HS-10365, a highly potent and selective RET tyrosine kinase inhibitor, demonstrates robust activity in RET fusion positive NSCLC patients

Abstract Background: Activating RET alterations drive oncogenic signaling in lung, thyroid, and other solid tumors.Until recently, only two RET tyrosine kinase inhibitor (TKI), BLU-667 and LOXO-292, had received approval for advanced NSCLC by FDA and NMPA. And it still had an unmet clinical need in this therapy area.HS-10365 is a highly potent and selective tyrosine kinase inhibitor, and the preclinical studies have indicated its favorable safety and antitumor activity in RET-altered tumor models. Here, we conducted a phase I study to assess the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of HS-10365 in RET-altered solid tumors. Methods: This study (NCT05207787) recruited patients (pts) with RET-altered advanced solid tumors, including RET fusion-positive (+) NSCLC, RET-mutated medullary thyroid carcinoma and so on. Pts were dosed orally in 21-day cycles. A rule-based accelerated titration combined with 3+3 dose-escalation scheme was used to determine the MTD as the primary endpoint. Secondary endpoints contained safety, PK parameters, ORR and DCR assessed by RECIST V1.1. Results: As of Dec.15th 2022, 31 RET fusion+ NSCLC pts with RET TKI-naïve were received HS-10365 at 6 doses (40 mg QD to 200 mg BID), including 25 previously received platinum-based chemotherapy pts and 6 treatment-naïve pts. Among all fusion variants, 15 pts had KIF5B, 14 pts had CCDC6, and 2 pts were others. Dose limiting toxicity occurred only in one pt. at 200 mg BID (grade 3 hypertension). The MTD was not been defined, and the 160mg BID was the potentially recommended phase II dose. The common (≥25%) TRAEs were AST increase, bilirubin increase, ALT increase, WBC decrease, PLT decrease, neutrophil decrease, serum creatinine increase, prolonged QT interval, hypoalbuminemia and anemia. No pts discontinued treatment owing to AEs. Efficacy data was available for 30 RET fusion+ NSCLC pts with 24 pretreated pts and 6 treatment naïve pts. The ORR was 70.0% (21/30, 95% CI 50.6%-85.3%), with 66.7% (16/24) in pretreated pts and 83.3% (5/6) in treatment naïve pts. Furthermore, the DCR was 96.7% (29/30, 95% CI 82.8%-99.9%), with 95.8% (23/24) in pretreated pts and 100% (6/6) in treatment naïve pts. The longest response time was more than 48 weeks. Meanwhile, 25 of 31 pts remained on treatment and responses were ongoing. Plasma exposure of HS-10365 increased proportionally following single dose and multiple doses. The mean plasma half-life of HS-10365 was 5~9 hours. Conclusions: HS-10365 showed a manageable safety profile and favorable PK properties. The promising antitumor activity with expectable response time was observed in RET fusion+ NSCLC pts, no matter with or without previous treatments. Citation Format: Shun Lu, Qiming Wang, Lin Wu, Ligang Xing, Yintao Li, Liang Han, Xiaorong Dong, Hongying Wei, Wen Xu, Chuan Li, Liuqing Yang, Qiong Wu. HS-10365, a highly potent and selective RET tyrosine kinase inhibitor, demonstrates robust activity in RET fusion positive NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT201.