Emergence of RAS mutations in patients with metastatic colorectal cancer receiving cetuximab-based treatment.

Abstract

208 Background: In management of patients with RAS wild-type mCRC, anti-EGFR therapies have demonstrated clinical benefit. However, the correlation between emergence of RAS mutations in circulating tumor DNA (ctDNA) and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy (NCT03401957). Methods: A total of 39 intention-to-treat (ITT) patients diagnosed with RAS wild-type mCRC, from Cathay General Hospital (CGH) and Kaohsiung Medical University Hospital (KMUH), were analyzed in this study. Of them, 24 were male and 15 were female, with median age of 55 years. Patients received cetuximab-based FOLFIRI or FOLFOX regimen as first-line treatment. Blood samples from enrolled patients were collected before and every 3 months during cetuximab-based treatment and also at disease progression. These blood samples were evaluated for RAS resistance mutations using MassARRAY platform. The primary endpoint is percentage of RAS mutations detected in ctDNA from patients during cetuximab treatment. The correlation between the tumor response of these patients and the emergence of RAS mutations in ctDNA is further analyzed. Results: Between January 2018 and July 2019, 3 (8.3%) of 36 per-protocol (PP) patients subsequently with newly detected ctDNA KRAS/NRAS mutations in their blood samples during the treatment period, and all of three patients developed progressive disease (PD). Of 36 PP patients, 19 (52.8%) patients had complete/partial response (CR/PR), 13 (36.1%) patients had stable disease (SD) and 4 (11.1%) patients had PD. The disease control rate was 88.9% in the present study. Three of 4 PD patients were detected with ctDNA KRAS/NRAS mutations in their blood sample, with time to onset of newly detected ctDNA RAS at 3 and 6 months posttreatment, respectively. Conclusions: In current study, the frequency of RAS mutations in blood samples during the treatment period was 8.3% and all of these 3 patients developed PD. The results of this study will offer substantial, valuable information for anti-EGFR therapeutic strategy in patients with mCRC.