Selumetinib in advanced non small cell lung cancer (NSCLC) harbouring KRAS mutation: endless clinical challenge to KRAS-mutant NSCLC.

Abstract

During the past few years, oncologists have witnessed the reclassification of non small cell lung cancer (NSCLC) as not one disease, but several molecularly defined subsets of disease with relevant therapeutic implications in the field of molecularly targeted therapies. Two not very common genetically defined subsets of NSCLC, including those with EGFR or ALK activating mutations, and show high sensitivity to tyrosine-kinase inhibitors such that patients frequently have sustained clinical responses to therapy. However, the largest subset harbours an activating KRAS mutation and up to now, no successful targeted therapy has been developed for RAS-mutant lung cancer, with few compounds being assessed by clinical trials. In fact, KRAS has remained an elusive target for cancer therapy for biologic reasons. The chief value of KRAS lies in providing information about the other biomarkers that are directly druggable, that is, EGFR and ALK. The presence of mutated KRAS rules out ALK and EGFR, and KRAS may therefore form part of an efficient pathway in a testing algorithm. Currently, KRAS itself remains undruggable despite decades of effort, but attention has recently focused on inhibition of the Ras-contingent downstream signalling. Selumetinib (AZD6244; ARRY-142886) is an oral, tight-binding, uncompetitive inhibitor of mitogen-activated protein kinase kinases (MEK) 1 and 2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers and currently in clinical development. The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. Recently, in a randomised, phase II trial selumetinib plus docetaxel has proven to improve progression free survival compared to docetaxel alone in previously treated patients with advanced KRAS-mutant NSCLC.