As reported by Alice T. Shaw, MD, and colleagues in The Lancet Oncology, a phase I/II trial has shown overall and intracranial activity of the third-generation ALK and ROS1 tyrosine kinase inhibitor lorlatinib in patients with advanced ROS1-positive non–small cell lung cancer (NSCLC).
Alice T. Shaw, MD
Lorlatinib is designed to penetrate the blood-brain barrier and exhibits preclinical activity against most known resistance mutations in ALK and ROS1.
Study Details
Sixty-nine patients from 28 sites in 12 countries were enrolled in the trial between January 2014 and October 2016. Patients received lorlatinib at 100 mg once daily in continuous 21-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, or death. In total, 36 patients (52%) were white and 22 (32%) were Asian; 21 (30%) were ROS1 tyrosine kinase inhibitor–naive; 40 (58%) had received only crizotinib, and 8 (12%) had received one noncrizotinib tyrosine kinase inhibitor or two or more tyrosine kinase inhibitors; and 39 patients (57%) had brain metastases at baseline, with 19 having received brain-directed radiotherapy.
Response Rates
The median duration of follow-up for response was 21.1 months. Among all 69 patients, 28 (41%) had an objective response on independent central review.
Of 21 tyrosine kinase inhibitor–naive patients, 13 (62%) had an objective response; 2 (10%) had a complete response; and 11 (52%) had a partial response. At data cutoff in this group, median duration of response was 25.3 months, with six responses ongoing at the time of analysis, and median time to response was 1.4 months. Median progression-free survival was 21.0 months in this group of patients.
Among 40 patients who had received only crizotinib as prior tyrosine kinase inhibitor therapy, 14 (35%) had objective response, with a complete response reported in 2. Median duration of response was 13.8 months, with eight responses ongoing at time of analysis, and median time to response was 2.1 months. Median progression-free survival was 8.5 months.
Among patients with central nervous system metastases at baseline, an intracranial response was achieved in 7 (64%) of 11 tyrosine kinase inhibitor–naive patients and 12 (50%) of 24 patients who had received only crizotinib; median duration of response was not reached in either group of responders.
“Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with central nervous system metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent.”— Shaw et al
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Adverse Events
Treatment-related grade 3 or 4 adverse events occurred in 49% of patients, with the most common being hypertriglyceridemia (19%) and hypercholesterolemia (14%). Serious treatment-related adverse events occurred in 7% of patients. Treatment-related adverse events led to discontinuation of treatment in one patient due to elevated aminotransferases. No treatment-related deaths occurred.
The investigators concluded, “Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with central nervous system metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent.”
Dr. Shaw, of Massachusetts General Hospital, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit thelancet.com.
