Lorlatinib in Tyrosine Kinase Inhibitor-Naive Advanced ROS1-Positive Non-Small Cell Lung Cancer: A Phase 2...

Area of Science:

• Oncology
• Pharmacology

Background:

• ROS1 rearrangement is a rare but actionable target in advanced non-small cell lung cancer (NSCLC).
• Approved therapies for ROS1-positive NSCLC include crizotinib, entrectinib, and repotrectinib.
• Lorlatinib, a third-generation tyrosine kinase inhibitor (TKI), targets ROS1 and ALK, but its efficacy in TKI-naive ROS1-positive NSCLC was unknown.

Purpose of the Study:

• To evaluate the efficacy and safety of lorlatinib in patients with advanced ROS1-positive NSCLC who have never been treated with any TKI.
• To assess lorlatinib's potential for earlier use in the treatment of ROS1-positive NSCLC.

Main Methods:

• A multicenter, phase 2, nonrandomized clinical trial (NCT03612154) enrolled TKI-naive patients with advanced ROS1-positive NSCLC.
• Patients received lorlatinib 100 mg daily until disease progression, unacceptable toxicity, or other discontinuation criteria were met.
• Objective response rate (ORR) was the primary endpoint, with progression-free survival (PFS) and safety as secondary endpoints.

Main Results:

• The study included 32 patients, with a median follow-up of 22.1 months. The ORR was 73% (22/30), and the disease control rate was 90% (27/30).
• Median PFS was 53.6 months. In TKI-naive patients, ORR was 90% and PFS was not reached; in previously treated patients, ORR was 60% and PFS was 35.8 months.
• Grade 3-4 adverse events included hypertriglyceridemia (16%) and hypercholesterolemia (25%). No treatment-related deaths occurred.

Conclusions:

• Lorlatinib demonstrated durable efficacy and manageable safety in TKI-naive advanced ROS1-positive NSCLC.
• These findings support the potential use of lorlatinib in earlier treatment settings for this patient population.
• Lorlatinib represents a promising therapeutic option for advanced ROS1-positive NSCLC, particularly in treatment-naive individuals.