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4400 A Novel Dual Covalent and Non-Covalent Next Generation Inhibitor of Bruton’s Tyrosine Kinase LP-168 in Patients with Relapsed/Refractory B Cell Non-Hodgkin Lymphoma: Safety and Efficacy Results from a Phase 1 Study

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, adult, Lymphomas, Clinical Research, B Cell lymphoma, Diseases, Lymphoid Malignancies, Study Population, Human
Monday, December 11, 2023, 6:00 PM-8:00 PM

Yuqin Song, MD1, Qingqing Cai, PhD2*, Ming Jiang3*, Keshu Zhou, MD4*, Lei Zhang, MD5*, Xiuhua Sun6*, Zhengming Jin, B.S.7*, Lanfang Li8*, Hongmei Jing9, Zhigang Peng, MD10*, Haiyan Yang11, Junyuan Qi, MD12*, Hui Zhou13*, Wei Yang, MD14*, Min Zhou15*, Chunyan Ji, md, phd16, Wei Xu17*, Kaiyang Ding18*, Li Yu19*, Zheng Wang20*, Nawei Liu20*, Yejiang Lou20*, Yue Shen, PhD20*, Yi Chen, PhD21*, Fenlai Tan20* and Jun Zhu22*

1Department of Lymphoma, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, BEIJING, China
2Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
3The State Key Laboratory of Pathogenesis and Prevention of Central Asian High Incidence Diseases, Urumqi, China
4Department of Hematology, Cancer Hospital Affiliated to Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
5Department of Oncology, The First Affiliated Hospital of Zhengzhou University&Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, China
6The Second Hospital of Dalian Medical University, Dalian, China
7Department of Hematology, Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation, the First Affiliated Hospital of Soochow University, Suzhou, China
8Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
9Peking University Third Hospital, Beijing, China
10Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
11Zhejiang Cancer Hospital, Hangzhou, China
12Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, Tianjin, China
13Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
14Shengjing Hospital of China Medical University, Shenyang, China
15Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
16Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
17Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
18Department of Hematology, The First Affiliated Hospital of University of Science and Technology of China, Anhui, China
19The Second Affiliated Hospital of Nanchang University, Nanchang, China
20Guangzhou Lupeng Pharmaceutical Co., Ltd., Guangzhou, China
21Newave Pharmaceutical Inc., Pleasanton, CA
22Department of Lymphoma, Peking University Cancer Hospital and Institute, BEIJING, China

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKis) have improved clinical outcomes and revolutionized the treatment landscape of several B cell Non-Hodgkin Lymphoma (B-NHL), including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). However, cBTKi intolerance and resistance remain the main causes of treatment failure. LP-168 is a highly selective, next-generation BTKi with high bioavailability and potency. It can act as a cBTKi which irreversibly inhibits wildtype BTK while can overcome the resistance of cBTKi by non-covalent binding and reversible inhibition of C481 mutated BTK. In this abstract are the results from a Phase 1 trial (NCT04993690) that evaluates the safety and efficacy of LP-168 monotherapy in Chinese patients with relapsed/refractory (R/R) B-NHL.

Methods: This multicenter Phase 1 study contains a “3+3” dose escalation part (Phase 1a) followed by a dose expansion part (Phase 1b). Subjects with R/R B-NHL are eligible to receive LP-168 once daily treatment until disease progression or unacceptable toxicity. This study was designed to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of LP-168. The efficacy assessment was based on Lugano 2014, 2018 International Workshop on CLL (iwCLL) and the 6th International Workshop for WM response criteria.

Results: Between 10 August 2021 and 31 May 2023, 68 subjects (33 MCL, 14 diffuse large B cell lymphoma [DLBCL], 15 marginal zone lymphoma [MZL], 3 CLL/SLL, 2 follicular lymphoma [FL] and 1 primary mediastinal large B cell lymphoma [PMBCL]) were enrolled. Cohorts of 100 mg (N=13) 150 mg (N=40) and 200 mg (N=15) taken QD were treated respectively. The median age was 59.2 (range, 32-79) years old; 22 (64.7%) were male. The median number of prior therapies was 2 (range, 1-10) and 25 (36.8%) subjects had received at least a cBTKi-containing regimen. The median follow-up was 4.5 (0.3-21.3) months with 46 subjects remaining on treatment.

No dose-limiting toxicities (DLTs) were observed during dose escalation from 100mg QD, 150mg QD to 200mg QD, and the maximum tolerated dose (MTD) was not reached. The most common treatment-emergent adverse events (TEAEs) occurring in ≥20% subjects included neutropenia, platelet count decreased and anemia, most of which were Grade 1 or 2 (as detailed in Table 1). ≥Grade 3 treatment related adverse events (TRAEs, including possibly related, probably related and definitely related) included neutropenia (7.4%), lung infection (2.9%), lymphopenia, leukocytosis, lymphocytosis and oral cavity infection (1.5% each). 9 (13.2%) subjects experienced Serious Adverse Event (SAE). Serious adverse reactions included lung infection, oral cavity infection and lymphocytosis. No major bleeding, hypertension, or atrial fibrillation was observed in this study. Dose reduction occurred in only 1 subject due to AE (immune-mediated pancreatitis, unlikely related). No TEAE led to drug discontinuation. 1 subject experienced Grade 5 lung infection (not related to LP-168). Of 60 efficacy-evaluable subjects, overall response rate (ORR) was 65.0%. In particular, ORR in R/R MCL (N=31) was 77.4% with a CR of 38.7%, non-GCB DLBCL (N=10) had an ORR of 70.0% with a CR of 40.0% and MZL (N=11) had an ORR of 72.7% with a CR of 9.1% (Figure 1). LP-168 steady state plasma exposure increases dose-dependently with limited accumulation at 100 to 200 mg. Plasma concentration peaks at approximately 2 to 3 hours at fasted state, the average terminal half-life was 15.1 hours, supporting once daily dosing.

Conclusion: The current results of the Phase 1 study showed that LP-168 was well tolerated at 100-200 mg QD with favorable PK profile and has demonstrated encouraging efficacy in multiple B-cell malignancies, including those who had progressed on prior cBTKi.

Disclosures: Shen: Guangzhou Lupeng Pharmaceutical Co: Current Employment. Chen: Newave Pharmaceutical Inc: Current Employment, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Newave Pharmaceutical Inc.

*signifies non-member of ASH