A retrospective observational study to evaluate the efficacy of trifluridine/tipiracil ± bevacizumab in metastatic colorectal cancer with MSI-high/deficient MMR.

152 Background: MSI-high (MSI-H)/deficient MMR (dMMR) metastatic colorectal cancer (mCRC) have reported to be resistant to various cytotoxic agents including fluorouracil. On the other hand, preclinical study showed that trifluridine was effective to fluorouracil-refractory dMMR CRC cell lines. Previous studies on trifluridine/tipiracil (FTD/TPI) ± bevacizumab (BEV) for mCRC as later line treatment showed an objective response rate (ORR) of 1.1-5.6% and disease control rate (DCR) of 44-76.6%. However, there are no reports on the efficacy of FTD/TPI± bevacizumab in MSI-H/dMMR mCRC patients. Methods: We retrospectively evaluated the efficacy and safety of FTD/TPI ± BEV as second- or later-line treatment which patients with MSI-H/dMMR mCRC received between June 2012 and January 2023 at the 10 institutions. The primary endpoint was investigator-assessed objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse event rates. We also compared the FTD/TPI + BEV (FTB group) with FTD/TPI (FT group). Results: A total of 18 patients (FTB/FT, 9/9) were included. Patient characteristics were as follows (FTB/FT): median age, 70 (70/70) years; ECOG PS of 0/1, 7 (5/2)/11(4/7); primary tumor location of right side/left side, 12(6/6)/6(3/3); BRAF V600E mutant/wild-type, 6(3/3)/11(6/5); number of previous treatment lines of 1/≥2, 2(1/1)/16(8/8); number of metastatic sites of 1-2/≥3, 8(4/4)/10(5/5); prior use of anti-PD-1 therapy, 10(3/7). Efficacies in the whole population were as follows: ORR, 16.7% (95%CI, 3.6-41.4); DCR, 72.2%; median (m) PFS, 5.5 months; mOS, 11.8 months. Efficacies in each group (FTB vs. FT) were as follows: ORR (22.2% vs. 11.1%) and DCR (88.9% vs. 55.6%) were favored in FTB group than in FT group, while the median PFS were similar between two groups (5.6 months vs. 5.2 months). OS in FTB group was longer than in FT group (median, 18.9 months vs. 7.1 months; hazard ratio, 0.22; p value=0.03). Of 11 (FTB/FT, 7/4) patients who received subsequent treatment, 6 in FTB group and 1 in FT group received anti-PD-1 therapy. The most common grade 3 or more adverse events in each group (FTB vs. FT) were neutropenia (77.8% vs.77.8%), anemia (22.2% vs. 33.3%) and febrile neutropenia (0% vs. 22.2%). Conclusions: FTD/TPI ± BEV showed a promising efficacy and favorable safety. Although this was retrospective study with a small sample size, FTD/TPI ± BEV therapy may have better efficacies for MSI-H/dMMR mCRC than those for MSS/proficient MMR mCRC in previous prospective studies. Next generation sequencing as biomarker analysis using pretreated tissue samples is ongoing.