Past and current developments in ALK-TKI resistant NSCLC

Abstract

EML4-ALK fusion gene-positive non-small cell lung cancer (NSCLC) was first reported in 2007. Crizotinib (Xalkori®), an ALK tyrosine kinase inhibitor (TKI), was subsequently reported to be effective for ALK fusion gene-positive NSCLC in 2010. This led to its clinical adoption for this indication in Japan two years later. In 2014, alectinib (Alecensa®) was clinically introduced in Japan. Meanwhile, it was reported as early as 2010 that secondary mutations in the ALK fusion gene occur as a mechanism of acquired resistance. Some conceivable mechanisms of acquired resistance to ALK-TKIs include secondary mutations (e.g., gatekeeper mutations), ALK fusion gene amplification, and the activation of the bypass track, though much has yet to be elucidated. It most likely will be necessary to develop treatment strategies in the future for each type of acquired resistance. Several clinical trials are ongoing or being planned as of 2015. In this article, we outline the development and current status of therapies for acquired resistance to ALK-TKIs.