OncoTargets and Therapy (Sep 2019)
Targeted Therapy For RET-Rearranged Non-Small Cell Lung Cancer: Clinical Development And Future Directions
Abstract
Christoph Jakob Ackermann,1 Gustavo Stock,2 Rebecca Tay,1 Mohammed Dawod,1 Fabio Gomes,1 Raffaele Califano1,3,4 1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; 2Department of Medical Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil; 3Department of Medical Oncology, Manchester University NHS Foundation Trust, Manchester, UK; 4Division of Cancer Sciences, University of Manchester, Manchester, UKCorrespondence: Raffaele CalifanoDepartment of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKTel +44 161 4463745Email [email protected]: Approximately 1–2% of unselected patients with Non-small Cell Lung Cancer (NSCLC) harbor RET rearrangements resulting in enhanced cell survival and proliferation. The initial treatment strategy for RET rearranged NSCLC has been multi-target tyrosine kinase inhibition. With overall response rates (ORR) of 16–53% and a median progression-free survival (PFS) of 4.5–7.3 months these outcomes are clearly inferior to the efficacy outcomes of selective tyrosine kinase inhibitors (TKI) in other oncogene-addicted NSCLC. Additionally, multi-kinase inhibition in RET-driven NSCLC patients showed concerning rates of high-grade toxicity, mainly induced by anti-VEGFR-kinase activity. Novel selective RET inhibitors like BLU-667, LOXO-292 and RXDX-105 have been recently investigated in early phase clinical trials showing promising efficacy with a manageable toxicity profile.Keywords: RET, NSCLC, LOXO-292, BLU-667, RXDX-105, selective RET-inhibition