Abstract 4559: Paired liquid biopsies analysis reveals resistance mechanisms and prognostic factors in patients treated with KRASG12C inhibitors

Abstract Background: KRASG12C inhibitors (G12Ci) represent an emerging class of therapeutics. We aimed to explore resistance mechanisms and prognostic factors using liquid biopsy (LB) analyses. Methods: We retrospectively assessed LBs from patients (pts) treated with G12Ci (February 2022 - November 2024), under the STING trial (NCT04932525). Paired LBs (baseline and progressive disease (PD)) were analyzed using the FoundationOne Liquid CDx assay. Survival outcomes were calculated, and univariate/multivariate analyses performed with R packages “survival” and “survminer” (v 3.3-1 and 0.4.9). Results: A total of 18 pts treated with one or more G12Ci were included: NSCLC (n=9), colon cancer (n=8), and pancreatic cancer (n=1). All pts had a confirmed KRASG12C mutation in tissue samples. Three pts received two G12Ci sequentially. Overall, 21 LBs pairs were available: 13 included co-treatments (e.g., EGFR inhibitor (n=5), immunotherapy (n=4), and another small molecule (n=3)). At baseline LBs, KRASG12C was detected in 18/21 pairs (85.7%), and in 15/21 pairs at PD (71.4%). In three pairs the mutation was not detected at any timepoint. Overall response rate was 42.8% (9/21). At progression, acquired genomic alteration that may be associated with treatment resistance were identified in 6/21 pts (28.6%). All six pts exhibited at least one on-target KRAS alteration: KRAS amplification (n=2), KRAS R68S mutation (n=1), KRAS G12V (n=1), or KRAS mutations at G12A/D/F/S/Y, G13D, Q61H, R68S, Y96D (n=1). EGFR mutations (n=3),primarily associated with anti-EGFR resistance, a MET amplification (n=1), an ETV6 fusion (n=1), and a CDKN2A mutation (n=1) were also observed. Impact of the baseline variant allelic frequency (VAF) of the KRASG12C mutation on progression free survival (PFS) was assessed. The median PFS for pts with a VAF lower than the median (2.5%) was 7.5 months (95% CI: 5-NA), vs 4 months (95% CI: 2-NA) for those with a VAF higher, which was associated with worse PFS (p=0.0097). Univariate analysis revealed that the number of metastatic sites at baseline (HR: 2.00, 95% CI: 1.30-3.00, p = 0.0013) was associated with worse PFS, as well as higher baseline VAF (HR: 3.40, 95% CI: 1.30-8.90, p = 0.015). Multivariate analysis confirmed higher VAF at baseline as a predictor of worse PFS (HR: 2.79, 95% CI: 1.01-7.75, p = 0.0049), as did the baseline number of metastatic sites (HR: 1.84, 95% CI: 1.09-3.11, p = 0.022). The correlation between Tumor Fraction (cut-off 10%) and PFS was no statistically significant (p=0.081). Conclusion: Paired LBs represent a potential method for idenfying up to 28.6% of the resistance mechanisms to G12Ci. Complementary molecular methods, such as tissue biopsy molecular analysis, are needed to comprehensively identify resistance mechanisms. Higher VAF at baseline LBs and a greater number of metastatic sites were both associated with worse PFS. Citation Format: Kristi Beshiri, Damien Vasseur, Julieta Rodriguez, Smolenschi Cristina, Francesco Facchinetti, Antoine Italiano, Nicotra Claudio, Maud Ngo-Camus, Anas Gazzah, Capucine Baldini, Luc Friboulet, Yohann Loriot, Fabrice Barlesi, Christophe Massard, Antoine Hollebecque. Paired liquid biopsies analysis reveals resistance mechanisms and prognostic factors in patients treated with KRASG12C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4559.