Real-world outcomes of trifluridine/tipiracil ± bevacizumab in refractory metastatic colorectal cancer: A SUNLIGHT validation study.

81 Background: The SUNLIGHT trial (2023) demonstrated improved overall survival (OS) with trifluridine/tipiracil (TAS-102) + bevacizumab compared to trifluridine/tipiracil alone in refractory metastatic colorectal cancer (mCRC). We evaluated the generalizability of these findings in a real-world U.S. cohort, including safety, healthcare utilization, and VEGF-related adverse events. Methods: Adults (≥18 y) with mCRC treated with trifluridine/tipiracil ± bevacizumab were identified in the TriNetX U.S. Collaborative Network. The index date was the first trifluridine/tipiracil exposure, with and without bevacizumab. Kaplan–Meier, log-rank, and Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs). Propensity score matching (1:1) was performed; matched cohorts were balanced for demographics, comorbidities, prior chemotherapy exposure, and genomic features, including BRAF and MSI/dMMR. Results: After matching (N=836 per arm), OS improved with trifluridine/tipiracil+bevacizumab vs trifluridine/tipiracil alone (median 290 vs 244 days; HR 0.84, 95% CI 0.75–0.95; p=0.002). Hospitalization (HR 1.36, 95% CI 0.99–1.88; p=0.13) and ER visits (HR 1.32, 95% CI 0.95–1.84; p=0.44) trended higher but were not significant. Neutropenia was increased (HR 1.48, 95% CI 1.06–2.06; p=0.02), while thrombocytopenia (HR 1.14, p=0.78) and anemia (HR 0.97, p=0.80) were not different. Pneumonia (HR 0.84, p=0.31) and septic shock (HR 0.95, p=0.80) showed no significant differences. Nausea/vomiting was higher (HR 1.51, p=0.007), liver enzymes trended higher (HR 1.60, p=0.06), and fatigue was not different (HR 1.14, p=0.30). VEGF-related events such as MI (HR 1.37, p=0.35), PE (HR 1.02, p=0.94), DVT (HR 1.11, p=0.57), and acute GI bleed (HR 0.79, p=0.26) were not significantly different. Outcomes of cardiac arrest, stroke, and new proteinuria could not be analyzed due to very low counts. Conclusions: In this large real-world analysis, trifluridine/tipiracil+bevacizumab conferred a significant OS benefit consistent with SUNLIGHT, at the cost of increased neutropenia and gastrointestinal toxicities (nausea/vomiting, trend toward liver enzyme elevation). Other cytopenias, infections, VEGF-related events, and exploratory endpoints were not significantly different. These findings confirm the external validity of SUNLIGHT in routine practice and signify the need for proactive toxicity monitoring.