Preclinical analysis and clinical validation to identify biomarkers for trifluridine/tipiracil (FTD/TPI) efficacy with or without bevacizumab in patients with metastatic colorectal cancer.

230 Background: We previously identified candidate biomarkers for FTD/TPI efficacy through preclinical and translational studies in patients with metastatic colorectal cancer (mCRC). Recent studies reported that FTD/TPI plus bevacizumab (BEV) improved survival compared to FTD/TPI alone. This study evaluated the clinical significance of these biomarkers in patients with refractory mCRC receiving either FTD/TPI plus BEV or FTD/TPI alone. Methods: Candidate biomarkers were selected based on our transcriptomic and cell biological analyses. We validated these biomarkers in mCRC patients treated with FTD/TPI plus BEV (cohort A) or FTD/TPI alone (cohort B). Blood samples were collected at baseline (BL), before the second cycle (2nd), and progressive disease (PD), with serum biomarker levels measured using ELISA. Change patterns were classified as ‘increased’ or ‘decreased’ from BL. To address the unbalanced distribution of baseline characteristics between cohorts, propensity score matching (PSM) was performed. Results: A total of 112 patients were included, with 34 in each cohort after PSM. Cohort A showed significantly longer overall survival (OS) (14.4 vs 6.2 months, HR 0.53, 95%CI: 0.30-0.93) and higher disease control (DC) (58.8 vs 34.4%, P=0.047) compared to cohort B. In univariate analysis, increased IL-8 or AREG at 2nd and increased IFI16 at PD were associated with poorer clinical outcomes. Grade ≥3 neutropenia (NEU) was linked to better survival in both cohorts. Multivariable analysis identified decreased AREG and Grade ≥3 NEU as better markers for progression-free survival and OS. OS was significantly longer in cohort A compared to B (12.8 vs 5.8 months, HR 0.43, 95%CI: 0.21-0.89) when IL-8 increased at 2nd. Cohort A also had longer OS compared to cohort B when EREG (12.8 vs 6.2 months, HR0.27, 95%CI: 0.11-0,65) or AREG (14.2 vs 9.7 months, HR 0.40, 95%CI: 0.17-0.95) decreased at 2nd. There was no significant interaction between the regimen and biomarkers (IL-8, EREG, and AREG) for OS. Conclusions: Our data suggest that AREG may serve as a prognostic marker for FTD/TPI efficacy. Changes in IL-8, EREG and AREG potentially contribute to the extended survival benefit of combining BEV with FTD/TPI.