New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2

Abstract

The 2004 discovery of EGFR mutations, followed by ALK rearrangements, ushered in a targeted therapy era for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC. In the last decade, rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies. Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets, including RET, NTRK fusions, c-MET alterations, and activating mutations in KRAS, BRAF, and HER2, all with frequencies greater than 1%. Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development. This review updates the therapeutic arsenal that especially targets those genes.

Keywords: BRAF; NTRK; KRAS; MET; RET; HER2; Non-small cell lung cancer; Targeted therapy; Uncommon mutations

Core Tip: Compared to other types of cancer, non-small cell lung cancer (NSCLC) is highly genetically altered. Outside of EGFR, ALK, and ROS1, reflecting 15%-20% of clinical practice, other molecular alterations with important recent advances in their therapeutic arsenal and already in phase II/III trials are BRAF, KRAS, RET, MET, NTRK, and HER2. The goal is to achieve, compared to conventional treatments such as chemotherapy, better symptom control, better response rates, and improved progression-free survival and overall survival in patients with NSCLC.