IASLC 2017: Lorlatinib in ALK-Positive and ROS1-Positive Advanced Non–Small Cell Lung Cancer
At the International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer in Yokohama, Japan, Pfizer announced full results from the phase II clinical trial of the investigational, next-generation tyrosine kinase inhibitor lorlatinib. The agent exhibited clinically meaningful activity against lung tumors and brain metastases in a range of patients with ALK-positive and ROS1-positive advanced non–small cell lung cancer (NSCLC), including those who were heavily pretreated. Further, side effects were generally manageable and primarily mild to moderate in severity. The results were presented by Benjamin Solomon, MBBS, PhD, FRACP, lead investigator and medical oncologist at Peter MacCallum Cancer Centre, Melbourne, Australia.
“The findings presented today suggest that lorlatinib...may represent an effective treatment option for patients with ALK-positive advanced non–small cell lung cancer across multiple lines of therapy. These are comprehensive data in non–small cell lung cancer patients previously treated with second-generation ALK inhibitors who currently have few available treatment options,” said Dr. Solomon. “Controlling brain metastases is very important to these patients and an especially challenging aspect of treating this disease. We saw excellent intracranial responses in all patient groups, including those who were heavily pretreated.”
Study Findings
The phase II study examined the antitumor activity and safety of lorlatinib in 275 patients with or without asymptomatic, untreated, or treated brain metastases. Patients were enrolled in six cohorts based on biomarker (ALK-positive or ROS1-positive) and prior therapy. The primary endpoints were objective response rate and intracranial objective response rate confirmed by independent central review. Results by clinically relevant groups showed:
- ALK-positive, treatment-naive: objective response rate was 90% (27/30; 95% confidence interval [CI] = 74–98) and intracranial objective response rate was 75% (6/8; 95% CI = 35–97)
- ALK-positive, previously treated with crizotinib (Xalkori) with or without chemotherapy: objective response rate was 69% (41/59; 95% CI = 56–81) and intracranial objective response rate was 68% (25/37; 95% CI = 50–82)
- ALK-positive, previously treated with a non-crizotinib ALK inhibitor with or without chemotherapy: objective response rate was 33% (9/27; 95% CI = 16–54) and intracranial objective response rate was 42% (5/12; 95% CI = 15–72)
- ALK-positive, previously treated with two or three prior ALK inhibitors with or without chemotherapy: objective response rate was 39% (43/111; 95% CI = 30–49) and intracranial objective response rate 48% (40/83; 95% CI = 37–59)
- ROS1-positive regardless of prior treatment: objective response rate was 36% (17/47; 95% CI = 23–52) and intracranial objective response rate was 56% (14/25; 95% CI = 35–76)
Lorlatinib was generally tolerable. Most adverse events were mild to moderate and were managed by dose reductions or delay or with standard medical therapy. There were no treatment-related deaths and a low (3%) rate of discontinuation due to drug-related adverse events. The most common adverse events were: hypercholesterolemia (81%), hypertriglyceridemia (60%), edema (43%), peripheral neuropathy (30%), weight increase (18%), cognitive effects (18%), mood effects (15%), fatigue (13%), diarrhea (11%), arthralgia (10%), and increased AST (10%).
The phase II data will form the basis of discussions with global regulatory authorities, including the U.S. Food and Drug Administration (FDA). On April 26, 2017, the FDA granted Breakthrough Therapy designation for lorlatinib for the treatment of patients with ALK-positive metastatic NSCLC previously treated with one or more ALK inhibitors.
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®.
