Codon-specific KRAS mutations predict overall survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.

• DOI: 10.1200/jco.2022.40.16_suppl.3593
• Publication Date: 2022-06-06T16:13:21Z
• Authors: Joris van de Haar; Xuhui Ma; Salo N. Ooft; Pim W. van der Helm; Louisa Rose Hoes; Sara Mainardi; Lodewyk F.A. Wessels; Emile E. Voest
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

3593 Background: Genomics-based precision medicine has greatly improved how patients with cancer are being treated targeted agents, but clinical-grade genomic biomarkers for chemotherapies currently lacking. The chemotherapeutic trifluridine/tipiracil (FTD/TPI) is approved the treatment of late-stage metastatic colorectal (mCRC). We aimed to find improve patient selection FTD/TPI in mCRC. Methods: In a discovery cohort FTD/TPI-treated mCRC (n = 37), genome-wide somatic variants were tested association duration and overall survival (OS). vitro drug testing on isogenic cell lines patient-derived organoids, as well re-analysis double-blind, placebo-controlled, phase 3 RECOURSE trial 800) performed support our findings. Results: cohort, KRAS codon G12 (KRAS ) mutation status was only significant determinant poor outcome treatment, which could be replicated by PDOs. these models, mutations associated increased resistance FTD-induced (geno)toxicity vitro. -based absent closely related 5-FU. study, predictive reduced OS benefit vs placebo (unadjusted interaction P= 0.0017, adjusted 0.017). For mutations, not significantly prolonged 279; HR, 0.97; 95% CI, 0.73−1.20; 0.85). An exploratory analysis showed that G13 mutant subgroup demonstrated clearly 60; unadjusted 0.29; 0.15−0.55; P< 0.001; 0.20; 0.092−0.45; 0.001), more pronounced compared WT populations (adjusted 0.001 0.036, respectively). Conclusions: Together, potential implications ̃28% now considered FTD/TPI. Furthermore, data show genomics-based may possible subset chemotherapies.