Targeted Therapy in Non-Small-Cell Lung Cancer (Beyond Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase)

Genomic alterations in non-small-cell lung cancer (NSCLC) define distinct subtypes with specific mechanisms leading to tumor growth and metastasis. Targeted therapy, usually with small molecule tyrosine kinase inhibitors (TKIs), has changed the paradigm for treatment of patients with NSCLC that harbor an activating mutation or gene rearrangement. The number of targets and treatments is growing for patients with NSCLC. Tumors with ROS1 gene rearrangements are responsive to crizotinib and ceritinib. BRAF inhibitors dabrafenib and vemurafenib have activity in patients with NSCLC with BRAF V600E mutation. In addition, the combination of dabrafenib and trametinib has demonstrated increased tumor responses in these patients. Emerging targets include the mesenchymal epidermal transition (MET) gene, through gene amplification and exon 14 skipping mutations, and tumors have been shown to have sensitivity to MET inhibitors. RET gene alterations occur in several tumor types, and multitargeted TKIs can inhibit RET, resulting in antitumor responses. Human epidermal growth factor receptor 2 (HER2) can be amplified in NSCLC, and HER2 mutations have also been described. Treatment with HER2-targeted therapy has resulted in varied responses. Rare alterations can be challenging to identify, and developing targeted treatments often needs an approach across multiple tumors. Neurotrophin tyrosine kinase receptor alterations are found in many tumor types, including pediatric tumors, and often the genomic alteration and response to therapy is not dependent on tumor type, demonstrating molecular connections between diverse tumors. Targeted therapies have led to improved outcomes for patients with lung cancer, and additional targets and treatments continue to emerge.