Monitoring of RAS/EGFR mutations in circulating tumor DNA to guide anti-EGFR therapy in mCRC patients: The CHRONOS trial. Monitoring of RAS/EGFR mutations in circulating tumor DNA to guide anti-EGFR therapy in mCRC patients: The CHRONOS trial

Anti-epithelial growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild type (WT) metastatic colorectal cancers (mCRC) but the emergence of tumor cell clones carrying resistance mutations restricts their efficacy. We showed previously that RAS, BRAF, and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti EGFR antibodies. We report here the results of CHRONOS, a phase II clinical trial exploiting blood-based identification of RAS/BRAF/EGFR ECD mutations levels to tailor a chemo-free anti-EGFR rechallenge with panitumumab in mCRC patients. In CHRONOS, patients with tissue-RAS WT tumors after a prior treatment with cetuximab or panitumumab-based regimens underwent an interventional ctDNA-based molecular screening. Out of 52 patients, 16 (31%) carried at least one anti-EGFR conferring resistance mutations in their ctDNA and were excluded from treatment.The responder patients were 30% while 63% achieved disease control with manageable side effects. In summary, CHRONOS’ results favorably compare with standard third line treatment options, and show that interventional liquid biopsies can be timely, effectively, and safely exploited to guide anti EGFR rechallenge therapy with panitumumab in mCRC patients.