Lorlatinib Shows Promise Against Brain Metastases in ALK+ Lung Cancer

Lorlatinib exhibits durable responses in pretreated patients with ALK-positive non–small-cell lung cancer (NSCLC) and promising intracranial activity and tumor responses in those patients who have brain metastases, regardless of prior therapy, according to findings from a phase I/II clinical study (abstract 9006) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.

“Lorlatinib demonstrated clinically meaningful and durable responses in ALK-positive patients receiving one or more prior ALK TKI [tyrosine kinase inhibitor], many of whom were heavily pretreated,” said coauthor Sai-Hong Ignatius Ou, MD, of the University of California Irvine Chao Family Comprehensive Cancer Center in Orange, California.

Lorlatinib is a selective and potent next-generation ALK/ROS1 TKI. The US Food and Drug Administration has granted it a Breakthrough Therapy Designation for patients with ALK-positive metastatic NSCLC who were previously treated with at least one line of ALK TKI therapy.

The authors enrolled 199 patients and assigned them to 6 expansion cohorts for study. Efficacy data were available for 82 patients at analysis. Sixty-two patients had brain metastases.

Treatment was safe and tolerable. “The most common adverse event was hyperlipidemia, successfully managed with lipid-lowering agents,” Ou explained. “Cognitive effects were generally mild and rapidly reversible upon dose modifications. Permanent discontinuations of treatment due to adverse events were infrequent.”

Treatment-related adverse events affected 113 patients, resulting in dose delays for 29% of patients, dose reductions in 20% of patients, and discontinuation in 3.4% of patients. The most common treatment-related adverse events were hypercholesterolemia, hypertriglyceridemia, peripheral edema, peripheral neuropathy, cognitive and mood effects, and weight gain.

The confirmed overall response rate (ORR) for ALK-positive patients who had received previous ALK TKI treatment was 32.9% but best overall response had not yet been determined for 13% of patients at the time of analysis, Ou cautioned. Duration of response data were not mature.

Of 35 patients with brain metastases evaluated for intracranial response, 24 had undergone prior brain radiotherapy for metastatic tumors and prior ALK TKI therapy; 18 had a complete (n = 7) or partial (n = 11) intracranial tumor response following lorlatinib treatment. The resulting confirmed ORR for intracranial lesions in ALK-positive patients following lorlatinib was 51% (18/35).

The phase III CROWN trial will compare lorlatinib with crizotinib as a first-line therapy for ALK-positive NSCLC, and has begun to enroll patients.