KRAS G12C mutations may be associated with a poorer prognosis with standard first-line chemotherapy regimens for patients with metastatic colorectal cancer (mCRC), according to Cathy Eng, MD.
In a poster presentation at the 2025 ESMO Gastrointestinal Cancers Congress, Eng and colleagues shared results from a retrospective real-world analysis evaluating outcomes of patients with KRAS G12C–mutated mCRC and KRAS non-G12C–mutated disease. In the KRAS G12C–mutated cohort (n = 304), the median overall survival (OS) was 18.2 months (95% CI, 14.7-20.0) compared with 19.1 months (95% CI, 18.4-19.8) in the non-mutated cohort (n = 3855) and 20.2 months (95% CI, 19.5-20.9) for the overall mCRC cohort (n = 8564). The median progression-free survival (PFS) was 7.1 months (95% CI, 5.9-8.5) in the KRAS G12C–mutated cohort (n = 180), 8.9 months (95% CI, 8.4-9.2) in the KRAS non-G12C cohort (n = 2185), and 9.0 months (95% CI, 8.8-9.3) in the overall cohort (n = 4905).
Notably, survival outcomes in the KRAS G12C–mutated cohort were comparable irrespective of chemotherapy backbone.
“[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 said in an interview with OncLive®.
In the interview, Eng highlighted the rationale for this real-world study, discussed the potential implications of the findings, and explained potential ways to approach treatment decisions for patients with KRAS G12C–mutated mCRC.
Eng is a professor of medicine and co-leader of the Gastrointestinal Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.
OncLive: What was the rationale and design behind the real-world analysis of KRAS G12C mutations in mCRC?
Eng: We dconducted a real-world analysis about the impact of the KRAS G12C mutation in mCRC, on behalf of data provided by Flatiron, as well as in collaboration with Amgen. We looked at [15,026] specimens, and we narrowed it down to [12,318] patients with mCRC.
As background, KRAS G12C [mutations occur in] approximately 2% of patients with CRC. Currently, we do have drugs that are specific to KRAS G12C, [such as sotorasib (Lumakras) and adagrasib (Krazati)].
The idea [for this analysis was to evaluate if the presence of KRAS G12C mutations] impacts overall prognosis when receiving standard chemotherapy [in the frontline setting], not necessarily specific to the KRAS G12C–[targeted] therapy. Out of those [12,318] specimens, they identified [5551] specimens with a KRAS non–G12C mutation, and then 455 specimens had a KRAS G12C mutation, which ended up being 3% [of the primary analysis set], so a little bit more than we had expected.
What trends in OS and PFS did the analysis reveal for patients with KRAS G12C mutations vs those with other KRAS mutations?
When looking at OS as well as PFS, it appears that [if] you have the presence of the KRAS G12C mutation, it actually may impact your overall prognosis a little bit less than what would be expected if you did not have it. For the entire patient population, for instance, the [median] OS [20.2] months. However, if you had the KRAS G12C mutation, [OS] was [numerically] less than the overall patient population, and it was even less vs those who had the KRAS non-G12C mutation. [KRAS G12C mutations] can have some impact on your OS, as well as your PFS.
Based on these findings, how might the presence of a KRAS G12C mutation influence treatment decision-making or prognostic assessment in clinical practice for patients with mCRC?
We have 2 drugs that have already been approved specifically in the setting of the previously treated mCRC [harboring KRAS G12C mutations]. We also now have trials more specific to the KRAS G12C patient population. As a provider, this entices me to try to obtain these drugs [for my patients] or have them participate in these clinical trials.
In the newly diagnosed setting, there is an ongoing trial specifically called [the phase 3] CodeBreaK 301 trial [NCT06252649] that involves sotorasib in combination with chemotherapy [and panitumumab (Vectibix)].
What does the future hold for the targeted treatment landscape in KRAS G12C–mutated mCRC, and how do you envision the role of personalized therapy evolving in this setting?
We’re finding that with a lot of our newest agents going further along in development that have a lot of great promise, instead of just keeping them in the heavily pretreated patient population, we want to try [to] move them forward so we can provide those options for our patients sooner and provide more selective therapy specific to their tumor type.
We want to encourage patients as much as possible to participate in clinical trials. That is of key importance and how we move the needle forward. If we don’t have patients participate in trials, it takes so much longer to make progress. [I would encourage clinicians to] continue to see what’s available to [patients].
Reference
Eng C, Fakih M, 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. Ann Oncol. 2025;36(suppl 1):S1-S65. doi: 10.1016/annonc/annonc1820