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3033 Safety and Efficacy Results from the Phase I Study of a Novel Dual Covalent and Non-Covalent Next Generation Inhibitor of Bruton’s Tyrosine Kinase LP-168 in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, adult, Lymphomas, Clinical Research, B Cell lymphoma, Diseases, Lymphoid Malignancies, Study Population, Human
Sunday, December 10, 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, 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: Relapsed/Refractory (R/R) mantle cell Lymphoma (MCL) has poor long-term survival compared with other B-cell malignancies. As a result, there is an urgent need for safe and effective treatments, particularly for patients who have progressed on covalent (c) Bruton tyrosine kinase inhibitors (BTKis) therapy. LP-168 is a highly selective, next-generation BTKi with a unique dual binding mode: covalent binding to wild-type BTK and reversible binding to mutated BTK. Pre-clinical data has demonstrated that LP-168 is highly potent in inhibiting C481 mutated BTK. Here, we report the safety and efficacy of LP-168 monotherapy in the R/R MCL patients as part of an ongoing phase 1 study (NCT04993690) in B-cell malignancies.

Methods: This is a Phase 1 first-in-human multicenter open-label study of LP-168 enrolling Chinese patients with B cell Non-Hodgkin Lymphoma (NHL) who have progressed after at least 1 or 2 prior treatments. The study has two parts: Phase 1a: "3+3" dose escalation and Phase 1b: dose expansion in disease-specific cohorts (e.g. R/R MCL, R/R MZL, etc.).

Results: Between 10 August 2021 and 31 May 2023, 33 R/R MCL patients who received at least one dose were enrolled and received LP-168 100mg (n=8), 150mg (n=24), and 200mg (n=1) QD, respectively. Baseline characteristics are summarized in Table 1. The median age was 58 (range, 32-79) years old; 27 (81.8%) were male. 15 (45.5%) subjects had intermediate to high risk disease per MCL International Prognostic Index (MIPI). Median lines of prior therapies were 2 (range, 1-11) with 24.2% refractory to the last prior treatment. All patients have received rituximab or a rituximab-containing regimen. 19 (57.6%) subjects have received at least a cBTKi or cBTKi-containing regimen.

The most common treatment emergent adverse events (TEAEs) (occurring in ≥20% subjects) were platelet count decreased (30.3%), neutropenia and anemia (27.3% each) and COVID-19 (24.2%), most of which were Grade 1. Grade 3 or more TEAEs were seen in 9 (27.3%) subjects. Serious AE (SAE) (lung infection, oral cavity infection and lymphocytosis, all Grade 3) occurred in 3 (9.1%) subjects. Dose interruptions due to AE occurred in 7 patients (21.2%),but no AE has led to dose adjustment, drug discontinuation or death.

Of 31 efficacy evaluable subjects with median follow up of 5.5 months (range: 2.0-22.5), 24 (77.4%) achieved response including 12 (38.7%) complete metabolic response or complete response (CMR/CR). In addition, 5 (71.4%) out of 7 subjects with blastoid/ pleomorphic variant MCL achieved response (2 CMR/CR, 3 PMR/PR). More importantly, of 17 subjects who had prior cBTKi exposure, 12 (70.6%) responded to LP-168 and 6 (35.3%) achieved CMR. LP-168 also showed efficacy in 2 subjects who have received ≥ 2 cBTKi treatments. Another 2 subjects responded to LP-168 even after disease progression on a cBTKi and a BTK degrader. 5 subjects have achieved progression-free survival (PFS) more than 1 year and are still on treatment (Figure 1).

Conclusion: In this Phase 1 trial, the novel BTK inhibitor LP-168 demonstrated a high CR rate and durable response in heavily pre-treated R/R MCL including blastoid/pleomorphic variant with favorable safety. Moreover, LP-168 could effectively overcome the acquired resistance to prior cBTKi. Based on the safety, PK and preliminary efficacy data from the Phase 1 study so far, we have determined the recommended phase 2 dose (RP2D) for MCL as 150 mg QD. A phase 2 trial of LP-168 in R/R MCL is currently ongoing (NCT05716087).

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