ISY-18-2 - Latest Advance to Clinical Development and Future Perspective for RAS/BRAF-mutated Metastatic Colorectal Cancer

Abstract

Expanded RAS (KRAS and NRAS) testing was the validated predictive biomarker for primary resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with metastatic colorectal cancer (mCRC) (Taniguchi H, Yoshino T, et al. Cancer Sci. 2015). Recently, around half of mCRC showing transformation of RAS status (wild to mutant) has been observed after treatment with anti-EGFR therapy by means of blood-based molecular testing using cell -free tumor DNA in a large-scale retrospective analysis from the pivotal phase 3 trial, suggesting RAS mutation confers acquired resistance to anti-EGFR therapy (Tabernero J, Yoshino T, et al. Lancet Oncol. 2015). On the basis of nonclinical research demonstrating the double blockade of EGFR and MEK intercepts heterogeneous mechanism of action of acquired resistance to anti-EGFR therapy in colorectal cancer, early clinical trials are ongoing to investigate feasibility and biologic activity of the combination with a MEK inhibitor plus an EGFR mAb. BRAF-mutated mCRC carries a poor prognosis, and reactivation of EGFR signaling with BRAF inhibition and/or uninhibited PI3K signaling may explain the limited efficacy of BRAF inhibitor monotherapy in patients with BRAF-mutated mCRC. Recent nonclinical data have demonstrated synergistic activity of the combination of a BRAF inhibitor and an EGFR inhibitor in in vitro and in vivo models of BRAF-mutated CRC. Ongoing early clinical studies, i.e., the combination of a BRAF inhibitor and an EGFR mAb W/or W/O a MEK inhibitor, and a BRAF inhibitor and an EGFR mAb W/or W/O a PI3Kα inhibitor, showed promising clinical activity, including improved overall response rate, progression-free survival and overall survival relative to historical data (Van Cutsem E, Yoshino T, et al. at ESMO-GI 2015 and Tabernero J, Yoshino T, et al. at ASCO2016). Current clinical development for RAS/BRAF-mutated mCRC may represent substantial progression toward more precision medicine.