CtDNA-guided rechallenge with anti-EGFR therapy in RASwt metastatic colorectal cancer: Evidence from clinical practice

Abstract

Aim: To apply extended ctDNA-based RAS genotyping to clinical criteria for improving the selection of patients eligible for anti-EGFR-based rechallenge in a real-world setting. Methods: ctDNA testing was prospectively applied to RASwt mCRC progressed after a first-line anti-EGFR-containing regimen and at least one other line. The primary endpoint was the objective response rate. Results: Among ten enrolled patients, the anti-EGFR rechallenge resulted in an objective response rate and disease control rate of 70% and 90%. The median progression-free survival was 11.3 months and overall survival was not reached. Compared with a historical cohort retreated with anti-EGFR agents based on clinical criteria, the ctDNA-driven approach resulted in a higher chance of achieving an objective response and longer survival. Conclusions: Blood-based RASwt status may enrich metastatic colorectal cancer more likely to benefit from anti-EGFR-based rechallenge. RAS genotyping in ctDNA represents a feasible, fast, and cost-effective tool to be implemented in the clinic for advancing precision medicine.

Cetuximab as third‐line rechallenge plus either irinotecan or avelumab is an effective treatment in metastatic colorectal cancer patients with baseline plasma RAS/BRAF wild‐type circulating tumor DNA: Individual patient data pooled analysis of CRICKET and CAVE trials

“…1,4 Despite the potential clinical relevance that rechallenge might represent in EGFR-dependent RAS WT mCRC, only a limited number of relatively small size and mostly retrospective anti-EGFR rechallenge studies has been published so far. [7][8][9][10] In this respect, CRICKET and CAVE phase II were the first prospective clinical trials that reported clinically meaningful antitumor activity with an acceptable safety profile of rechallenge therapy with cetuximab in combination with the topoisomerase I inhibitor irinotecan or with the anti-programmed death ligand 1 (PD-L1) monoclonal antibody avelumab, respectively, in a subset of patients with RAS WT mCRC [i.e., with RAS/BRAF WT disease at baseline, as assessed by liquid biopsy analysis of circulating tumor DNA, (ctDNA)]. 11,12 Currently, analysis of RAS/BRAF WT ctDNA by liquid biopsy represents the only biomarker, that could identify patients that are potentially benefiting from anti-EGFR rechallenge, although new findings suggest that MAPK mutational status as well might be useful for rechallenge strategy.…”