The efficacy and safety of sosimerasib monotherapy in pretreated colorectal cancer with KRAS G12C mutation: Results from a phase 1b study.

Abstract

3596 Background: KRAS G12C mutation is a key driver in approximately 3-4% of colorectal cancer (CRC) cases with poor prognosis. Sosimerasib is a novel, potent, and highly selective KRAS G12C inhibitor. This Phase 1b study evaluates the efficacy and safety of sosimerasib in patients with KRAS G12C-mutated locally advanced or metastatic CRC. Methods: Eligible patients who had received prior standard chemotherapy were enrolled in this study. Patients were administered sosimerasib at 500 mg orally once daily. The primary efficacy endpoint was the objective response rate (ORR) assessed by investigators according to RECIST 1.1. Results: As of May 3, 2025, a total of 56 patients were enrolled with a median age of 59 years (53.6% male). All patients had stage IV disease at baseline with an ECOG score of 0 (19.6%) or 1 (80.4%). Prior treatment lines ranged from 1 to 3, and most patients (38; 67.9%) had received oxaliplatin, irinotecan, and fluoropyrimidine as systemic therapy during the advanced disease period. With a median follow-up period of 9.9 months (range: 2.1-13.4), the confirmed ORR was 39.3% (95% CI: 26.5-53.3), the median time to response was 1.4 months (range: 1.3-4.2), and the disease control rate was 98.2% (95% CI: 90.5-100). The median duration of response was 8.6 months (95% CI: 4.2-NA). The median progression-free survival was 8.3 months (95% CI: 5.6-11.0). The median overall survival (OS) was not reached, with a 12-month OS rate of 71.5%. Among the patients who had previously received oxaliplatin, irinotecan, and fluoropyrimidine in the advanced setting, the confirmed ORR was 31.6% (95% CI: 17.5-48.7). Treatment-related adverse events (TRAEs) were reported in 53 (94.6%) patients, with grade 3-4 TRAEs occurring in 14 (25.0%) patients. No TRAE was fatal. The most common TRAEs were increased alanine aminotransferase (48.2%), increased aspartate aminotransferase (46.4%), anaemia (32.1%), and decreased white blood cell count (26.8%). TRAEs led to drug interruption in 9 (16.1%) patients, dose reduction in 3 (5.4%) patients, and permanent discontinuation in 1 (1.8%) patient. Conclusions: Sosimerasib monotherapy demonstrated clinically meaningful anti-tumor activity with an acceptable safety profile in patients with KRAS G12C-mutated locally advanced/metastatic CRC, supporting its potential for further development. Clinical trial information: ChiCTR2200059986.