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83 Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP) with T315I Mutation

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Novel Agents
Hematology Disease Topics & Pathways:
CML, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Saturday, December 10, 2022: 10:30 AM

Qian Jiang1*, Zongru Li2*, Yue Hou3*, Yu Hu4*, Weiming Li4*, Xiaoli Liu5*, Na Xu5*, Yanli Zhang6*, Yongping Song6*, Li Meng7*, Zhenya Hong7*, Bingcheng Liu8*, Yan Li9*, Suning Chen10*, Mengxing Xue11*, Huanling Zhu12*, He Li12*, Xin Du13*, Jin Lou13*, Xiaohan Zhang13*, Yang Liang, MD, PhD14, Yu-Jun Dai14*, Zi Chen15*, Qian Niu15*, Lichuang Men15*, Dajun Yang15,16*, Yifan Zhai16,17 and Xiao-Jun Huang3*

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
4Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
5Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
6Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
7Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
8Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
9Institute of Hematology and Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Tianjin, China
10National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
11Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
12Department of Hematology, West China Hospital of Sichuan University, Chengdu, China
13Division of Hematology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
14Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
15Guangzhou Healthquest Pharma Co. Ltd., Guangzhou, China
16Ascentage Pharma Group Inc., Rockville, MD
17Healthquest Pharma Co. Ltd., Guangzhou, China

Background

BCR-ABL1 T315I, “gatekeeper,” mutation can confer a high degree of resistance to many first- and second-generation TKIs. Olverembatinib is a novel, orally active, third-generation BCR-ABL1 TKI with promising efficacy and a preliminary favorable safety profile for the treatment of patients with CML. These phase 2 trials, HQP1351-CC-201 (NCT03883087) and
HQP1351-CC-202 (NCT03883100), were conducted based on favorable phase 1 trial results.

Methods

These open-label, single-arm, multicenter pivotal trials evaluated the efficacy and safety of olverembatinib in Chinese pts with CML-CP (HQP1351-CC-201) or CML-AP
(HQP1351-CC-202) with the T315I mutation. Olverembatinib was administered at 40 mg orally on alternate days (QOD) for 28-day cycles. Primary endpoints were major cytogenetic response (MCyR) in pts with CML-CP and major hematologic response (MaHR) in those with CML-AP by the end of Cycle 12. Secondary study endpoints included 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

HQP1351-CC-201

As of the cutoff date of April 30,2022, 41 pts were enrolled, of whom 21 (51.2%) were male, with a median (range) age of 47 (22-70) years. The median (range) interval from CML diagnosis to first olverembatinib dose was 5.31 (0.6-23.2) years, and 32 (78.1%) pts had received ≥ 2 prior TKIs. The median (range) treatment duration was 32.7 (3.1-36.7) months. All pts, 31/31 (100%), achieved CHR (10 others had CHR at baseline), 34/41 (82.9%) MCyR, 29/41 (70.7%) CCyR, and 24/41 (58.5%) MMR (Figure 1). Median time to CHR was 1 (95% CI: 1.0-1.9) month, median time to MCyR was 2.8 (95% CI: 2.8-5.6) months, and median time to MMR was 6.5 (95% CI: 2.8 to not reached [NR]) months. At 36 months, the PFS rate was 86.3% (95% CI: 70.2%-94.1%) and the OS rate was 95.1% (95% CI: 81.9%-98.8%) (Figure 2). A total of 5 pts withdrew because of progressive disease (PD), 4 intolerance, 3 consent withdrawal, and 2 for other reasons. Frequent TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (70.7%; 48.8%; 7.3%), anemia (70.7%; 31.7%; 2.4%), leukopenia (51.2%; 14.6%; 0), and neutropenia (41.4%; 21.9%; 0). Common nonhematologic TRAEs (all grades; grade 3-4) included skin pigmentation (56.1%; 0%) and elevations in creatine kinase (56.1%; 19.5%), ALT (43.9%; 2.4%) and AST (36.6%; 0) levels (Table 1).

HQP1351-CC-202

As of the cutoff date of April 30,2022, 23 pts were enrolled, of whom 18 (78.3%) were male, with a median (range) age of 41 (21-74) years. The median (range) interval from CML diagnosis to first olverembatinib dose was 4.96 (0.4-10.2) years, and 19 (82.6%) pts had received ≥ 2 prior TKIs. The median (range) treatment duration was 19.7 (1.4-36.4) months. A total of 18 (78.3%) patients experienced MaHR (73.9% CHR and 4.4% no evidence of leukemia [NEL]); 12 (52.2%) MCyR; 12 (52.2%) CCyR; and 11 (47.8%) MMR (Figure 1). Median time to MaHR was 2.8 (95% CI: 1.0-4.7) months, median time to MCyR was 5.6 (95% CI: 2.00-NR) months, and median time to MMR was 13.1 (95% CI: 5.6-22.4) months. At 36 months, the PFS rate was 57.1% (95% CI: 33.3%-75.1%) and the OS rate was 69.6% (95% CI: 46.6%-84.2%) (Figure 3). Six pts withdrew because of progressive disease (PD), 4 intolerance, and 1 for other reasons; two pts died. Common TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (78.3%; 56.5%; 17.4%), anemia (69.6%; 34.8%; 13.0%), leukopenia (56.5%; 30.4%; 0), and neutropenia (26.1%; 26.1%; 0). Common nonhematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (56.5%), hypertriglyceridemia (60.9%), hyperphosphatemia (47.8%), hyperuricemia (26.1%), and arthralgia (34.8%), of which most were grade 1-2 (Table 2).

Conclusions

Olverembatinib was efficacious and well tolerated in pts with TKI-resistant
CML-CP and CML-AP with the BCR-ABL1 T315I mutation. Based on the results of these pivotal trials, the Chinese health authority granted conditional approval for olverembatinib on November 24, 2021.

Disclosures: Jiang: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Chen: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company, Other: Leadership, Patents & Royalties. Zhai: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company, Other: Leadership, Patents & Royalties.

*signifies non-member of ASH