Efficacy and safety of SY-3505, a third-generation ALK TKI, in ALK-positive advanced non-small cell lung cancer: Results from a phase I/II, multi-center study.

9110 Background: SY-3505 is a potent, brain-penetrant, 3 rd -generation (gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with preclinical activity against both wild-type and most known resistance mutations of ALK occurring in 1 st and 2 nd -gen ALK TKI-resistant patients. Here we report the efficacy and safety results from the ongoing phase I/II study of SY-3505. Methods: Patients aged ≥18 years with histologically/cytologically confirmed, advanced, ALK-positive non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were recruited from 13 hospitals in China. In phase I study, patients received SY-3505 from 25-800mg once daily in dose-escalation phase, followed by dose-expansion at 500/600mg. Patients received alectinib only or ≥2 prior ALK TKIs were recruited in phase II study and treated with SY-3505 at 600mg once daily. The primary endpoint was investigator (INV)-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off date of Feb.03, 2023, 92 ALK-positive NSCLC patients were enrolled in phase I/II, 82 were evaluable for efficacy, the ORR was 34.2% (95% confidence interval [CI] 24.0-45.5%), DCR was 74.4% (95% CI 63.6-83.4%). Herein the ORR and DCR of 59 patients in phase I for dose-escalation and dose-expansion was 32.3% (95% CI 20.6-45.6%) and 69.5% (95% CI 56.1-80.8%), respectively; median DoR and PFS was 11.1 (95% CI 5.28-not reached [NR]) and 6.20 (95% CI 3.08-10.3) months, respectively. Fifty-six patients received SY-3505 at 600mg once daily (two patients received non-alectinib 2 nd -gen ALK TKI only, 22 received alectinib only and 32 received ≥2 prior ALK TKIs). Thirty-two (57.1%) patients experienced treatment-related adverse events (TRAEs) and two (3.6%) had grade ≥3 TRAEs. The most common TRAEs were diarrhea (42.9%), nausea (28.6%) and vomiting (26.8%), consistent with previous reported in phase I. Forty-seven patients were evaluable for efficacy, the ORR and DCR was 38.3% (95% CI 24.5-53.6%) and 83.0% (95% CI 69.2-92.4%), respectively. Median DoR and PFS were NR. Twenty-two patients had baseline central nervous system metastases, the ORR and DCR was 50.0% and 86.4%, respectively. Conclusions: SY-3505 was well-tolerated and showed significant and durable clinical activity in ALK-positive NSCLC patients who received at least one prior 2 nd -gen ALK TKI, demonstrating a potential new treatment option for these patient population. Pivotal clinical study will be performed in future. Clinical trial information: NCT05257512 .