Glecirasib-Based Regimens Show Promise in KRAS G12C-Mutant Metastatic Colorectal Cancer

Clinical Summary:

• Design/Population: The JAB-21822-1002 and JAB-21822-1007 trials evaluated glecirasib both alone and in combination with cetuximab in previously treated patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer.
• Key Outcomes: Glecirasib demonstrated promising antitumor activity both alone and in combination with cetuximab, with improved activity observed with combination treatment and generally manageable toxicity.
• Clinical Relevance: Glecirasib plus cetuximab overcame EGFR-mediated resistance, supporting further development of KRAS and EGFR combination strategies. 

According to combined results from the phase 1/2 JAB-21822-1002 and JAB-21822-1007 trials, glecirasib demonstrated clinical promise both alone and in combination with cetuximab among patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC). 

“KRAS G12C mutations… are associated with lower treatment response rates and overall survival [primarily because] EGFR signaling has been identified as a primary mechanism of resistance to KRAS G12C inhibitors,” stated Jian Li, MD, Peking University Cancer Hospital & Institute, Beijing, China, and coauthors. Here, researchers “aimed to evaluate the efficacy and safety of a novel, covalent, small molecule KRAS G12C inhibitor, glecirasib, as monotherapy or in combination with the anti-EGFR cetuximab.” 

In these open-label, nonrandomized trials, previously treated patients with locally advanced or metastatic CRC who had progressed on, were intolerant to, or were not candidates for standard-of-care therapy received 800 mg of once daily glecirasib either alone (n = 15) or in combination with cetuximab (n = 46), with cetuximab administered intravenously using a loading dose (400 mg/m²) followed by weekly (250 mg/m²) or biweekly dosing (500 mg/m²). 

The primary end point in the monotherapy trial was safety. Primary end points in the combination trial included dose-limiting toxicities, maximum-tolerated dose, objective response rate (ORR), and safety. 

At monotherapy analysis, no dose-limiting toxicities or unexpected grade ≥3 laboratory values, changes in vital signs, physical exams, or electrocardiography were reported. Treatment-emergent adverse events were reported in 100% of patients, of which 53% were grade ≥3. Grade ≥3 treatment-related adverse events were reported in 27% of patients. Serious treatment-emergent adverse events were reported in 33% of patients. 

At combination analysis, no dose-limiting toxicities were reported, and the maximum-tolerated dose was not reached. The median ORR was 23% in the glecirasib arm and 50% in the glecirasib plus cetuximab arm. The most freuent treatment-related adverse events reported in the glecirasib arm included anemia (55%), elevated bilirubin (52%), and elevated conjugated bilirubin (39%). The most frequent treatment-related adverse events reported in the glecirasib plus cetuximab arm included rash (83%), elevated blood bilirubin (62%), and elevated conjugated bilirubin (36%). Grade 3/4 treatment-related adverse events were reported in 20% and 19% of patients, respectively. Serious treatment-related adverse events were reported in 5% of patients in the glecirasib arm and 9% of patients in the combination arm. No treatment-related deaths were reported in either trial. 

“Glecirasib monotherapy and its combination with cetuximab represent potential treatment options for patients with advanced, refractory colorectal cancer harboring KRAS G12C mutations,” concluded Dr Li et al. “The promising efficacy and safety support further exploration of glecirasib-based combinations in earlier lines of treatment.”

Source:

Li J, Wang Z, Huang J, et al. Glecirasib with or without cetuximab in previously treated locally advanced or metastatic colorectal cancer with KRASG12C mutation (JAB-21822-1002 and JAB-21822-1007): Two open-label, non-randomized phase 1/2 trials. Lancet Gastroenterol Hepatol. Published online: December 1, 2025. doi:10.1016/s2468-1253(25)00267-5