Liquid Biopsy-Guided Cetuximab Rechallenge in mCRC: ESMO GI Cancers Congress | July 2026

Introduction: Resistance to anti-EGFR therapy has traditionally been considered irreversible in metastatic colorectal cancer (mCRC). However, emerging evidence suggests that resistance is dynamic and can be monitored using circulating tumor DNA (ctDNA). The CAPRI-2 trial evaluated whether liquid biopsy could identify patients who remain sensitive to cetuximab beyond disease progression.

Why was this study needed?

• Most patients eventually develop resistance to anti-EGFR therapy.
• RAS/BRAF wild-type status alone may not identify patients suitable for cetuximab rechallenge.
• Liquid biopsy offers a non-invasive method to detect acquired resistance mutations.
• Better patient selection could maximize benefit while avoiding ineffective therapy.
• Precision-guided rechallenge strategies require prospective validation.

Results:

• Patients with no ctDNA-detected anti-EGFR resistance mutations ("negative hyperselected") consistently achieved higher response rates, longer progression-free survival, and superior overall survival with continued cetuximab-based therapy.
• Cetuximab retained meaningful activity beyond disease progression in carefully selected patients, suggesting that EGFR dependence can persist despite radiological progression.
• These findings support liquid biopsy-guided treatment selection, although randomized studies are still needed before routine clinical adoption.

Clinical Impact:

This study strengthens the role of ctDNA as a real-time biomarker for guiding anti-EGFR rechallenge in metastatic colorectal cancer. Rather than discontinuing cetuximab solely because of disease progression, clinicians may be able to personalize therapy based on molecular evolution detected by liquid biopsy.

Bottom Line:

Liquid biopsy is redefining anti-EGFR rechallenge in metastatic colorectal cancer. Patients without ctDNA evidence of resistance mutations appear to derive continued benefit from cetuximab, moving treatment selection from radiological progression to molecular progression.