Pretreatment Plasma Circulating Tumor DNA RAS/BRAF Mutational Status in Refractory Metastatic Colorectal Cancer Patients Who Are Candidates for Anti-EGFR Rechallenge Therapy: A Pooled Analysis of the CAVE and VELO Clinical Trials

Rechallenge with epidermal growth factor (EGFR) inhibitors represents a promising therapeutic strategy in patients with refractory RAS/BRAF wild-type metastatic colorectal cancer (mCRC). The maximal benefit is observed in patients without resistance mutation at the baseline plasma circulating tumor DNA (ctDNA) evaluation. In the CAVE and VELO clinical trials, 1 out of 4 patients had ctDNA RAS/BRAF mutant disease at pretreatment liquid biopsy assessment. There was no direct association between the length of anti-EGFR drug-free interval and the presence of plasma ctDNA RAS/BRAF mutations at pretreatment liquid biopsy analysis. Interestingly, even the disappearance of mutant clones was time-dependent, and resistance mutations were found at liquid biopsy analysis in approximately 15% of patients after 18 or more months of anti-EGFR drug-free window. These results support the use of liquid biopsy to appropriately select amenable patients to EGFR inhibitor rechallenge. Rechallenge with anti-EGFR drugs represents a promising strategy in refractory RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC). We performed the pooled analysis of the CAVE and VELO studies to evaluate the percentage of patients with WT circulating tumor DNA (ctDNA) tumors and the association of mutational status with time from the last anti-EGFR drug administration. At baseline, 97/129 patients had RAS/BRAF WT plasma ctDNA, while 32/129 had RAS/BRAF mutated plasma ctDNA. Median anti-EGFR drug-free interval was 10.6 (CI 95%, 8.9-13.4) months in the plasma RAS/BRAF mutant group as compared to 13.0 (CI 95%, 11.1-16.6) months in RAS/BRAF WT group (p = 0.169). To investigate the time window of the RAS/BRAF mutant cancer cell clone disappearance, descriptive analysis using different time points was performed. No difference in the proportion of patients whose baseline plasma ctDNA was RAS/BRAF WT or mutated was found between 4 and 18 months since the last administration of anti-EGFR drugs. In contrast, 38/44 of patients with anti-EGFR drug-free interval of 18 months or more displayed a ctDNA RAS/BRAF WT status. Taken together, these results shows that the length of anti-EGFR free interval is not a sufficient criterion for patient selection, supporting the role of liquid biopsies for improving treatment efficacy.