Management of Non-Metastatic Non-Small Cell Lung Cancer (NSCLC) with Driver Gene Alterations: An Evolving Scenario

The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of mutations or gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than and . To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected -mutated NSCLC in stage IB-IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable -mutated NSCLC showed the relevant PFS improvement. In the -positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)-IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in and -positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than or . In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease.