Dirozalkib

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).

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.

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. C_max 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.

Dirozalkib exhibited favorable safety, antitumor activity and pharmacokinetics in patients with advanced ALK-rearranged NSCLC. The recommended phase II dose was 500 mg/day.

Clinicaltrials.gov (NCT05055232) and Chinadrugtrials.org.cn (CTR20190984).