European journal of cancer (Oxford, England : 1990) · 2026
Preclinical characterization and first-in-human, phase I trial of the novel ALK inhibitor dirozalkib in advanced non-small cell lung cancer.
СтатьяКлиническое исследование I фазыМногоцентровое исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Ai Xinghao, Guo Renhua, Zhang Liang, Fang Jian, Zhang Yiping, Chen Jianhua, Zhao Jun, Ye Feng, Wang Shumei, Shi Meiqi, Zhang Xinwei, Zhang Fang, Li Jiakui, Wang Li, Guo Xuejie, Xu Lingmei, Duan Xianghui, Hu Yan, Lu Shun
Аннотация
BACKGROUND: To investigate the preclinical characterization of dirozalkib, a novel anaplastic lymphoma kinase (ALK) inhibitor, and its safety, pharmacokinetics, and preliminary antitumor activity in advanced non-small cell lung cancer (NSCLC).
METHODS: The preclinical inhibitory effects of dirozalkib were evaluated in vitro and in vivo. The first-in-human phase I study (NCT05055232) enrolled patients with advanced NSCLC harboring ALK or ROS1 rearrangements. Participants received 50-600 mg/day dirozalkib following a 3 + 3 dose-escalation design with rapid titration, and 300-600 mg/day in the dose-expansion phase. The primary endpoint was safety.
RESULTS: Dirozalkib demonstrated potent inhibition of ALK fusion-positive cell lines and common resistance mutations, and suppressed tumor growth in patient-derived and intracranial xenograft lung cancer models. No dose-limiting toxicities occurred, establishing 600 mg/day as the maximum tolerated dose. Among 114 patients enrolled, 55 (48.2 %) experienced grade ≥ 3 treatment-emergent adverse events, most commonly diarrhea (8.8 %). The objective response rate (ORR) among patients with ALK rearrangements was 47.4 % (9/19) and 46.3 % (38/82) in the dose-escalation and dose-expansion cohort (89.3 % in ALK inhibitor-naive patients receiving 500 mg/day). After a single dose of 50-600 mg dirozalkib, median time to maximum concentration ranged from 3 to 4 h. Cmax and area under the curve of dirozalkib increased near-dose-proportional, with a geometric mean terminal elimination half-life of 19.6-25.4 h.
CONCLUSIONS: Dirozalkib exhibited favorable safety, antitumor activity and pharmacokinetics in patients with advanced ALK-rearranged NSCLC. The recommended phase II dose was 500 mg/day.
TRIAL REGISTRATION: Clinicaltrials.gov (NCT05055232) and Chinadrugtrials.org.cn (CTR20190984).
METHODS: The preclinical inhibitory effects of dirozalkib were evaluated in vitro and in vivo. The first-in-human phase I study (NCT05055232) enrolled patients with advanced NSCLC harboring ALK or ROS1 rearrangements. Participants received 50-600 mg/day dirozalkib following a 3 + 3 dose-escalation design with rapid titration, and 300-600 mg/day in the dose-expansion phase. The primary endpoint was safety.
RESULTS: Dirozalkib demonstrated potent inhibition of ALK fusion-positive cell lines and common resistance mutations, and suppressed tumor growth in patient-derived and intracranial xenograft lung cancer models. No dose-limiting toxicities occurred, establishing 600 mg/day as the maximum tolerated dose. Among 114 patients enrolled, 55 (48.2 %) experienced grade ≥ 3 treatment-emergent adverse events, most commonly diarrhea (8.8 %). The objective response rate (ORR) among patients with ALK rearrangements was 47.4 % (9/19) and 46.3 % (38/82) in the dose-escalation and dose-expansion cohort (89.3 % in ALK inhibitor-naive patients receiving 500 mg/day). After a single dose of 50-600 mg dirozalkib, median time to maximum concentration ranged from 3 to 4 h. Cmax and area under the curve of dirozalkib increased near-dose-proportional, with a geometric mean terminal elimination half-life of 19.6-25.4 h.
CONCLUSIONS: Dirozalkib exhibited favorable safety, antitumor activity and pharmacokinetics in patients with advanced ALK-rearranged NSCLC. The recommended phase II dose was 500 mg/day.
TRIAL REGISTRATION: Clinicaltrials.gov (NCT05055232) and Chinadrugtrials.org.cn (CTR20190984).
Предметные рубрики MeSH
HumansCarcinoma, Non-Small-Cell LungLung NeoplasmsAnaplastic Lymphoma KinaseMaleFemaleAnimalsMiddle AgedAgedAdultProtein Kinase InhibitorsMaximum Tolerated DoseXenograft Model Antitumor AssaysReceptor Protein-Tyrosine KinasesMiceAntineoplastic AgentsCell Line, TumorProtein-Tyrosine KinasesGene RearrangementAged, 80 and overDose-Response Relationship, DrugProto-Oncogene Proteins