Targeting Infrequent Driver Alterations in Non-Small Cell Lung Cancer

The discovery of oncogenic driver mutations led to the development of targeted therapies with non-small cell lung cancer (NSCLC) being a paradigm for precision medicine in this setting. Nowadays, the number of clinical trials focusing on targeted therapies for uncommon drivers is growing exponentially, emphasizing the medical need for these patients. Unfortunately, similar to what is observed with most targeted therapies directed against a driver oncogene, the clinical response is almost always temporary and acquired resistance to these drugs invariably emerges. Here, we review the biology of infrequent genomic actionable alterations in NSCLC as well as the current and emerging therapeutic options for these patients. Mechanisms leading to acquired drug resistance and future challenges in the field are also discussed.