Novel targeted therapy beyond EGFR and ALK: ROS1, BRAF, RET and MET

Abstract

Non-small-cell lung cancer (NSCLC) has recently been recognized as a heterogeneous set of diseases at the molecular level. Targeted therapy based on driver oncogenes such as EGFR and ALK has become standard of care in patients with advanced NSCLC. ROS1 rearrangements, BRAF V600E mutation, RET rearrangements and MET exon 14 skipping mutation are reported to be effective therapeutic targets for patients with advanced NSCLC. To date, crizotinib as ROS1 inhibitor and dabrafenib plus trametinib as BRAF and MEK inhibitors are also approved as driver oncogenes guided targeted therapy for patients with advanced NSCLC. However, the incidence of each driver oncogenes is low except for EGFR mutations in East-Asian patients. A nationwide lung cancer genomic screening project in Japan, so called LC-SCRUM-Japan has been operated since February 2013 for the development of targeted therapy for NSCLC patients with rare driver oncogenes. In 2012, RET rearrangements were identified as new driver oncogenes occurring in 1% to 2% of patients with NSCLC. Several phase 2 trials to evaluate single-agent multi-targeted RET inhibitors including cabozantinib, vandetanib, or lenvatinib, have demonstrated clinical antitumor activity in patients with RET-rearranged NSCLC. However, this efficacy was lower than that of targeted therapy in NSCLC patients harboring EGFR and ALK. Development of highly selective RET inhibitors might help to have greater antitumor activity. More recent investigations focusing on MET exon 14 skipping mutation have been notable for meaningful clinical responses to MET inhibitor in patients with MET-mutated NSCLC. MET exon 14 skipping mutation are also rare occurrence in NSCLC. Several clinical trials to evaluate MET inhibitors such as crizotinib, tepotinib, or capmatinib are ongoing in patients with MET-mutated NSCLC. Patients with NSCLC harboring rare driver oncogenes as ROS1, BRAF, RET and MET, will derive more effective benefit from specific targeted therapy.