Abstract:

Third-line treatment for metastatic colorectal cancer (mCRC) refers to subsequent therapeutic interventions following the failure or intolerance of first- and second-line treatments. This represents a critical challenge in clinical practice and a core focus of translational medicine research in recent years. With advancements in molecular typing technologies and the emergence of novel therapies, the third-line treatment strategy has evolved from traditional chemotherapy toward precision targeting and immunotherapy. A comprehensive literature search was conducted across PubMed, ClinicalTrials.gov database and American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO) conference abstracts. Phase Ⅲ randomized controlled trials, phase Ⅰ/Ⅱ frontier clinical studies, and authoritative reviews were included, with an emphasis on data related to survival benefits, drug resistance mechanisms, and biomarkers. This review provided an in-depth analysis of significant progress in third-line treatment strategies for mCRC, encompassing standard therapies [regorafenib, fruquintinib, trifluridine/tipiracil, anti- epidermal growth factor receptor (EGFR) rechallenge therapy], targeted therapies (e.g., BRAF V600E inhibitors, ERBB2 amplification inhibitors, KRAS G12C inhibitors) and immunotherapies [microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR), microsatellite stable (MSS)/proficient mismatch repair (pMMR) and target-immune combination therapies]. Notable breakthroughs have been achieved in targeted therapies. Anti-EGFR rechallenge therapy extended the median overall survival (OS) to 17.3 months in RAS/BRAF wild-type patients identified through dynamic circulating tumor DNA (ctDNA) monitoring. However, drug resistance remains complex, with high secondary mutation rates necessitating further optimization of dynamic monitoring systems. For BRAF V600E mutations, triple therapy (encorafenib+binimetinib+cetuximab) demonstrated a median OS of 9.3 months [hazard ratio (HR)=0.52], surpassing conventional treatments. The combination of KRAS G12C inhibitor adagrasib with cetuximab achieved an objective response rate (ORR) of 34% and a median OS of 15.9 months, though tumor resistance continued to pose challenges. In the realm of immunotherapy, dual immunotherapy (nivolumab+ipilimumab) yielded a 4-year OS rate of 71% in MSI-H/dMMR patients. For MSS patients, immune-targeted combination strategies (e.g., cabozantinib+atezolizumab) increased the ORR to 27.6%. Emerging therapies include artificial intelligence platforms for precision medicine, gut microbiota-based biomarkers and fecal microbiota transplantation, as well as advancements in chimeric antigen receptor-T (CAR-T) cell therapy. By summarizing the current status and progress of third-line treatment for mCRC, this review aims to inform clinical decision-making and guide future research directions.

Key words: Metastatic colorectal cancer, Third-line treatment, Targeted therapy, Immunotherapy, Biomarkers, Drug resistance mechanism