Background: SOLSTICE, a phase 3 study, tested trifluridine/tipiracil+bevacizumab (FTD/TPI+bev) vs capecitabine+bevacizumab (cape+bev) in first-line for patients with unresectable metastaic CRC who were ineligible for intensive chemotherapy (full-dose doublet/triplet). As previously reported, the study did not meet the primary endpoint (progression-free survival (PFS): 9.4 months [95% CI, 9.1-10.9] for FTD/TPI+bev vs 9.3 months [95% CI: 8.9-9.8] for cape+bev, HR 0.87 [95% CI: 0.75-1.02]). Here we report on the key secondary endpoint – overall survival (OS) and an update of the safety data. Methods: From 21 Mar 2019 to 14 Sep 2020, 856 patients were randomized (1:1) to either FTD/TPI+bev or cape+bev. Stratification factors were: ECOG performance status (0 vs 1 vs 2), reason for non-eligibility for intensive therapy (clinical condition vs non-clinical condition) and tumor localization (right vs left). The primary endpoint was PFS based on investigator assessment according to RECIST 1.1 criteria. The key secondary endpoint was OS, defined as the time from randomization to death from any cause. Other secondary endpoints included overall response rate, disease control rate, quality of life, and safety. OS was analyzed after 578 events to detect a hazard ratio of 0.79 with 80.0% power at one-sided 2.5% level of significance. Results: 426 patients were randomly assigned to FTD/TPI+bev and 430 to cape+bev. The median OS was 19.74 months with FTD/TPI+bev and 18.59 months with cape+bev (HR, 1.06; 95% CI, 0.90, 1.25) with survival probabilies for FTD/TPI+bev vs cape+bev comparable at different timepoints. In the multivariate analysis, factors significantly associated with higher OS in the whole population were age < 70 years, left location of the primary disease, surgical resection of the primary tumor, number of metastatic sites (1-2 vs ≥3 sites), absence of liver metastasis, neutrophils lymphocyte ratio < 3, Charlson score 0 vs 1-2, and ECOG PS 1 vs 2. No significant treatment effect was observed after adjustment for the prognosis factors (HR, 1.08; 95% CI, 0.92, 1.28), which is consistent with the main OS analysis. The updated safety data was consistent with those communicated at the time of the primary PFS analysis. No new safety signal was identified. As previously reported, the most common severe emergent adverse events were neutropenia 54% vs 1%, neutrophil count decreased 19% vs 1%, anemia 16% vs 4%, hand-foot syndrome 0% vs 15%, and hypertension 9% vs 11% in FTD/TPI+bev vs cape+bev, respectively. Conclusions: This was the largest phase 3 study that explored two treatment regimens in a population ineligible for intensive therapy. FTD/TPI+bev was not superior to cape+bev in terms of PFS and OS. The risk of death was similar in both treatment arms. With a different and manageable safety profile, FTD/TPI+bev represents a feasible alternative to cape+bev in this population. Clinical trial information: NCT03869892.