Evolving Third-Line mCRC Treatment: Mechanisms, Efficacy, and Insights

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EP: 1.Evolving Third-Line mCRC Treatment: Mechanisms, Efficacy, and Insights

This educational program focuses on advancing care strategies for patients with metastatic colorectal cancer who have experienced disease progression after initial therapy. The discussion emphasizes the evolving treatment landscape, highlighting how third-line options have significantly expanded beyond the historically limited choices of FOLFOX and FOLFIRI. The current approach prioritizes comprehensive biomarker testing and molecular profiling to identify potential therapeutic targets, including rare fusions, before considering other available agents. This molecular-guided strategy is crucial as overall survival benefits tend to diminish in later treatment lines.

The available third-line therapeutic options include regorafenib, trifluridine/tipiracil, trifluridine/tipiracil plus bevacizumab, and fruquintinib, each with distinct mechanisms of action and tolerability profiles. Fruquintinib functions as a potent VEGFR inhibitor causing angiogenesis-related side effects like hypertension, palmar-plantar erythrodysesthesia, and wound healing complications. Trifluridine/tipiracil operates as a cytotoxic thymidine-based nucleoside analog, presenting typical chemotherapy-associated adverse events including neutropenia, thrombocytopenia, and gastrointestinal toxicities. Regorafenib acts as a multi-kinase inhibitor targeting VEGFR, KIT, and PDGFR pathways, producing similar angiogenesis-related side effects to fruquintinib.

Clinical efficacy data suggests that trifluridine/tipiracil may demonstrate superior objective response rates and disease control compared to regorafenib and fruquintinib, with fruquintinib showing favorable overall survival outcomes when utilized earlier in treatment sequences. However, the absence of direct head-to-head comparative studies necessitates reliance on indirect comparisons and real-world evidence for sequencing decisions. Optimal patient outcomes depend on thoughtful agent sequencing, effective adverse event management, and maintaining treatment adherence to maximize clinical benefit in this challenging patient population.