Novel Tyrosine Kinase Inhibitor for ALK- or ROS1-Rearranged NSCLC

Key Points

  • Response to lorlatinib was observed in approximately half of both ALK-positive and ROS1-positive patients.
  • An intracranial response was observed in nearly half of patients with measurable CNS disease. 

A phase I trial has shown that the ALK and ROS1 tyrosine kinase inhibitor lorlatinib is active in patients with advanced ALK- or ROS1-positive non–small cell lung cancer (NSCLC), including those with central nervous system (CNS) metastases and failure on at least two prior tyrosine kinase inhibitor. The findings were reported in The Lancet Oncology by Shaw et al.

Study Details

In the multicenter study, 54 patients enrolled between January 2014 and July 2015 received at least 1 dose of lorlatinib given at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily in 21-day cycles, with a minimum of 3 patients receiving each dose. The primary endpoint was dose-limiting toxicity during cycle 1. Of the 54 patients, 41 (77%) were ALK-positive and 12 (23%) were ROS1-positive; 28 patients (52%) had received at least 2 tyrosine kinase inhibitors, and 39 patients (72%) had CNS metastases.

Toxicity

The most common treatment-related adverse events of any grade were hypercholesterolemia (72%), hypertriglyceridemia (39%), peripheral neuropathy (39%), and peripheral edema (39%). A dose-limiting toxicity occurred at 200 mg, consisting of grade 2 neurocognitive adverse events (slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. A dose of 100 mg once daily was selected for phase II study.

Response Rates

Among ALK-positive patients, an objective response was observed in 19 of 41 patients (46%), including 11 of 26 (42%) who had received at least 2 tyrosine kinase inhibitors; the median duration of response was 12.4 months. In ROS1-positive patients, response was observed in 6 of 12 patients (50%), including 2 of 7 patients with prior crizotinib (Xalkori) treatment; the median duration of response was 12.0 months. Among 24 patients with measurable CNS disease, intracranial response was observed in 11 (46%).

The investigators concluded: “In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more [tyrosine kinase inhibitor] treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available [tyrosine kinase inhibitors], including second-generation ALK [tyrosine kinase inhibitor], and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib.”

The study was funded by Pfizer.

Alice T Shaw, MD, of the Massachusetts General Hospital, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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