Who Truly Benefits from Anti-EGFR Rechallenge in Metastatic Colorectal Cancer? From Clinical Enrichment to ctDNA-Guided Molecular Hyperselection.

Later-line treatment of metastatic colorectal cancer (mCRC) remains challenging because established salvage options often provide limited objective response and predominantly cytostatic benefit. Anti-epidermal growth factor receptor (EGFR) rechallenge has re-emerged as a rational strategy for a selected subgroup of patients who previously benefited from EGFR blockade. This narrative review summarizes the biologic rationale, clinical evidence, and practical implementation of anti-EGFR rechallenge, with emphasis on the distinction between currently supported practice and investigational concepts. The most established selection principles are prior clinical benefit from anti-EGFR therapy and real-time molecular reassessment, particularly the absence of detectable RAS/BRAF and, where feasible, EGFR extracellular-domain resistance alterations in circulating tumor DNA (ctDNA). Broader molecular hyperselection and longitudinal ctDNA-guided decision models are promising but remain less standardized and require prospective validation. Outcomes across studies differ not only because of selection depth, but also because of regimen backbone, eligibility criteria, assay timing and breadth, disease setting, and study design. Anti-EGFR rechallenge should therefore be viewed as an emerging biomarker-guided retreatment strategy within the later-line continuum of care rather than as empirical drug re-use after a washout interval or as a fully standardized precision-oncology algorithm.