ETD

• Anti-EGFR retreatment
• Circulating tumor DNA
• Colorectal cancer
• Metastatic disease

Circulating tumor DNA-guided anti-EGFR retreatment is an emerging strategy in the continuum of care of metastatic colorectal cancer (mCRC). This thesis reviews the biological rationale and clinical evidence supporting anti-EGFR rechallenge and presents the PARERE trial, a prospective randomized phase II study comparing two treatment sequences: panitumumab followed by regorafenib (Arm A) versus regorafenib followed by panitumumab (Arm B). All patients were prospectively screened by liquid biopsy, and only those with RAS/BRAF wild-type ctDNA were enrolled and randomized.
PARERE did not meet its primary endpoint of overall survival, but demonstrated clear superiority of panitumumab over regorafenib in terms of objective response rate, disease control rate, and progression-free survival, regardless of treatment position. The trial also showed that clinical criteria alone are insufficient to guide selection of candidates for anti-EGFR retreatment, as 38% of clinically eligible patients harbored ctDNA resistance alterations.
Exploratory analyses further suggested that a more stringent molecular selection approach, so called, hyperselection, encompassing resistance-associated alterations beyond RAS and BRAF, may further refine identification of the population most likely to benefit from retreatment.
Overall, PARERE establishes anti-EGFR rechallenge as a core therapeutic option within the continuum of care for chemo-refractory, RAS/BRAF wild-type mCRC.