Onkológia 1/2021

Inhibition ALK and ROS1 in the treatment of metastatic non-small lung cancer – new treatment options and recommendations

Lung cancer is one of the most common cancers worldwide. About 60% of all lung tumors belong to the non-small cell histological subtype group. With the development of molecular genetic testing (IHC, FISH, NGS), lung cancer has become quite a heterogeneous group. 5% of the non-small lung cancer (NSCLC) group have a positive rearrangement of EML4-ALK and a 1-2% presence of rearrangement of the ROS1 gene. Presently, lung cancer with EML4-ALK rearrangement represents a frequently used disease model for the use of various targeted molecules. A breakthrough in the treatment of these tumors occurred in 2007, when Japanese authors first described the fusion of the ALK gene with the EML4 gene (echinoderm microtubule associated protein like)1. The first identified molecule to exert a significant effect was krizotinib. Since then, tyrosine kinase inhibitors have developed with high efficacy and pushed chemotherapy into the background. In an effort to overcome resistance to krizotinib, the development of new drugs has advanced significantly. Based on clinical studies ALEX and ALTA-1L, second generation ALK inhibitors alectinib and brigatinib uncompromisingly displaced krizotinib from first lineage treatment. They exhibit much higher systemic efficacy and have significantly better penetrating effect into the central nervous system (CNS). In addition, lorlatinib and brigatinib are the preferred line of treatment after progression to ALK inh. second generation, resp. after krizotinib failure. Notable development has also occurred in the treatment of ROS1 positive disease. The ROS1 and ALK genes are structurally similar, therefore ALK inhibitors form the basis of treatment for ROS1-positive patients. Based on the impressive results of the PROFIL 1001 clinical study, the FDA and subsequently the EMA approved krizotinib in the first-line treatment of ROS1-positive NSCLC patients. The main limitations of krizotinib are decreased blood-brain barrier penetration and an increasing number of cases wtih disease progression. This has ultimately led to latest clinical trials and the use of novel TKIs to treat ROS1 - positive patients such as lorlatinib, entrectinib and repotrectinib.

Keywords: metastatic non-small cell lung cancer, EML4-ALK, aquired resistance, ROS1, alectinib, brigatinib, lorlatinib, entrectinib, crizotinib