Abstract CT138: Safety and efficacy of HS-10370 in KRAS G12C-mutated advanced solid tumors: Updated results from phase 1 study

Abstract Background: HS-10370 is a selective, covalent, and orally bioavailable KRAS G12C inhibitor. Here, we report updated results from HS-10370-101 (NCT05367778), a first-in-human phase I trial to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of HS-10370 monotherapy. Methods: Eligible patients with advanced or metastatic solid tumors were enrolled. HS-10370 was administered orally at doses ranging from 200 to 1600 mg once daily (QD) until disease progression, intolerance, or consent withdrawal. Rolling 6 was utilized for dose escalation. The primary objectives of the dose escalation part were to evaluate safety and tolerability. Secondary objectives included assessment of PK profile and efficacy. Results: As of Nov 25th, 2024, 63 pts with advanced solid tumors were enrolled in this study, including 57 pts harboring a KRAS G12C mutation [48 non-small cell lung cancer (NSCLC), 8 colorectal cancer (CRC), and 1 pancreatic cancer]. After a median follow-up of 16.7 months, treatment-related adverse events (TRAEs) occurred in 81% of the pts. TRAEs ≥ 10% were AST increased (28.6%), ALT increased (28.6%), anemia (25.4%), diarrhea (17.5%), weight increased (14.3%), decreased appetite (12.7%), rash (12.7%), hypertriglyceridemia (11.1%), nausea (11.1%), asthenia (11.1%) and sinus tachycardia (11.1%). Grade 3 TRAEs occurred in 22.2% of pts and no Grade 4 or 5 TRAEs were reported. The most common Grade 3 TRAEs were AST increased (3.2%) with a low incidence rate, QTc prolongation (3.2%) and blood CK increased (3.2%), and all other Grade 3 TRAEs were isolated cases. The incidences of TRAE-induced dose interruption, dose reduction and treatment discontinuation were 11.1%, 7.9% and 1.6%, respectively. Among the 48 efficacy evaluable pts with KRAS G12C mutant NSCLC, the unconfirmed objective response rate (uORR) was 62.5% and the confirmed ORR (cORR) was 54.2% as assessed by investigator. The disease control rate (DCR) was 93.8%. The median duration of response (mDoR) and the median progression free survival (mPFS) were 13.5 months and 11.3 months, respectively. In the 22 efficacy evaluable pts with 1L KRAS G12C mutant NSCLC who received HS-10370 ≥ 400 mg QD, the uORR was 77.3%, with a cORR of 72.7% and a DCR of 95.5%. The mDoR and mPFS were 9.7 months and 11.1 months, respectively. Among the 19 efficacy evaluable pts with ≥ 2L KRAS G12C mutant NSCLC who received HS-10370 ≥ 400 mg QD, the uORR was 57.9%, with a DCR of 94.7%. The mDoR and mPFS were 20.3 months and 12.5 months, respectively. In the 5 efficacy evaluable pts with KRAS G12C mutant CRC, the cORR was 60%, with a DCR of 80% and a mPFS of 7.8 months. Conclusions: With extended follow-up, HS-10370 continued to demonstrate impressive and durable antitumor activity and was well tolerated in patients with advanced KRAS G12C-positive solid tumor. Citation Format: Xiangjiao Meng, Yan Zhang, Yan Wang, Liang Han, Jianhua Chen, Qiming Wang, Zhong Lin, Shujun Feng, Zhenzhong Su, Xiaoqing Zhang, Xiaorong Dong. Safety and efficacy of HS-10370 in KRAS G12C-mutated advanced solid tumors: Updated results from phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT138.