Abstract CT119: Safety and efficacy of HS-10370 in KRAS G12C-mutated solid tumors including non-small cell lung cancer (NSCLC)

Abstract Background: KRAS G12C mutation occurs in ~13% of NSCLC and up to 4% of other solid tumors. HS-10370 is a selective, covalent, orally bioavailable KRAS G12C inhibitor. We conducted a first-in-human phase I trial to evaluate the dose-limiting toxicity (DLT), safety, tolerability, pharmacokinetics, and efficacy of HS-10370 in patients (pts) with advanced solid tumors bearing KRAS G12C mutation. Methods: In a phase I study HS-10370-101 (NCT05367778), patients of advanced or metastatic solid tumors with measurable disease were recruited. HS-10370 monotherapy was given at oral doses of 200~1600 mg QD until disease progression, intolerance, or withdrawal from consent. Rolling 6 was applied as the dose escalation schedule in this phase I dose escalation trial. The primary objectives of the dose escalation part was safety and tolerability. The secondary objectives included pharmacokinetics (PK) profile and efficacy. Results: As of Dec 15th, 2023, 55 patients with advanced solid tumors were enrolled in this study, including 49 patients with KRAS G12C mutation. Of the 49 patients, 43 were with NSCLC, 5 with colon cancer, and 1 with pancreatic cancer. Safety: No dose-limiting toxicity was observed, neither maximum tolerated dose (MTD) been identified. Treatment-emergent adverse events (TEAEs) occurred in 87. 3% of the treated patients (48/55), the most common TEAEs (≥10%) were AST increase (29. 1%, 16/55), ALT increase (29. 1%, 16/55), anemia (27. 3%, 15/55), diarrhea (25. 5%, 14/55), weight gain (18. 2%, 10/55), decreased appetite (14. 5%, 8/55), hypoproteinemia (12. 7%, 7/55), nausea (12. 7%, 7/55), fatigue (14. 5%, 8/55) and rash (12. 7%, 7/55). The TEAEs ≥Grade 3 occurred in 27. 3% patients (15/55). TEAEs leading to dose interruptions and dose reductions were reported in 18. 2% patients (10/55) and 7. 3% patients (4/55), respectively. Efficacy: Of the 49 patients with KRAS G12C mutant status, 24 had partial response (PR) and 20 had stable disease (SD). The confirmed objective response rate (ORR) and disease control rate (DCR) were 49. 0% and 89. 8% respectively. Objective responses were observed in patients received 400mg QD or above. In patients with KRAS G12C mutant NSCLC who received more than or equal to 400mg daily dose, the confirmed ORR and DCR were 51. 2% (21/41) and 95. 1% (39/41), respectively. Of the same subpopulation, the median duration of response was not reached (5. 4, NA). Meanwhile, the median progression-free-survival (PFS) was 11. 3 month (6. 1, NA), with the 6-months PFS rate 75% and the 9-months PFS rate 63. 6%. Responses were also observed in patients with colon cancer and pancreatic cancer. Conclusions: HS-10370 was well tolerated and showed inspiring antitumor activities in KRAS G12C mutated advanced solid tumors, especially in NSCLC. Citation Format: Xiaorong Dong, Xiangjiao Meng, Yan Zhang, Yan Wang, Jianhua Chen, Liang Han, Qiming Wang, Zhong Lin, Hongying Wei, Siheng Lin, Chuan Li, Qiong Wu. Safety and efficacy of HS-10370 in KRAS G12C-mutated solid tumors including non-small cell lung cancer (NSCLC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT119.