Treatment of Advanced Non-Small Cell Lung Cancer with RET Fusions: Reality and Hopes

RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles. This class of medications currently represents the standard of care for both naive and patients that have not received selective RET-TKIs in the first-line setting. However, we presently lack a satisfactory understanding of resistance mechanism developing after selective RET-TKIs usage, as well as a specific treatment for patients progressing on selpercatinib or pralsetinib. Chemotherapy +/- immunotherapy is considered as a recommended subsequent second-line regimen in these patients. Therefore, it is of paramount importance to better define and understand the resistance mechanisms triggered by RET-TKIs. With this in mind, the present review article has been conceived to provide a comprehensive overview about RET+ advanced NSCLC, both from a therapeutic and molecular point of view. Besides comparing the clinical outcome achieved in RET+ advanced NSCLC patients after multikinase inhibitors (MKIs) and/or RET-selective TKIs' administration, we focused on the molecular mechanisms accountable for their long-term resistance. Finally, a critical perspective on many of today's most debated issues and concerns is provided, with the purpose of shaping the possible pharmacological approaches for tomorrow's therapies.

Automated summary

RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have transformed the treatment landscape for RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) due to their effectiveness and safety profiles. However, there is still limited understanding of resistance mechanisms after treatment with these TKIs. Chemotherapy +/- immunotherapy is currently recommended as a second-line treatment for patients progressing on selpercatinib or pralsetinib. Therefore, further research on the resistance mechanisms triggered by RET-TKIs is crucial.