Review Note

1. EGFR: Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are observed in approximately 15% of NSCLC adenocarcinomas in the West, even more frequent in non-smokers and Asian populations. The use of EGFR tyrosine kinase inhibitors (TKIs – such as Osimertinib, Gefitinib and Erlotinib) is based upon the detection of these mutations, which may be detected either in solid tissue biopsies or in liquid biopsies. In advanced NSCLC, the presence of an EGFR mutation confers a more favourable prognosis and strongly predicts for sensitivity to EGFR TKIs, and therefore, targeted therapy should be used ahead of chemotherapy and immunotherapy in EGFR-positive NSCLC. For patients treated progressing on a first- or second-generation EGFR TKI, we offer repeat tumour or liquid biopsy to identify mechanisms of acquired resistance. 

2. ALK: Rearrangements involving the anaplastic lymphoma kinase (ALK) tyrosine kinase are present in approximately 4 percent of NSCLC adenocarcinomas in the United States and occur more frequently in nonsmokers and younger patients. ALK translocations can be identified by fluorescence in-situ testing (FISH), immunohistochemistry (IHC), or most next-generation sequencing (NGS) panels. In advanced-stage NSCLC, the presence of an ALK gene rearrangement (ALK-positive NSCLC) strongly predicts for sensitivity to ALK TKIs (eg, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib), and treatment with these agents significantly prolongs progression-free survival (PFS). 

3. ROS1: c-ROS oncogene 1 (ROS1) is a receptor tyrosine kinase that acts as a driver oncogene in 1 to 2 percent of NSCLCs via a genetic translocation between ROS1 and other genes, the most common of which is CD74. Histologic and clinical features that are associated with ROS1-positive NSCLC include adenocarcinoma histology, younger patients, and never-smokers. ROS1 translocations are identified by a FISH break-apart assay, similar to that used for ALK translocations, or by some NGS panels. The ROS1 tyrosine kinase is highly sensitive to the ROS1/MET inhibitor crizotinib as well as the ROS1/tropomyosin receptor kinase (TRK) inhibitor entrectinib. 

4. MET: MET is a tyrosine kinase receptor for hepatocyte growth factor. MET abnormalities include MET exon-14-skipping mutations (in 3 percent of lung adenocarcinomas and up to 20 percent of the relatively rare sarcomatoid-histology NSCLC) and MET gene amplification (in 2-4% of treatment-naïve NSCLC, and 5 to 20 percent of EGFR-mutated tumours that have acquired resistance to EGFR inhibitors). Exon-14-skipping mutations are most commonly found by DNA or RNA NGS, while MET amplification may be detected by FISH or some NGS panels. MET inhibitors include Capmatinib. 

5. RET re-arrangements: the rearranged during transfection gene (RET) encodes a cell surface tyrosine kinase receptor that is frequently altered in medullary thyroid cancer. Recurrent rearrangements between RET and various fusion partners (coiled-coil domain containing 6 [CCDC6], kinesin family member 5B [KIF5B], nuclear receptor coactivator 4 [NCOA4]) have been identified in 1 to 2 percent of adenocarcinomas, and occur more frequently in younger patients and in never-smokers. Rearrangements can be detected with break-apart FISH or NGS. 

6. BRAF: BRAF is a downstream signaling mediator of Kirsten rat sarcoma viral oncogene homolog (KRAS) that activates the mitogen-activated protein kinase (MAPK) pathway. Activating BRAF mutations have been observed in 1 to 3 percent of NSCLCs and are usually associated with a history of smoking. Detected by PCR or NGS. Patients with V600 BRAF mutations appear to have a better prognosis than those with non-V600 BRAF mutations, improving response to immunotherapy. 

7. NTRK fusions: very rare (<1 percent prevalent) in NSCLC. The oral TRK inhibitor larotrectinib is FDA approved for advanced tumours that have all of the following characteristics: harbour a neurotrophic receptor tyrosine kinase (NTRK) gene fusion, lack a known acquired resistance mutation, and have no satisfactory alternative treatments available (or have progressed following treatment)