Real-World Analysis Reveals Shorter Survival in KRAS G12C–Mutant Metastatic CRC After First-Line Treatment

Metastatic colorectal cancer|

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Numerically shorter overall survival (OS) and progression-free survival (PFS) was observed among patients with KRAS G12C–mutant metastatic colorectal cancer (mCRC) in the first-line setting compared with patients who displayed non-G12C mutations, according to findings from a real-world analysis presented at the 2025 ESMO Gastrointestinal Cancers Congress.1

In the overall patient cohort (n = 12,318), the median OS was 20.2 months (95% CI, 19.5-20.9). Of note, the median OS was 18.2 months (95% CI, 14.7-20.0) in the KRAS G12C–mutant mCRC cohort (n = 455) compared with 19.1 months (95% CI, 18.4-19.8) in the KRAS non-G12C mCRC cohort (n = 5551).

“Outcomes were similar among [patients with] KRAS G12C mutations treated with different first-line chemotherapy doublet regimens,” lead study author Cathy Eng, MD, FACP, FASCO, and colleagues wrote in a poster. “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.”

Eng is the David H. Johnson Endowed Chair in Surgical and Medical Oncology, a professor of medicine in Hematology and Oncology, and the co-leader for the Gastrointestinal Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Background and Real-World Study Design

KRAS mutations are present in approximately 40% of CRC cases; however, KRAS G12C mutations occur in only approximately 3% of CRC tumors.2 Furthermore, KRAS G12C mutations could be associated with a poorer prognosis compared with other KRAS mutations and wild-type KRAS.3

The real-world study included patients at least 18 years of age with a diagnosis of mCRC between January 1, 2011, and March 31, 2023, and documented KRAS mutation for the KRAS G12C and KRAS non-G12C mCRC cohorts.1 The study evaluated patient demographics, clinicopathologic characteristics and treatment patterns, and survival outcomes in patients with mCRC and KRAS G12C–mutant mCRC through the Flatiron Foundation Medicine Clinico-Genomic database.

The primary end point of the study was OS in the first-line setting, and the secondary end point was real-world PFS (rwPFS) in the first-line setting.

Baseline Patient Characteristics

The demographics and treatment characteristics were comparable across cohorts. Specifically, in the KRAS G12C–mutant cohort, the mean age at initial diagnosis was 59 years, with the mean age at advanced diagnosis at 60 years of age. Additionally, 47.9% of patients were female, and the majority were White (64.0%) and non-Hispanic or Latino (77.4%). Of note, most patients were treated in a community setting (71.4%), and 55.4% had metastatic disease at initial diagnosis. Patients either had an ECOG performance status of 0 or 1 (22.8%), 2 (1.1%), 3 (0.2%), or not available (75.8%). Moreover, the mean body mass index was 29.8 kg/m2, and the number of total lines of therapy included 0 (14.3%), 1 (30.1%), 2 (21.1%), 3 (12.7%), and 4 or more lines (21.8%). Positive biomarker status included BRAF (3.3%), BRAF V600E (1.3%), and microsatellite instability-high and mismatch repair deficient status (MSI-H/dMMR; 1.3%). Lab measurements at index data included carcinoembryonic antigen (15.5 ug/L; q1, 4.3 ug/L; q3, 72.4 ug/L), aspartate aminotransferase (22 U/L; q1, 16 U/L; q3, 30 U/L), alanine transaminase (18 U/L; q1, 12 U/L; q3, 33 U/L), and hemoglobin (12.5 g/dL; q1, 10.9 g/dL; q3, 13.9 g/dL).

Additional Efficacy Data

In a similar trend to that observed for OS, the median rwPFS was numerically lower in the KRAS G12C mCRC cohort vs the non-G12C mutation cohort. In the overall cohort, the median rwPFS was 9.0 months (95% CI, 8.8-9.3). Furthermore, in the KRAS G12C mCRC cohort, the median rwPFS was 7.1 months (95% CI, 5.9-8.5) vs 8.9 months (95% CI, 8.4-9.2) in the non-G12C mCRC cohort.

Additionally, the median OS and rwPFS by first-line chemotherapy backbone treatment were associated with comparable outcomes in patients from the KRAS G12C mCRC cohort. In particular, patients treated with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) with or without bevacizumab (Avastin) had a median OS of 18.7 months (95% CI, 14.1-20.9), those treated with FOLFIRI (5-FU, leucovorinl, and irinotecan [Onivyde]) with or without bevacizumab had a median OS of 19.0 months (95% CI, 11.2-22.1). Those treated with FOLFOX alone had a median OS of 18.7 months (95% CI, 7.3-23.8), and those treated with FOLFIRI alone had a median OS of 18.1 months (95% CI, 5.6-23.9).

Patients who received FOLFOX with or without bevacizumab had a median rwPFS of 7.1 months (95% CI, 5.9-8.5), and those treated with FOLFIRI with or without bevacizumab had a median rwPFS of 8.8 months (95% CI, 4.5-11.1). Those treated with FOLFOX alone had a median rwPFS of 4.8 months (95% CI, 3.5-12.8), and 6.9 months (95% CI, 4.2-14.3) among those treated with FOLFIRI alone.

Disclosures: Eng disclosed having financial interests, personal, and advisory board participation with AbbVie, Amgen, EMD Serono, GSK, Janssen, Merck, Pfizer, Revolution Medicine, Taiho, and Takeda; financial interests, personal, advisory board, and KOL participation with Merus; participation in financial interests, institutional, and as an invited speaker for Agenus, Gritstone, Hutchinson, Janssen, Merck, Pfizer, and Sumitomo; and financial interests, institutional, and research grant participation with Haystack and Natera.

References

1. Eng C, Fakih MG, Sahin IH, et al. Real world first-line treatment outcomes of patients with KRAS G12C-or non-G12C KRAS mutated metastatic colorectal cancer in the US. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 46P.
2. Awad MM, Liu S, Rybkin II, et al. Acquired Resistance to KRASG12C Inhibition in Cancer. N Engl J Med. 2021;384(25):2382-2393. doi:10.1056/NEJMoa2105281
3. Koulouridi A, Karagianni M, Messaritakis I, et al. Prognostic Value of KRAS Mutations in Colorectal Cancer Patients. Cancers (Basel). 2022;14(14):3320. Published 2022 Jul 7. doi:10.3390/cancers14143320