Clinical study of lorlatinib/lorlatinib in the treatment of ROS1-positive non-small cell lung cancer

Lorlatinib/lorlatinib (Lorlatinib), as a highly effective, oral, selective third-generation tyrosine kinase inhibitor (TKI), can specifically act on ALK and ROS1. Through a unique structural design, lorlatinib can effectively cross the blood-brain barrier and reduce the efflux of P-glycoprotein-1, thereby increasing the concentration of the drug in the central nervous system. Preclinical experimental data show that lorlatinib has a significant inhibitory effect on ROS1, and also shows different inhibitory effects on various ROS1 resistance mutations.

The pathogenesis of ROS1-rearranged tumors is highly similar to ALK-positive non-small cell lung cancer. Currently, the treatment options for patients with advanced ROS1-rearranged non-small cell lung cancer mainly rely on first-line drugs such as crizotinib, ceritinib, or entrectinib. The median progression-free survival (mPFS) of these drugs ranges from 6 to 20 months. However, due to the emergence of resistance mechanisms such as mutations in the kinase domain, all ROS1 NSCLC patients will eventually experience tumor progression.

In one clinical study, a total of 364 patients were evaluated, 69 of whom had ROS1-positive non-small cell lung cancer. Among these patients, 21 (30%) were treated with TKI for the first time, 40 (58%) had previously received only crizotinib treatment, and 8 (12%) had received one or more ROS1 TKI treatments other than crizotinib. The median follow-up time for efficacy was approximately 2.1 months. The study results showed that 62% of patients who received TKI treatment for the first time experienced an objective response; in terms of intracranial response, 64% of patients who received TKI treatment for the first time experienced a response.

In summary, lorlatinib has demonstrated significant clinical activity in patients with advanced ROS1-positive non-small cell lung cancer, especially in patients with central nervous system metastases and those who have previously received crizotinib treatment. Given the limited treatment options for patients refractory to crizotinib, lorlatinib is expected to become an important treatment option for these patients.