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Ref Type Abstract
Authors Hongyun Zhao, Jianhua Chen, Zhengbo Song, Yanqiu Zhao, Yubiao Guo, Gang Wu, Yuxiang Ma, Wenwei Zhou, Xiaoqing Yu, Fangfang Gao, Yugang Dong, Ruiguang Zhang, Chen Yang, Xiaohong Tian, Hengbang Wang, Yanhua Tu, Juan Yu, Xuemei Sun, Li Zhang, Yifan Zhai
Title First-in-human phase I results of APG-2449, a novel FAK and third-generation ALK/ ROS1 tyrosine kinase inhibitor (TKI), in patients (pts) with second-generation TKI-resistant ALK/ROS1+ non–small cell lung cancer (NSCLC) or mesothelioma.
Abstract Text Background: Investigational agent APG-2449 is a novel, orally active FAK inhibitor and a third-generation ALK/ROS1 TKI that has shown potent activity against a range of ALK-resistant mutations, including G1202R, L1196M, V1180L, E1210K, S1206F, G1269A, F1174L, I1171S, and C1156Y in preclinical NSCLC, mesothelioma, and other solid tumor models. Methods: This dose escalation and dose expansion study evaluated APG-2449 in patients with second-generation TKI-resistant ALK/ROS1+ NSCLC or mesothelioma. APG-2449 was administered orally once daily at the assigned doses on a 28-day cycle using a “3+3” dose escalation design under fasted/fed conditions. Study aims were to assess safety/tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of the data cutoff date of December 30, 2021, 84 pts (median age 52 [range 21-78] years; 42% female) with NSCLC or mesothelioma enrolled were treated with APG-2449 at doses ranging from 150 to 1,500 mg. PK analyses indicated an approximately dose-proportional increase in plasma exposure under fed conditions across dose levels tested. Cerebrospinal fluid PK analyses showed that APG-2449 was brain-penetrant. Low-fat meals increased APG-2449 Cmax and AUC by approximately 40% to 80% compared to fasting conditions. Based on PK, biomarker, efficacy, and safety results, the RP2D was determined to be 1,200 mg. Four partial responses (PRs) were observed in 14 ALK+ pts resistant to second-generation TKIs treated at the RP2D. Another pt with the G1202R mutation following alectinib treatment had tumor shrinkage of 27.9%. Among 8 pts with brain metastases, 1 complete response and 3 PRs were observed intracranially. In 10 TKI-naïve pts, the overall response rate was 80% (ALK+, 6/8; ROS1+, 2/2) and the disease control rate (DCR) was 100%. Preliminary biomarker data showed decreased FAK phosphorylation in peripheral blood mononuclear cells and increased IFN-γ levels in serum after multiple doses of APG-2449. No dose-limiting toxicity was observed. A total of 66 (78.6%) pts experienced treatment-related adverse events (TRAEs). The most frequent TRAEs included elevated blood creatinine (33.3%), ALT (25.0%), and AST (19.0%) levels and gastrointestinal disorders: nausea (22.6%), vomiting (17.9%), and diarrhea (13.1%). Only 6 (7.1%) TRAEs were grade ≥ 3. Conclusions: APG-2449 has a favorable safety and PK profile and was well tolerated in 84 subjects. Preliminary efficacy was observed in pts whose disease was resistant to second-generation TKIs, especially among those with brain metastases, and in TKI-naïve pts. Biomarker data indicated potential target engagement on FAK and immunomodulatory effects of APG-2449. Clinical trial information: NCT03917043.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK fusion lung non-small cell carcinoma predicted - sensitive APG-2449 Phase I Actionable In a Phase I trial, APG-2449 treatment was well tolerated and resulted in preliminary efficacy with 4 partial responses among 14 patients with non-small cell lung cancer harboring an ALK fusion who previously progressed on a second-generation ALK inhibitor, 1 intracranial complete response and 3 partial responses among 8 patients with brain metastases, and an overall response rate of 80% and a disease control rate of 100% among 10 TKI-naive patients (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 9071-9071). detail...