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3598 Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant BCR-ABL1T315I-Mutated Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP)

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research, Diseases, Lymphoid Malignancies
Monday, December 13, 2021, 6:00 PM-8:00 PM

Jiang Qian, MD1, Dayu Shi2*, Zongru Li2*, Yue Hou3*, Yu Hu4*, Weiming Li5*, Xiaoli Liu6*, Na Xu6*, Yongping Song7*, Gongli Zhang8*, Li Meng9*, Zhenya Hong9*, Bingcheng Liu10*, Yan Li11*, Suning Chen12*, Mengxing Xue13*, Huanling Zhu14*, He Li14*, Xin Du15*, Jin Lou16*, Xiaohan Zhang16*, Yang Liang, MD, PhD17, Yujun Dai, MD, PhD18*, Zi Chen19*, Qian Niu19*, Lichuang Men19*, Dajun Yang20,21*, Yifan Zhai19,22 and Xiaojun Huang23

1Peking University Institute of Hematology, Peking University People's Hospital, Beijing, Beijing, China
2Peking University Institute of Hematology, Peking University People’s Hospital, Beijing, China
3Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China
4Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
5Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
6Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
7Department Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
8Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
9Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
10Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
11Institute of Hematology and Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Tianjin, China
12National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
13Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
14Department of Hematology, West China Hospital of Sichuan University, Chengdu, China
15Division of Hematology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, CA, China
16Division of Hematology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
17Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
18Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Shanghai, China
19Guangzhou Healthquest Pharma Co. Ltd., Guangzhou, China
20Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
21Ascentage Pharma (Suzhou) Co., Ltd., Suzhou, China
22Ascentage Pharma Group Inc., Rockville, MD
23Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing China, Beijing, China

Background: Management of CML with TKIs is constrained by treatment resistance, which portends a poor prognosis particularly in pts failing 2nd-generation TKIs. Cells with BCR-ABL1T315I mutations are insensitive to 1st- and 2nd -generation TKIs, and compound BCR-ABL1 mutations complicate management with all TKIs (including 3rd-generation ponatinib). Olverembatinib is a novel, potent, 3rd-generation, orally active BCR-ABL1 TKI with promising activity against CML , largely irrespective of genotype and has a preliminary favorable safety profile.

Methods: HQP1351-CC201 and HQP1351-CC202 are Chinese open, single-arm, multicenter phase 2 trials evaluating the safety and efficacy of olverembatinib in adults with TKI-resistant (BCR-ABL1T351-mutated) CML-CP and CML-CP, respectively. Olverembatinib was administered at 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response (MaHR) by the end of Cycle 12 in CML-CP and CML-AP, respectively. Secondary study endpoints include : complete CyR (CCyR), complete hematologic response (CHR), major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety, including treatment-related adverse events (TRAEs) and serious AEs (SAEs).

Results:

Baseline characteristics

Study CC201(CML-CP

On the study cutoff date of August 25,2020, 41 pts were enrolled, of whom 32 (78%) completed ≥ 12 cycles and 21 (51.2%) were male. The median (range) follow-up was 13 (3.1-16.3) months, age was 47 (22-70) years, and interval from CML diagnosis to first olverembatinib dose was 5.31 (0.6-23.2) years. In all, 32 (78.1%) pts had received ≥ 2 prior TKIs and 9 pts withdrew because of progressive disease (PD), intolerance, or consent withdrawal before Cycle 12.

Study CC202(CML-AP

On the cut-off date of July 27, 2020, 23 pts were enrolled, of whom 14 (61%) had completed ≥ 12 cycles and 18 (78.3%) were male. The median (range) follow-up was 13.5 (1.4-15.2) months, age was 41 (21-74) years, and interval from CML diagnosis to first olverembatinib dose was 4.96 (0.4-10.2) years. In all, 18 (78.3%) pts had received ≥ 2 prior TKIs, and 11 pts withdrew because of PD or intolerance before Cycle 12.

Efficacy

Study CC201(CML-CP

After ≥ 12 treatment cycles in pts without responses at baseline, all 31 (100%) experienced CHR (10 other pts had CHR at baseline); 31/41 (75.6%) MCyR; 28/41 (68.3%) CCyR; and 23/41 (56.1%) MMR (Figure 1). The median time to CHR was 1 (95% CI = 1.0-1.9) month, the median time to MCyR was 2.8 (95% CI = 2.8-5.6) months, and the median time to MMR was 6.5 (95% CI = 2.8 to not reached [NR]) months. At 12 months, the PFS rate was 89.3% (95% CI = 73.9%-95.8%), and the OS was 100% (95% CI = 100%-100%).

Study CC202(CML-AP

After ≥ 12 treatment cycles in pts without responses at baseline, 17/23 (73.9%) experienced MaHR (65.2% CHR and 8.7% no evidence of leukemia [NEL]); 12/23 (52.2%) MCyR; 11/23 (47.8%) CCyR; and 9/23 (39.1%) MMR (Figure 1). The median time to MaHR was 2.8 (95% CI = 1.0-4.7) months, the median time to MCyR was 5.6 (95% CI = 2.00-NR) months, and the median time to MMR was 13.1 (95% CI = 5.6-NR) months. At 12 months, the PFS rate was 74.1% (95% CI = 48.2%-88.4%), and the OS was 91.3% (95% CI = 69.5%-97.8%).

Safety

Study CC201(CML-CP

Frequent TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (70.7%; 48.8%; 7.3%), followed by anemia (61%; 26.8%; 2.4%), leukopenia (43.9%; 17.1%; 0), and neutropenia (36.6%; 19.5%; 0). Common nonhematologic TRAEs (all grades; G3-4) included skin pigmentation (56.1%, 0%) and elevations in creatine kinase (51.2%, 14.6%), ALT (39%, 2.4%) and AST (34.1%, 0) (Table 1). No deaths occurred.

Study CC202(CML-AP

Common TRAEs (all grades; G3-4; SAEs) included thrombocytopenia (73.9%; 56.5%; 17.4%), anemia (60.9%; 34.8%; 13.0%), leukopenia (56.5%; 30.4%; 0), and neutropenia (26.1%; 21.7%; 0). Common nonhematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (47.8%), hypertriglyceridemia (56.5%), hyperphosphatemia (47.8%), hyperuricemia (21.7%), and arthralgia (34.8%), of which most were grade 1-2 (Table 2).

Conclusions: Olverembatinib was efficacious and well tolerated when administered as monotherapy in pts with TKI-resistant CP-CML and AP-CML and the BCR-ABL1T315I mutation. Internal study identifiers: HQP1351-CC201-CC202. ClinicalTrials.gov identifiers: NCT03883087 and NCT03883100.

Disclosures: Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

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