Abstract 105P
Background
KRASG12C inhibitors (G12Ci) represent an emerging class of therapeutics. We explored resistance mechanisms and prognostic factors using liquid biopsy (LB) analyses.
Methods
Retrospective analysis of LBs was conducted for patients (pts) treated with G12Ci from 2022 to 2024 under the STING trial (NCT04932525). Paired LBs (baseline and progressive disease [PD]) were evaluated using the FoundationOne Liquid CDx assay. Survival outcomes were analyzed using the “survival” and “survminer” R packages (v3.3-1 and 0.4.9).
Results
A total of 18 pts were included: NSCLC (n=9), colon cancer (n=8) and pancreatic cancer (n=1). All pts had a confirmed KRASG12C mutation in tissue samples. Overall, 21 pairs LBs were available: 13 included co-treatments (e.g., EGFR inhibitors [n=5], immunotherapy [n=4], small molecules [n=3]). At baseline, KRASG12C was detected in 18/21 pairs (85.7%), and in 15/21 at PD (71.4%). Three pairs showed no KRASG12C detection. Overall response rate was 42.8% (9/21). At PD, resistance-associated genomic alterations were observed in 28.6% (6/21), with a multiple mechanisms in four pts and unique in two. All six developed at least one on-target alteration affecting KRAS: two KRAS amplification, one KRAS R68S mutation, one KRAS G12V , one KRAS mutations at G12A/D/F/S/Y, G13D, Q61H, R68S, and Y96D, and one KRAS G12A/F and R68S. 3 EGFR mutations, a MET amplification, a ETV6 fusion, primarily associated with anti-EGFR resistance, and a CDKN2A mutation, were identified. 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). These data were confirmed in multivariate analysis, where a VAF higher than the median (2.5%) remained a significant predictor of worse PFS (HR: 2.79, 95% CI: 1.01-7.75, p = 0.0049), as did the number of metastatic sites (HR: 1.84, 95% CI: 1.09-3.11, p = 0.022). Correlation between Tumor Fraction (cut-off 10%) and PFS was no statistically significant (p=0.081).
Conclusions
Paired LBs identified resistance mechanisms in 28.6% of cases with higher VAF at baseline and a greater number of metastatic sites associated with worse PFS.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
D. Vasseur: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca. C. Smolenschi: Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Institutional, Other, Pi: BMS; Financial Interests, Personal, Other, Funding: Merck. A. Italiano: Other, Institutional, Other: Merck, Lilly, AstraZeneca, BMS, MSD, Bayer. C. Baldini: Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Expert Testimony: MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Invited Speaker: iTeos, AZ, Janssen, Amgen, Bicycle Therapeutics, MSD, Seattle Genetics, Taiho, Pyramid Bioscience, Tango, Roche Genentech; Non-Financial Interests, Personal, Member: ASCO, SIOG, SOFOG, AACR, ESMO. L. Friboulet: Financial Interests, Institutional, Other: Nuvalent, Sanofi, Debiopharm, Incyte, Relay Therapeutics. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck Kga, Pfizer, Gilead, Seattle Genetics, Taiho; Financial Interests, Personal, Other, lectures, advisory boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, lectures, advisory boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Invited Speaker: Janssen, Pfizer, Janssen, MSD, Janssen, Exelixis, AstraZeneca, Pfizer, Merck Kga, BMS, Astellas, Gilead, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Astellas, Gilead/Immunomedics, Basilea, Taiho; Non-Financial Interests, Personal, Member: ESMO, ASCO, AACR; Non-Financial Interests, Personal, Other, scientific committee: ARC. F. Barlesi: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd., Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda, AbbVie, ACEA, Amgen, Eisai, Ignyta, Summit Therapeutics; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. C.P. Massard: Other, Personal, Other, Christophe Massard: Consultant/Advisory fees from Amgen, Astellas, AstraZeneca, Bayer Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Netcancer, PegascyPrincipal/sub-Investigator of Clinical Trials for AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo Pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 Biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, MedImmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor. A. Hollebecque: Financial Interests, Personal, Invited Speaker: Servier, Incyte, Eisai, BMS; Financial Interests, Personal, Advisory Board: Basilea, Taiho, Relay Theraeutics, QED Therapeutics, Debiopharm, MSD, Boehringer Ingelheim; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, M19-345; M21-404: AbbVie; Non-Financial Interests, Personal, Principal Investigator, CO42216; WP42627; CO40939; GO44479; GO42216: Roche; Non-Financial Interests, Personal, Principal Investigator, MCLA-158; MCLA-128: Merus; Non-Financial Interests, Personal, Principal Investigator, SGNB6A: Seatle Genetics; Non-Financial Interests, Personal, Principal Investigator, TAS-120-202: Taiho; Non-Financial Interests, Personal, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Personal, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Personal, Principal Investigator, ACT16902: Sanofi; Non-Financial Interests, Personal, Principal Investigator, C4201002; SGNB6A: Pfizer; Non-Financial Interests, Personal, Principal Investigator, RLY-4008: Relay Therapeutics; Non-Financial Interests, Personal, Principal Investigator, CC-90011: Celgene/BMS; Non-Financial Interests, Personal, Principal Investigator, Loxo-IDH; Loxo-RAS: Loxo/Lilly; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, SN-201 study: Sotio; Non-Financial Interests, Personal, Principal Investigator, Tropics-03: Gilead; Non-Financial Interests, Personal, Principal Investigator, BI1403: Boehringer Ingelheim; Non-Financial Interests, Personal, Principal Investigator, CA120-1001: BMS. All other authors have declared no conflicts of interest.