30P A phase I, dose-escalation and dose-expansion study of SY-3505: A third-generation ALK TKI in Chinese ALK-positive advanced non-small cell lung cancer

Abstract

SY-3505 is a third-generation Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) against both wild-type and a broad range of mutations occurring in first-generation and second-generation ALK inhibitor-resistant patients. This First-in-human phase I study is to investigate the safety, pharmacokinetics (PK) and clinical efficacy of SY-3505 in Chinese ALK-positive advanced non-small cell lung cancer (NSCLC) patients. Eligible Patients in this multi-center, open-label phase I study (CTR20191702) were administered orally with SY-3505 (25,50,100,200,300,400,500,600 or 800mg) once daily. Primary endpoints included safety, tolerability, maximum tolerated dose (MTD), dose limited toxicities (DLTs) and RP2D. Secondary endpoints included preliminary efficacy and PK parameters. Between Apr.26, 2020 and Dec.31, 2021, totally 32 ALK+ NSCLC patients including 2 (6.25%) ALK TKI-naive and 30 (93.75%) previously treated with ALK inhibitors were enrolled into 9 dose escalation cohorts (n=24) and 2 dose expansion cohorts (500mg/600mg, n=8). Totally, 22 (68.7%) of 32 patients experienced treatment-related adverse events (TRAEs), and grade 3-4 TRAEs were observed in 1 (3.12%) patient. One DLT (grade 3 diarrhea) was occurred in the 800mg dose cohort. The most common TRAEs (>10% frequency) were diarrhea (all grade 25.00%; grade 3-4 3.12%), nausea (all grade 15.63%; grade 3-4 0.00%), vomiting (all grade 15.63%, grade 3-4 0.00%), aspartate aminotransferase elevation (all grade 12.50%; grade 3-4 0.00%). Tumor regression was observed in 18 (64.30%) of 28 assessable patients who had received at least one ALK TKI. PK analyses indicated the accumulation of SY-3505 in the patients with an approximately t1/2 of 26-56 hours. RP2D will be identified based on the safety, PK parameters and anti-tumor activity in dose-expansion period. SY-3505 was well tolerated in patients including those previously treated with two or more ALK TKIs, and most of the TRAEs were minor and reversible. Preliminary anti-tumor activity was also observed in patients who had received more than one first or second-generation ALK TKI. The dose-expansion phase of this study is ongoing.