Lorlatinib/lorlatinib clinical treatment of ros1

Lorlatinib/Lorlatinib (Lorlatinib) is a potent, oral, selective, third-generation macrocyclic TKI that targets ALK and ROS1. Through the use of structure-based design, lorlatinib was specifically developed to penetrate the blood-brain barrier by reducing P-glycoprotein-1-mediated efflux. Preclinical studies have shown that lorlatinib can effectively inhibit ROS1 and maintain different potencies against different ROS1 resistance mutations. In the Phase 1 portion of an ongoing Phase 1-2 study, lorlatinib showed preliminary antitumor activity in patients with ROS1-positive non-small cell lung cancer, the majority of whom had previously received crizotinib.

The pathogenesis of ROS1-rearranged tumors is very similar to that of ALK-positive non-small cell lung cancer. Management of patients with advanced ROS1-rearranged NSCLC relies on first-line crizotinib, ceritinib, or entrectinib, with mPFS ranging from 6 to 20 months. Similarly, all ROS1 NSCLC patients eventually exhibit tumor progression due to resistance mechanisms such as kinase domain mutations.

Between January 2014 and October 2016, 364 patients were evaluated, 69 of whom were ROS1-positive NSCLC. Twenty-one of the 69 patients (30%) were TKI-naïve, 40 (58%) had previously received crizotinib as the only TKI, and 8 (12%) had previously received one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. Median follow-up for efficacy was estimated to be 2.1 months (IQR 15.2-30.3). Thirteen of 21 TKI-naïve patients (62%; 95% CI, 38-82) and 14 of 40 patients (35%; 95% CI, 21-52) who had previously received crizotinib as the sole TKI therapy had an objective response. Intracranial reactions occurred in 7 of 11 TKI-naïve patients (64%; 95% CI, 31-89) and in 12 of 24 patients (50%; 95% CI, 29-71) who had previously received only crizotinib. The most common grade 3-4 treatment-related adverse events were hypertriglyceridemia (13 of 69 patients [19%]) and hypercholesterolemia (10 [14%]). Serious treatment-related adverse events occurred in 5 of 69 patients (7%). No treatment-related deaths were reported.

Lorlatinib has shown clinical activity in patients with advanced ROS1-positive non-small cell lung cancer, including those with central nervous system metastases and those previously treated with crizotinib. Because there are few treatment options for patients refractory to crizotinib,lorlatinib may be an important next step in targeted therapy.