A comprehensive real-world analysis has revealed that patients with KRAS G12C-mutant metastatic colorectal cancer (mCRC) experience numerically shorter survival outcomes when treated with standard first-line chemotherapy compared to those with other KRAS mutations, according to findings presented at the 2025 ESMO Gastrointestinal Cancers Congress.
The retrospective analysis, conducted using the Flatiron Foundation Medicine Clinico-Genomic database, evaluated 12,318 patients with mCRC diagnosed between January 2011 and March 2023. Among these patients, 455 (3%) harbored KRAS G12C mutations, while 5,551 had KRAS non-G12C mutations.
Survival Outcomes Reveal Prognostic Differences
The study's primary endpoint analysis showed that patients with KRAS G12C-mutant mCRC had a median overall survival (OS) of 18.2 months (95% CI, 14.7-20.0) compared to 19.1 months (95% CI, 18.4-19.8) in the KRAS non-G12C cohort. The overall patient cohort demonstrated a median OS of 20.2 months (95% CI, 19.5-20.9).
Similarly, progression-free survival (PFS) patterns followed the same trend. The median real-world PFS was 7.1 months (95% CI, 5.9-8.5) in the KRAS G12C mCRC cohort versus 8.9 months (95% CI, 8.4-9.2) in the non-G12C mutation cohort. The overall cohort achieved a median PFS of 9.0 months (95% CI, 8.8-9.3).
"Outcomes were similar among [patients with] KRAS G12C mutations treated with different first-line chemotherapy doublet regimens," noted lead study author Cathy Eng, MD, FACP, FASCO, David H. Johnson Endowed Chair in Surgical and Medical Oncology at Vanderbilt-Ingram Cancer Center. "Differences were modest and may be attributed to the small sample size, limited follow-up, and evolving access to G12C-targeted therapies in later lines of treatment."
Comparable Outcomes Across Chemotherapy Regimens
The analysis revealed that survival outcomes within the KRAS G12C-mutant cohort remained consistent regardless of the specific first-line chemotherapy backbone used. Patients treated with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) with or without bevacizumab achieved a median OS of 18.7 months (95% CI, 14.1-20.9), while those receiving FOLFIRI (5-FU, leucovorin, and irinotecan) with or without bevacizumab had a median OS of 19.0 months (95% CI, 11.2-22.1).
For progression-free survival, patients receiving FOLFOX with or without bevacizumab had a median PFS of 7.1 months (95% CI, 5.9-8.5), compared to 8.8 months (95% CI, 4.5-11.1) for those treated with FOLFIRI with or without bevacizumab.
Clinical Context and Mutation Prevalence
KRAS mutations are present in approximately 40% of colorectal cancer cases, but KRAS G12C mutations occur in only about 3% of CRC tumors. The current analysis found a slightly higher prevalence of 3% among the study population, which may reflect the specific characteristics of the database used.
The study population demonstrated comparable baseline characteristics across cohorts. In the KRAS G12C-mutant group, the mean age at initial diagnosis was 59 years, with 47.9% being female and the majority being White (64.0%) and non-Hispanic or Latino (77.4%). Most patients (71.4%) were treated in community settings, and 55.4% had metastatic disease at initial diagnosis.
Treatment Implications and Future Directions
The findings have significant implications for treatment decision-making in clinical practice. "[With the] possibility [that KRAS G12C mutations] may impact the OS and PFS for our patient population, rather than just giving them standard chemotherapy [in the frontline setting], why wouldn't I want to consider participation in a clinical trial specific to that patient, if they're eligible?" Eng explained.
Currently, two KRAS G12C-targeted therapies, sotorasib (Lumakras) and adagrasib (Krazati), have received approval for previously treated mCRC harboring KRAS G12C mutations. The phase 3 CodeBreaK 301 trial (NCT06252649) is evaluating sotorasib in combination with chemotherapy and panitumumab (Vectibix) in the newly diagnosed setting.
Study Limitations and Considerations
The researchers acknowledged several limitations, including the relatively small sample size of KRAS G12C-mutant patients, limited follow-up duration, and the evolving landscape of targeted therapy access during the study period. These factors may have contributed to the modest differences observed between groups.
The analysis underscores the potential prognostic significance of KRAS G12C mutations in mCRC and supports the rationale for developing mutation-specific treatment strategies and encouraging clinical trial participation for eligible patients with this molecular subtype.
