New Generations of Tyrosine Kinase Inhibitors in Treating NSCLC with Oncogene Addiction: Strengths and Limitations

SIMPLE SUMMARY: This manuscript focuses on improving the treatment of non-small cell lung cancer, with actionable gene alterations. The aim is to understand how the treatment with Tyrosine Kinase Inhibitors (TKIs) can be used and improved. Newer generations of TKIs have better results in controlling the disease and extending patient survival. These drugs also work better in the brain, which is crucial for patients with brain metastases. However, there are challenges. The use of newer TKIs may limit the role of older ones, and resistance to the drugs can emerge. The considerations from this manuscript suggest that understanding the biology of the tumor and the properties of the drugs could help develop new treatment strategies and ultimately benefit patients with this type of lung cancer. ABSTRACT: Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring most driver gene alterations. Starting from the first generation, research rapidly moved to the development of newer, more selective generations of TKIs, obtaining improved results in terms of disease control and survival. However, the use of novel generations of TKIs is not without limitations. We reviewed the main results obtained, as well as the ongoing clinical trials with TKIs in oncogene-addicted NSCLC, together with the biology underlying their potential strengths and limitations. Across driver gene alterations, novel generations of TKIs allowed delayed resistance, prolonged survival, and improved brain penetration compared to previous generations, although with different toxicity profiles, that generally moved their use from further lines to the front-line treatment. However, the anticipated positioning of novel generation TKIs leads to abolishing the possibility of TKI treatment sequencing and any role of previous generations. In addition, under the selective pressure of such more potent drugs, resistant clones emerge harboring more complex and hard-to-target resistance mechanisms. Deeper knowledge of tumor biology and drug properties will help identify new strategies, including combinatorial treatments, to continue improving results in patients with oncogene-addicted NSCLC.