How many generic versions of lorlatinib are there?

Patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement or ROS proto-oncogene 1 (ROS1) rearrangement are generally sensitive to tyrosine kinase inhibitor (TKI) therapy, but drug resistance issues, particularly in the central nervous system, are common. This study focused on the safety, efficacy and pharmacokinetics of lorlatinib in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer. Lorlatinib, as a novel, potent, selective and brain-permeable ALK and ROS1TKI, has shown activity against most known resistance mutations in preclinical studies.

This study included patients over 18 years of age, with a performance status of Eastern Cooperative Oncology Group grade 0 or 1, and with adequate end-organ function, with advanced ALK-positive or ROS1-positive non-small cell lung cancer. Lorlatinib is administered orally at doses of 10 to 200 mg once daily or 35 to 100 mg twice daily, with at least 3 patients in each dose group participating. Some patients underwent tumor biopsies prior to treatment with lorlatinib to identify ALK-resistant mutations. All patients who received at least one dose of lorlatinib were evaluated for safety and efficacy in an intended-to-treat population, including those who received at least one dose of study therapy with confirmed ALK or ROS1 rearrangements. The primary endpoint of the study was dose-limiting toxicity in the first cycle, while the secondary endpoints covered safety, pharmacokinetics, and overall response.

A total of 54 patients received at least one dose of lorlatinib, of whom 41 (77%) were ALK-positive and 12 (23%) had ROS1-positive non-small cell lung cancer; In addition, the ALK and ROS1 status of one patient was not confirmed. Of these patients, 28 (52%) had received two or more TKIs, and 39 (72%) had central nervous system (CNS) metastases. The most common adverse events during treatment included hypercholesterolemia (72%), hypertriglyceridemia (39%), peripheral neuropathy (39%), and peripheral edema (39%). A dose-limiting toxicity was observed in the 200 mg dose group as a grade 2 neurocognitive adverse event, including speech and thinking delays and difficulty finding words. The maximum tolerated dose was not determined, and the recommended phase 2 dose was 100 mg once daily.

The objective response rate was 46 percent (95% CI 31-63) in ALK-positive patients and 42 percent in patients who had received two or more TKIs. Among ROS1-positive patients, including seven patients who had received crizotinib, the objective response rate was 50 percent (95% CI 21-79).

The results showed that lorlatinib demonstrated systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, especially for those with CNS metastases who had failed multiple prior TKIs. Therefore, lorlatinib can be considered an effective therapeutic strategy for patients with ALK-positive non-small cell lung cancer that are resistant to currently available TKIs, including second-generation ALKTKIs.