Glecirasib Plus Cetuximab Shows Promise in KRAS G12C-Mutant Metastatic Colorectal Cancer
Clinical Summary:
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Design/Population: The phase 1/2 JAB-21822-1002 and JAB-21822-1007 trials evaluated glecirasib as monotherapy and in combination with cetuximab in previously treated patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer.
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Key Outcomes: Glecirasib demonstrated clinical activity as monotherapy, with higher objective response rates observed when combined with cetuximab. Both regimens demonstrated manageable safety profiles, with no dose-limiting toxicities or treatment-related deaths reported.
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Clinical Relevance: These findings support combined KRAS G12C and EGFR inhibition as a promising treatment strategy for KRAS G12C-mutated metastatic colorectal cancer and warrant further evaluation in earlier treatment settings.
Results from the phase 1/2 JAB-21822-1002 and JAB-21822-1007 trials demonstrated that glecirasib, a covalent KRAS G12C inhibitor, showed encouraging clinical activity both as monotherapy and in combination with cetuximab in patients with previously treated KRAS G12C-mutated locally advanced or metastatic colorectal cancer (mCRC).
“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, non-randomized trials, previously treated patients with locally advanced or mCRC received 800 mg of once daily glecirasib either as monotherapy (n = 15) or in combination with a loading dose of 400 mg/m2 of cetuximab followed by weekly 250 mg/m² or biweekly 500 mg/m² maintenance cetuximab (n = 46). Primary end points included safety, dose-limiting toxicities, maximum tolerated dose, and objective response rate (ORR).
No dose-limiting toxicities were observed in either study, and the maximum tolerated dose was not reached in the combination trial. The ORR was 23% with glecirasib monotherapy and 50% with glecirasib plus cetuximab.
Treatment-emergent adverse events occurred in all patients receiving glecirasib monotherapy, with grade ≥3 treatment-related adverse events reported in 27%. In the combination study, grade 3/4 treatment-related adverse events occurred in 19% of patients. The most common treatment-related adverse events included anemia and hyperbilirubinemia with monotherapy and rash and hyperbilirubinemia with combination therapy. Serious treatment-related adverse events occurred in 5% of patients receiving monotherapy and 9% receiving combination therapy. No treatment-related deaths were reported.
“Glecirasib monotherapy and its combination with cetuximab represent potential treatment options for patients with advanced, refractory [mCRC] 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
