{"title":"ALK阳性非小细胞肺癌患者服用deulorlatinib（TGRX-326）的安全性、疗效和生物标志物分析：一项多中心、开放标签、1/1b期试验。","authors":"Shen Zhao, Huaqiang Zhou, Nong Yang, Zhehai Wang, Wenjian Jin, Yuxiang Ma, Jinhui Xue, Xingya Li, Yunpeng Liu, Rui Meng, Jianying Zhou, Ying Cheng, Yongsheng Wang, Zhuang Yu, Yu Cao, Yuanyuan Zhao, Yan Huang, Wenfeng Fang, Yang Zhang, Shaodong Hong, Bo Wu, Yanxia Shi, Jingrong Cao, Mingyan Xu, Xiaoni Zhang, Longyu Hu, Bo Peng, Yunpeng Yang, Li Zhang, Hongyun Zhao","doi":"10.1016/j.jtho.2024.11.010","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Patients with ALK-positive NSCLC developing resistance to second-generation inhibitors have limited treatment options. Deulorlatinib is a highly brain-penetrant, new-generation ALK/ROS1 inhibitor. We evaluated the safety, efficacy and pharmacokinetics of deulorlatinib in ALK-positive NSCLC.</p><p><strong>Methods: </strong>This 3-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in China (ClinicalTrials.gov, NCT05441956). Eligible patients had advanced ALK/ROS1-positive NSCLC. Patients enrolled into dose-escalation/dose-expansion parts were previously treated with ≥1 second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive); received deulorlatinib 5-125mg once daily. Patients enrolled into cohort-expansion parts were either crizotinib-treated, second-generation TKI-treated or TKI-naïve; received deulorlatinib at recommended phase 2 dose (RP2D). Primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in ALK-positive patients.</p><p><strong>Results: </strong>Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive=171, ROS1-positive=27). Most common treatment-related adverse events (TRAEs) were hypercholesterolemia (79.3%), hypertriglyceridemia (77.3%) and weight gain (53.0%). 40.4% of patients had grade≥3 TRAEs. TRAE-associated dose interruptions, reduction and discontinuation occurred in 11.1%, 3.0% and 1.5% of patients, respectively. The RP2D was set at 60mg once daily. A total of 144 ALK-positive patients were treated at RP2D. For crizotinib-treated (n=14), second-generation TKI-treated (n=97) and TKI-naïve (n=33) patients, ORR to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial ORR was 50%, 70.4%, and 75%. Median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for crizotinib-treated and TKI-naïve patients. Biomarker analyses identified undetectable ALK alterations at baseline and ALK ctDNA clearance at week 6 as potential predictive biomarkers.</p><p><strong>Conclusions: </strong>Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0000,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Safety, efficacy and biomarker analysis of deulorlatinib (TGRX-326) in ALK-positive non-small-cell lung cancer: a multicentre, open-label, phase 1/1b trial.\",\"authors\":\"Shen Zhao, Huaqiang Zhou, Nong Yang, Zhehai Wang, Wenjian Jin, Yuxiang Ma, Jinhui Xue, Xingya Li, Yunpeng Liu, Rui Meng, Jianying Zhou, Ying Cheng, Yongsheng Wang, Zhuang Yu, Yu Cao, Yuanyuan Zhao, Yan Huang, Wenfeng Fang, Yang Zhang, Shaodong Hong, Bo Wu, Yanxia Shi, Jingrong Cao, Mingyan Xu, Xiaoni Zhang, Longyu Hu, Bo Peng, Yunpeng Yang, Li Zhang, Hongyun Zhao\",\"doi\":\"10.1016/j.jtho.2024.11.010\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Patients with ALK-positive NSCLC developing resistance to second-generation inhibitors have limited treatment options. Deulorlatinib is a highly brain-penetrant, new-generation ALK/ROS1 inhibitor. We evaluated the safety, efficacy and pharmacokinetics of deulorlatinib in ALK-positive NSCLC.</p><p><strong>Methods: </strong>This 3-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in China (ClinicalTrials.gov, NCT05441956). Eligible patients had advanced ALK/ROS1-positive NSCLC. Patients enrolled into dose-escalation/dose-expansion parts were previously treated with ≥1 second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive); received deulorlatinib 5-125mg once daily. Patients enrolled into cohort-expansion parts were either crizotinib-treated, second-generation TKI-treated or TKI-naïve; received deulorlatinib at recommended phase 2 dose (RP2D). Primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in ALK-positive patients.</p><p><strong>Results: </strong>Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive=171, ROS1-positive=27). Most common treatment-related adverse events (TRAEs) were hypercholesterolemia (79.3%), hypertriglyceridemia (77.3%) and weight gain (53.0%). 40.4% of patients had grade≥3 TRAEs. TRAE-associated dose interruptions, reduction and discontinuation occurred in 11.1%, 3.0% and 1.5% of patients, respectively. The RP2D was set at 60mg once daily. A total of 144 ALK-positive patients were treated at RP2D. For crizotinib-treated (n=14), second-generation TKI-treated (n=97) and TKI-naïve (n=33) patients, ORR to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial ORR was 50%, 70.4%, and 75%. Median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for crizotinib-treated and TKI-naïve patients. Biomarker analyses identified undetectable ALK alterations at baseline and ALK ctDNA clearance at week 6 as potential predictive biomarkers.</p><p><strong>Conclusions: </strong>Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.</p>\",\"PeriodicalId\":17515,\"journal\":{\"name\":\"Journal of Thoracic Oncology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":21.0000,\"publicationDate\":\"2024-11-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Thoracic Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jtho.2024.11.010\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thoracic Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jtho.2024.11.010","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Safety, efficacy and biomarker analysis of deulorlatinib (TGRX-326) in ALK-positive non-small-cell lung cancer: a multicentre, open-label, phase 1/1b trial.
Introduction: Patients with ALK-positive NSCLC developing resistance to second-generation inhibitors have limited treatment options. Deulorlatinib is a highly brain-penetrant, new-generation ALK/ROS1 inhibitor. We evaluated the safety, efficacy and pharmacokinetics of deulorlatinib in ALK-positive NSCLC.
Methods: This 3-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in China (ClinicalTrials.gov, NCT05441956). Eligible patients had advanced ALK/ROS1-positive NSCLC. Patients enrolled into dose-escalation/dose-expansion parts were previously treated with ≥1 second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive); received deulorlatinib 5-125mg once daily. Patients enrolled into cohort-expansion parts were either crizotinib-treated, second-generation TKI-treated or TKI-naïve; received deulorlatinib at recommended phase 2 dose (RP2D). Primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in ALK-positive patients.
Results: Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive=171, ROS1-positive=27). Most common treatment-related adverse events (TRAEs) were hypercholesterolemia (79.3%), hypertriglyceridemia (77.3%) and weight gain (53.0%). 40.4% of patients had grade≥3 TRAEs. TRAE-associated dose interruptions, reduction and discontinuation occurred in 11.1%, 3.0% and 1.5% of patients, respectively. The RP2D was set at 60mg once daily. A total of 144 ALK-positive patients were treated at RP2D. For crizotinib-treated (n=14), second-generation TKI-treated (n=97) and TKI-naïve (n=33) patients, ORR to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial ORR was 50%, 70.4%, and 75%. Median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for crizotinib-treated and TKI-naïve patients. Biomarker analyses identified undetectable ALK alterations at baseline and ALK ctDNA clearance at week 6 as potential predictive biomarkers.
Conclusions: Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.
期刊介绍：
Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer,is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies.The readship includes epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonologists, radiologists, pathologists, nuclear medicine physicians, and research scientists with a special interest in thoracic oncology.
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