Effectiveness of First-Line Treatment with Anaplastic Lymphoma Kinase and ROS1 Protoncogene Inhibitors in Non-Small Cell Lung Cancer Patients—Real-World Evidence of Two Polish Cancer Centers

<b>Introduction</b>: The use of ALK (anaplastic lymphoma kinase) and ROS1 (ROS1 protoncogene) inhibitors are the standard of care in advanced non-small-cell lung cancer (NSCLC) patients with <i>ALK</i> or <i>ROS1</i> gene rearrangements (approximately 5.5% of patients). Three generations of inhibitors are available, but there is no direct comparison of their efficacy in homogeneous Caucasian populations in real-world practice. In this retrospective study, we compare the efficacy of crizotinib, brigatinib, and alectinib in NSCLC patients with different clinical courses of the disease. <b>Materials and Methods</b>: One hundred four NSCLC patients with <i>ALK</i> or <i>ROS1</i> gene rearrangement were enrolled for first-line therapy with ALK inhibitors (crizotinib in 25 patients, brigatinib in 22 patients, and alectinib in 41 patients) or the ROS1 inhibitor (crizotinib in 16 patients) as part of daily clinical practice in two Polish cancer centers. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to treatment methods and clinical data. <b>Results</b>: In <i>ALK</i>-rearranged patients, ORR was insignificantly higher in patients treated with second-generation ALK inhibitors than in patients receiving crizotinib (68.25% vs. 48% of patients, <i>p</i> = 0.0547). Median PFS in the crizotinib group was 8 months, and in the group that received second-generation ALK inhibitors this was not reached (HR = 5.2182, 95% CI: 2.6163-10.4079, <i>p</i> < 0.0001). Similarly, median OS was significantly lower in patients treated with crizotinib than in patients receiving second-generation ALK inhibitors (26 vs. not reached, HR = 3.529, 95% CI: 1.5559-7.2258, <i>p</i> = 0.002). The efficacy of crizotinib in patients with <i>ROS1</i> and <i>ALK</i> gene rearrangement did not differ significantly (ORR-37.5 vs. 48%, median PFS-6 vs. 7 months, median OS-8 vs. 26 months, respectively). In <i>ALK</i>-rearranged patients, multivariate analysis showed that the only factor significantly increasing the risk of progression was liver metastases (HR = 2.1917, <i>p</i> = 0.0418). The risk of death was significantly higher in patients treated with crizotinib (HR = 2.4823, <i>p</i> = 0.0359) and in patients with liver metastases (HR = 3.1266, <i>p</i> = 0.0104). <b>Conclusions</b>: Second-generation ALK inhibitors are more effective than crizotinib in <i>ALK</i>-rearranged patients. Liver metastases, but not brain metastases, are the main clinical factors shortening PFS and OS in NSCLC patients treated with ALK inhibitors.