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1320 Updated Results from the Phase II Study of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia

Program: Oral and Poster Abstracts
Session: 642. CLL: Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Leukemia, Biological, Diseases, CLL, Therapies, B-Cell Lymphoma, Lymphoid Malignancies, TKI
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Wei Xu, MD, PhD1, Yongping Song, MD2*, Tingyu Wang3*, Shenmiao Yang4*, Lihong Liu, MD5*, Yu Hu, MD6*, Wei Zhang7*, Jianfeng Zhou, MD, PhD8*, Sujun Gao9*, Kaiyang Ding10*, Huilai Zhang, MD, PhD11*, Zunmin Zhu, MD12*, Shun-Qing Wang13*, Bing Xu, MD, PhD14*, Jianda Hu15*, Ting Liu, MD, PhD16, Chunyan Ji, MD17*, Zhongjun Xia, MD, PhD18, Yan Li, PhD, MD19*, Xin Wang, MD, PhD20, Huaqiang Zhu, MD21*, Renbin Zhao, PhD21*, Bin Zhang, PhD21*, Zhixin Xu, MD, PhD21* and Jianyong Li, MD, PhD1

1Department of Hematology, Pukou CLL Center, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, China
2Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
3National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Blood Diseases Hospital & Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
4Hematology, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, CHN
5The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
6Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
7Peking Union Medical College Hospital, Beijing, Beijing, CHN
8Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
9Jilin University First Hospital, Changchun, China
10The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
11Department of Lymphoma, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
12Hematology, Henan Provincial People's Hospital, Zhengzhou, CHN
13Guangzhou First People's Hospital, Guangzhou, CHN
14Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China
15Department of Hematology, Fujian Medical University Union Hospital, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fuzhou, Fu, CHN
16Department of Hematology, West China Hospital of Sichuan University, Chengdu, China
17Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
18Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
19Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang City, China
20Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
21Beijing InnoCare Pharma Tech Co., Ltd, Beijing, China

Orelabrutinib (ICP-022) is a novel and highly selective irreversible BTK inhibitor. We previously reported that orelabrutinib had high bioavailability with ~100% BTK occupancy at 24 hours at 150 mg daily dosing regimen and demonstrated excellent safety and efficacy profiles at median follow-up of 8.7 months in a Phase I/II trial of refractory/relapsed (r/r) CLL/SLL (Chronic Lymphocytic Leukemia/Small Cell Leukemia). Here we present an updated analysis of efficacy and safety results from the clinical study of Orelabrutinib in Chinese patients with r/r CLL/SLL following extended treatment. This is an open-label, multicenter, phase II study with objectives to evaluate its safety and efficacy following an oral daily administration. The primary endpoint was objective response rate (ORR). The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints. Response was assessed per 2008 IWCLL criteria with modification for partial remission (PR) with lymphocytosis (PR-L) (Hallek 2012) or the Lugano Classification (Cheson, 2014) for CLL and SLL, respectively.

Results: A total of 80 patients with r/r CLL (n=70)/SLL (n=10) were enrolled. Eligible patients had relapsed after or were refractory to ≥1 prior treatment with median age of 60.0 (range, 36.0-78.0 years). There are 70% of patients for Rai stage 3-4 disease, 22.5% for 17p13.1 deletion [del(17p)] and/or TP53 mutation, 41.3% for unmutated immunoglobulin heavy chain variable region (IGHV) and 23.8% for 11q22.3 deletion [del(11q)]. The median follow-up time was 14.3 months (range, 0.2-21.6 months), and the last patient completed a minimum of 12 cycles of orelabrutinib treatment.

Efficacy: The efficacy results presented here were evaluated by IRC (Independent review committee). Following a minimum of 12 cycles treatment, the ORR (PR-L or above) was 91.3% (95% confidence interval [CI]: 82.80~96.41%) with 10.0% of patients having complete response (CR), 63.8% PR and 17.5% PR-L. Median time for achieving first response was 1.87 months (range, 1.84 - 1.94 months). The median DOR and PFS were not reached. The estimated 12-month DOR was 77.1% (95% CI: 62.50-86.60%), PFS 81.1% (95% CI: 70.53 - 88.13%) and OS 86.3% (95% CI: 76.55 - 92.14%). Patients with Del(17p) and/or TP53 mutation achieved 100% ORR. The ORR is 94.7% for Del(11q)) and 93.9% for unmutated IGHV. Comparing to the first analysis results of which the median follow-up was 8.7 months, the CR rate had increased from 3.8% to 10.0%, and 8 patients with PR-L had converted to a deeper response. So, orelabrutinib showed a significant higher CR rate comparing to other BTK inhibitors at a similar treatment period and we anticipate a further increase of CR rate with longer duration of treatment.

Safety: Most adverse events (AEs) were mild to moderate, similar to the first reported safety profiles at median follow-up of 8.7 months. Extended follow-up analysis did not reveal new safety nor toxicity concerns. The most frequent adverse events (AEs) of any cause/any grade were well characterized as hematological toxicities: thrombocytopenia, neutropenia, and anemia; upper respiratory tract infection, pneumonia and hypokalemia. No case of atrial fibrillation nor secondary malignancy was reported, no patient was observed for ≥3 hypertension and only one patient had ≥3 grade diarrhea. Major hemorrhage was reported in 2 patients, one with intracranial hemorrhage (65-year-old male patient with more than 10 years hypertension) and the other with vitreous hemorrhage which were resulted from posterior vitreous detachment that was assessed as unlikely related to the treatment of orelabrutinib. Once again, it has been further confirmed that orelabrutinib has excellent safety profiles following extended treatment.

Conclusion: This updated and extended study further confirms that orelabrutinib is efficacious in treating r/r CLL patients with a higher CR rate, durable response and improved safety profiles. As a highly selective BTK inhibitor with favorable pharmacokinetic and pharmacodynamic properties, orelabrutinib provides a favorable therapeutic choice for patients with r/r CLL/SLL and a potential best candidate for combination therapy.

Disclosures: Zhu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhang: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

*signifies non-member of ASH