Open-label, dose-escalation phase 1a study of SPH5030, a tyrosine kinase inhibitor (TKI) targeting HER2, in patients with HER2 positive advanced solid tumors.

3117 Background: Although existing HER2-targeted agents have driven treatment strategies of HER2-overexpressed advanced solid tumor, unmet need still occurred in clinical setting. SPH5030, is a novel tyrosine kinase inhibitor targeting HER2, with a modified structure from tucatinib and pyrotinib. It has advantages such as target selectivity of tucatinib and the irreversible inhibitory effect of pyrotinib. Methods: This Phase Ia, open-label, multi-center study was conducted to evaluate the safety, pharmacokinetics and preliminary activity of SPH5030 in patients (pts) with HER2-positive advanced solid tumor. A 3+3 dose-escalation was conducted with six dose levels of SPH5030 (50,100,200,300,400,600 mg) administered orally once every day (QD) to evaluate dose limiting toxicity (DLT). Adverse events were assessed using CTCAE V5.0; tumor response per RECIST 1.1 every 6 weeks. Results: As of Feb 2, 2024, 30 pts were enrolled with a median age of 51 years, including 28 (93.3%) pts with breast cancer (BC) and 2 (6.7%) pts with colorectal cancer (CRC). All pts were heavily treated with a median of 4 (range, 1-9) prior lines of therapy. All the 28 BC pts received previous anti-HER2 therapy, and 23 of them received anti-HER2-TKI therapy. Treatment-emerged adverse events (TEAEs) and ≥grade (G) 3 TEAEs occurred in 30 pts (100.0%) and 10 pts (33.3%), respectively. Treatment-related adverse events (TRAEs) and ≥G3 TRAEs occurred in 28 pts (93.3%) and 8 pts (26.7%), respectively; the most common TRAEs (≥20%) were diarrhea (66.7%, 16.7% ≥ G3), creatinine increased (30.0%, 0% ≥ G3), hypokalemia (23.3%, 3.3% ≥ G3), fatigue (23.3%, 3.3% ≥ G3), AST increased (20.0%, 0% ≥ G3), and bilirubin increased (20.0%, 0% ≥ G3). One in 6 pts receiving 600 mg dose experienced a DLT (diarrhea, G3). SPH5030 plasma exposures from single-dose and steady-state showed a proportional dose increase, but absorption of SPH5030 was found to reach a plateau from 400 to 600mg. Of the 28 evaluable pts for efficacy (BC = 26, CRC = 2),6 pts (21.4%) achieved partial response (PR, BC = 5, CRC = 1), while 16 pts (57.1%) achieved stable disease (4 pts SD≥ 24 weeks,14.3%). Objective response rate (ORR) was 21.4%, disease control rate was 78.6%, and clinical benefit rate was 35.7%. Three pts in the 600 mg dose group achieved PR, with ORR of 50.0%. Conclusions: This study demonstrated that SPH5030 was well tolerated at doses ranging from 50 to 600mg. A dose of 600 mg QD regimen could be considered for further clinical trials. Clinical trial information: NCT05245058 .