Abstract CT299: Dirozalkib versus crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): Results from the multicenter, randomized, open-label phase 3 trial

Abstract Background: Dirozalkib is a novel, highly selective inhibitor of anaplastic lymphoma kinase (ALK). This open-label, multicenter, randomized, phase 3 study (NCT05204628) was to evaluate the efficacy and safety of dirozalkib versus crizotinib in patients (pts) with advanced ALK-positive NSCLC. Methods: This study enrolled pts with advanced ALK-positive NSCLC who were treatment-naïve or had received only one previous chemotherapy regimen. Pts were stratified by prior chemotherapy and brain metastasis at baseline, and then randomized (1:1) to receive dirozalkib 500 mg once daily or crizotinib 250 mg twice daily. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS). Secondary endpoints included PFS assessed by the blinded independent central review (BICR), objective response rate (ORR), duration of response (DoR), intracranial ORR (IC-ORR), intracranial DoR (IC-DoR) and overall survival (OS), etc. Results: 275 pts were enrolled and randomly assigned to receive dirozalkib (n=137) or crizotinib (n=138). 58 (21.1%) pts had brain metastases at baseline and 27 (9.8%) pts had previously received chemotherapy for advanced disease. As of May 31, 2025, the median follow-up was 32.79 months (mo) in the dirozalkib group and 31.61 mo in the crizotinib group. The INV-assessed median PFS (mPFS) was significantly longer in the dirozalkib group than in the crizotinib group (29.50 mo [95%CI: 20.30-not reached] vs. 12.94 mo [11.07-17.61]; hazard ratio [HR] = 0.474, P < 0.0001). Median PFS by BICR was 27.50 mo versus 12.91 mo (HR = 0.537; P < 0.0001). In the modified intention-to-treat (m-ITT)* population, the mPFS was 31.28 mo in the dirozalkib group versus 12.94 mo in the crizotinib group (HR = 0.465; P < 0.0001). In the dirozalkib group, the ORR was 88.5% with a mDoR of 32.10 mo (HR = 0.439; P < 0.0001). Among pts with measurable intracranial lesions at baseline, the IC-ORR was 91.7% and 11.1% in the two groups, respectively. The median IC-DoR was not reached versus 3.55 mo (HR = 0.000; P = 0.0013). In the m-ITT population, the median intracranial PFS (IC-PFS) was not reached in the dirozalkib group versus 29.21 mo in the crizotinib group (HR = 0.445; P = 0.0003). OS data were not yet mature in both groups. The incidence of ≥ grade 3 TRAEs was lower in dirozalkib than in crizotinib (52.6% vs. 62.3%). Treatment discontinuation due to TRAEs occurred in 1.5% of pts receiving dirozalkib. Conclusions: Dirozalkib demonstrated significant improvement in PFS compared with crizotinib for ALK-positive advanced NSCLC. Notably, it showed robust intracranial antitumor activity and durable treatment responses in pts with brain metastases at baseline. *mITT: eight pts were excluded from ITT population due to unavailable information regarding the regulatory approval status of the NGS kits used for ALK rearrangement testing at baseline. Citation Format: Ying Liu, Xiangjiao Meng, Yan Yu, Jianhua Chen, Runxiang Yang, Laiyu Liu, Yanqiu Zhao, Ruifen Tian, Dianming Li, Ruiling Ning, Qingshan Li, Guowu Wu, Li Wang, Xianghui Duan, Xuejie Guo, Yan Hu, Weili Liu, Haifeng Liu. Dirozalkib versus crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): Results from the multicenter, randomized, open-label phase 3 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT299.