Second line EGFR-inhibitors in RAS mutant metastatic colorectal cancer: the plasma RAS wild type “window of opportunity”
RAS mutations are found in 30-50% of metastatic colorectal cancer (mCRC) and determine the ineligibility for EGFR-targeted therapies. Recent studies have demonstrated that the analysis of circulating tumor DNA (ctDNA) is a surrogate of tumor biopsy for mutations detection. To date, studies have been focused on the appearance of RAS-mutant clones in patients with RAS-wild type mCRC, as biomarkers of anti-EGFR therapy resistance. We here describe a population of RAS mutant mCRC who converted to wt -RAS status in blood over the course of first-line treatments. As proof of concept, the absence of any clinically relevant mutation of RAS genes in blood has been used as a therapeutically exploitable window. To this purpose five patients received second-line treatment with anti-EGFR, achieving a durable clinical benefit.
Blood samples from 20 patients with mutant RAS status were prospectively collected before initiating first- line therapies. RAS mutational status was assessed on tumor tissue and plasma samples at baseline. In all cases with plasma-tissue concordance at baseline (n. 15), RAS mutations were serially monitored every 3 months. Idylla™(Biocartis) was used to investigate RAS mutational profile from plasma. Specifically, Idylla™ ctKRAS Mutation Assay and Idylla™ ctNRAS/BRAF/EGFR Mutation Assay were used.
15 mCRC patients harboring any RAS mutation in tumor tissue and plasma at the time of diagnosis were serially monitored through plasma ctDNA analysis. Eleven patients (73%) switched to a wild- type RAS status in blood during the course of first line treatments. At disease progression in the first-line setting, 5 of them have received EGFR inhibitors as a second-line treatment, achieving a durable clinical benefit.
ctDNA analysis might reveal a therapeutically exploitable window of opportunity, characterized by the prevalence of wt -RAS clones, which can be converted in a clinically meaningful benefit for patients. Our planned KAIROS trial might determine whether the response to EGFR inhibition, in patients with RAS mutant cancers converted to RAS wild-type in course of treatments, might become the rule rather than the exception.