Targeted Therapy For RET-Rearranged Non-Small Cell Lung Cancer: Clinical Development And Future Directions

: 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.