<i>RAS</i> Mutations in Circulating Tumor DNA and Clinical Outcomes of Rechallenge Treatment With Anti-EGFR Antibodies in Patients With Metastatic Colorectal Cancer.

Abstract

Several trials have evaluated the efficacy of rechallenge treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that <i>RAS</i> status in circulating tumor DNA (ctDNA) may potentially predict patients with <i>RAS</i> wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for <i>KRAS</i> wild-type mCRC. <i>RAS</i> in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. <i>RAS</i> mutations were found at baseline in six patients. The DCR was 33% in patients with <i>RAS</i> mutations in ctDNA, whereas it was 80% in patients without <i>RAS</i> mutation at baseline. Patients with <i>RAS</i> mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without <i>RAS</i> mutation (median PFS, 2.3 <i>v</i> 4.7 months; hazard ratio [HR], 6.2; <i>P</i> = .013; median OS, 3.8 <i>v</i> 16.0 months; HR, 12.4; <i>P</i> = .0028). Six of 10 patients without <i>RAS</i> mutation at baseline acquired <i>RAS</i> mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with <i>RAS</i> mutation at progression. <i>RAS</i> status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in <i>RAS</i> wild-type mCRC.