolled; median (range) follow-up was 74.3 (0.1-217.1) weeks; median (range) age, 50 (21-80) years; and 38 (56.7%) were male. At baseline, 19 (28.4%) pts had the T315I mutation; 34 (50.7%) had cardiovascular comorbidities; and BCR::ABL1 IS levels were ≥10% in 49 (73.1%) pts, 1% to 10% in 13 (19.4%), and <1% in 4 (6%); data for 1 pt were missing. The median (range) time from CML diagnosis to first olverembatinib dose was 6.3 (0.4-24.0) years. A total of 21 (31.3%) and 34 (50.7%) pts had received 3 or ≥4 TKIs, respectively. In pts treated with ponatinib (n = 32; 47.8%), 23 (71.9%) were resistant; 8 (25%), intolerant; and 1 (3.1%), uncategorized. In pts treated with asciminib (n = 20; 29.9%), 15 (75%) had resistance; 4 (20%), intolerance; and 1 (5%), uncategorized; 12 pts with CP-CML were resistant to both ponatinib and asciminib. Among 66 dosed subjects, a total of 62 (93.9%) reported TEAEs of any grade, with 44 (66.7%) experiencing ≥G3 TEAEs and 30 (45.5%) serious TEAEs. In addition, 60 (90.9%) pts reported TRAEs of any grade, with 30 (45.5%) experiencing ≥G3 TRAEs and 11 (16.7%) SAEs; 4 (6.1%) pts discontinued olverembatinib due to TRAEs (none fatal). Common TRAEs (≥20%) were elevated CPK (37.9%), thrombocytopenia (24.2%), and increased ALT (22.7%). Common ≥G3 TRAEs (≥10% incidence) included thrombocytopenia (16.7%), neutropenia (13.6%), and elevated CPK (12.1%). Treatment-related SAEs occurring in ≥2 (3%) pts included anemia, febrile neutropenia, and increased troponin (in 2 pts each). There was no report of treatment-related SAEs associated with arterial occlusive events. After a median (range) treatment duration of 59.4 (0.1-190.6) weeks, 30 (45.5%) pts required dose reductions, 42 (63.6%) had dose interruptions, and 22 (33.3%) discontinued treatment. Reasons for discontinuation included intolerance (n = 6), disease progression (n = 3), and other factors (n = 13), such as noncompliance, withdrawal, lack of response, and/or switching to transplantation.

Thirty-five of 60 (58.3%) evaluable pts achieved CCyR and 29/64 (45.3%) MMR. The median (range) time to MMR was 91 (29-489) days. At 12 months, the MMR rate was 61.4% (27/44). Comparable response rates were observed regardless of T315I mutation status, with CCyR achieved by 66.7% of pts with the T315I mutation vs 54.8% without it, and MMR achieved by 50.0% vs 43.5%, respectively. MMR rates for pts treated with 2, 3, or ≥4 TKIs were 66.7%, 40.0%, and 40.6%, respectively. Of 28 cytogenetic response-evaluable pts with ponatinib-failed CP-CML, 15 (53.6%) achieved CCyR, including 12/23 (52.2%) with prior ponatinib resistance and 3/4 (75.0%) with intolerance. A total of 12/30 (40.0%) evaluable pts previously treated with ponatinib achieved MMR, including those with prior resistance (11/23 [47.8%]) or intolerance (1/6 [16.7%]). In evaluable pts with asciminib treatment failure, 37.5% (6/16) achieved CCyR and 30% (6/20) MMR, including those with prior resistance (4/13 [30.8%] in CCyR, 4/15 [26.7%] in MMR) or intolerance (1/2 [50.0%] in CCyR, 1/4 [25.0%] in MMR). CCyR and MMR rates in pts previously treated with both ponatinib and asciminib were 30% and 25%, respectively. The comprehensive E-R analyses show a positive exposure-efficacy correlation with no significant exposure-safety relationship for Grade 3+ TRAEs or TEAEs, serious TEAE, serious TRAEs, and neutropenia.

Conclusions

Olverembatinib was well tolerated and showed strong and durable antileukemic activity in pts with heavily pretreated CP-CML. The registrational study (POLARIS-2, NCT06423911) is recruiting.

Disclosures: Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Koller: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Oehler: Novartis: Consultancy; Terns Pharmaceuticals: Consultancy; Pfizer: Research Funding. Lomaia: Pfizer: Other: Travel, accommodation, and expenses, Speakers Bureau; Novartis: Other: Travel, accommodation, and expenses, Speakers Bureau; Fusion Pharma: Speakers Bureau. Hunter: GSK: Consultancy, Honoraria; PharmaEssentia: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Sobi​ (formerly CTI biopharma): Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Cogent Biosciences: Research Funding; Ascentage Pharma: Research Funding; Syntrix Biosystems: Research Funding; Novartis: Research Funding; PharmaEssentia: Research Funding. Cortes: Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Sun Pharma: Consultancy, Research Funding; Biopath Holdings: Consultancy, Research Funding; Takeda: Consultancy; Nerviano: Consultancy; Pfizer: Consultancy, Research Funding; Rigel: Consultancy. Kim: Ascentage: Consultancy; Paladin: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Other: Advisory board, Research Funding. Turkina: Novartis Pharma: Speakers Bureau; R-pharm: Speakers Bureau. Guo: Guangzhou Healthquest Pharma Co. Ltd.: Current Employment; Ascentage Pharma Goup International: Current holder of stock options in a privately-held company. Chen: Ascentage Pharma Group International: Current holder of stock options in a privately-held company; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment. Wang: Ascentage Pharma Group International: Current holder of stock options in a privately-held company; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment. Fu: Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Jiang: Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Yang: Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Wang: Ascentage Pharma Group Inc.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Yang: 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; Ascentage Pharma Group Inc.: Current Employment, Other: Leadership and fiduciary officer roles, Patents & Royalties. Zhai: Ascentage Pharma Group International: Current holder of stock options in a privately-held company; 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 Inc.: Current Employment, Other: Leadership role, Patents & Royalties.

*signifies non-member of ASH