Non-Small-Cell Lung Cancer: New Rare Targets—New Targeted Therapies—State of The Art and Future Directions

Simple Summary The use of novel therapeutic drugs in lung cancer has changed the paradigm of the diagnosis and treatment of lung cancer. Due to the development of advanced diagnostic procedures (e.g., next generation sequencing (NGS)) around half of non-small-cell lung cancer (NSCLC) patients can be identified with genetic aberrations. The presence of activating mutations of EGFR, ALK and ROS-1 have already been well explored. New targets that can be successfully targeted include NTRK, MET, RET and HER 2 genes. Some particles have already received FDA approval, whereas many more are in the late stages of clinical trials. Considering rapid changes in thoracic oncology, an up-to-date summary is needed. In this review, we present the current landscape of approved therapeutic drugs, as well as important ongoing clinical trials. Abstract Lung cancer is the most common cause of cancer-related death worldwide, and the prognosis for stage IV remains poor. The presence of genetic alterations in tumor cells, such as EGFR and BRAF gene mutations, as well as ALK and ROS1 gene rearrangements, are indications for targeted therapies. Many such treatments are already registered and used on a wide scale. In comparison to standard chemotherapy, they can prolong not only progression-free survival but also overall survival. Moreover, they are able to provide excellent quality of life and rapid improvement of cancer-related symptoms such as dyspnea, cough and pain. Recent years have witnessed great advances in both molecular diagnostics and new molecular therapies for non-small-cell lung cancer. This review presents new therapeutic targets in NSCLC, as well as drugs of which the activity against NTRK, RET, MET or HER2 gene alterations (including EGFR exon 20 insertions) has either been confirmed or is currently being evaluated. Although these particular genetic alterations in NSCLC are generally rare, each accounting for 1–2% of patients, in total about half of all patients have molecular alterations and may ultimately receive targeted therapies.