A Retrospective Analysis of the Prognostic Impact of KRAS G12D Mutation in Patients with RAS-mutated Metastatic Colorectal Cancer.

105 Background: KRAS is an oncogene that is mutated in about half of all metastatic colorectal cancers (mCRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising efficacy for advanced solid tumors, including mCRC. A therapy targeting KRAS G12D mutation is also under development and promising efficacy is expected. However, the prognostic impact of the KRAS G12D mutation in patients with mCRC is still unclear. Methods: We retrospectively reviewed the medical records of patients with mCRC harboring RAS mutation who received first-line chemotherapy between January 2013 and December 2022 at our hospital in Japan. We compared the survival outcomes between patients with KRAS G12D mutation (G12D group) and those with non- KRAS G12D mutations (non-G12D group) in terms of progression-free survival (PFS) and overall survival (OS), using the Kaplan–Meier method and the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated by univariate and multivariate Cox regression analysis. Results: A total of 340 patients were included in this study. The main RAS mutations were KRAS G12D in 80 patients (23.4%), KRAS G12V in 72 (21.2%), KRAS G13D in 43 (12.6%) and KRAS G12C in 16 (4.7%). There were 80 patients in the G12D group and 260 in the non-G12D group. Patient backgrounds did not differ significantly in terms of age (median 61/63), sex (male 49%/48%), performance status (PS0 32%/32%), site of primary tumor (right 33%/32%), number of metastatic sites (3≤ 28%/23%), treatment regimen (doublet 90%/92%, triplet 3%/4%), or first line bevacizumab (yes 81%/79%). Median PFS was 9.2 months (95%CI: 7.8-12.2) in the G12D group vs. 11.5 months (95%CI: 9.2-13.1) in the non-G12D group (HR 0.97 [95%CI: 0.73-1.28]; p=0.81). Median OS was 25.8 months (95%CI: 18.8-39.8) vs 32.9 months (95%CI: 28.5-36.1) (HR 0.84 [95%CI: 0.60-1.19]; p=0.33). Second-line treatment was administered in 55 (69%) vs 192 (74%) patients in the G12D and non-G12D group, respectively. Conversion surgery was performed in 4 (5%) vs 18 (7%) patients in the G12D and non-G12D group, respectively. Multivariate analysis adjusted for PS, sex, age, site of primary tumor, number of metastatic sites and treatment regimen showed no significant differences in PFS and OS between the G12D and non-G12D groups. Conclusions: The KRAS G12D mutation did not show a detrimental prognostic impact on PFS and OS compared to KRAS non-G12D mutations in patients with RAS-mutated mCRC.