Lorlatinib shows promising activity against ALK-positive advanced NSCLC
medwireNews: Patients with ALK-positive advanced non-small-cell lung cancer (NSCLC) respond to the third-generation ALK and ROS1 tyrosine kinase inhibitor lorlatinib irrespective of previous ALK tyrosine kinase inhibitor treatment status, phase II study data show.
Furthermore, the drug had “[s]ubstantial intracranial activity” among the 228 patients studied, 62% of whom had brain metastases at baseline, report Benjamin Solomon (MacCallum Cancer Centre, Melbourne, Victoria, Australia) and colleagues in The Lancet Oncology.
The researchers found that 90% of 30 treatment-naïve patients who received oral lorlatinib 100 mg daily in continuous 21-day cycles had an overall objective response. Two (66.7%) of three treatment-naïve patients with measurable baseline central nervous system (CNS) lesions also had an objective intracranial response.
In addition, the overall response rate was 47.0% in the 198 patients who had received at least one previous ALK tyrosine kinase inhibitor, while the intracranial response rate was 63.0% in the 81 patients with baseline CNS lesions.
More specifically, the overall and intracranial response rates were 69.5% of 59 patients and 87.0% of 23 patients, respectively, who had only received previous crizotinib; 32.1% of 28 patients and 55.6% of nine patients, respectively, who had one previous non-crizotinib ALK tyrosine kinase inhibitor; and 38.7% of 111 patients and 53.1% of 49 patients, respectively, who had received two or more previous ALK tyrosine kinase inhibitors.
The researchers note that the median time to first tumor response was rapid, at 1.4 months in each group, with the median response duration not reached after approximately 6.9–7.2 months of follow-up.
In a safety analysis that also included 47 patients with ROS1-positive NSCLC, hypercholesterolemia and hypertriglyceridemia were the most common adverse events, occurring at rates of 81% and 60%, respectively, with 16% in each case being grade 3 or higher.
There were 19 (7%) serious treatment-related adverse events and seven (3%) patients permanently discontinued treatment because of these.
“Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors,” Soloman et al remark.
“Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy,” the researchers conclude.
In an accompanying comment, Saiama Waqar and Daniel Morgensztern, both from Washington University School of Medicine in St Louis, Missouri, USA, say the findings “establish lorlatinib as a valuable addition for the treatment of ALK-rearranged tumours.”
They suggest that the drug might best be used “in patients with disease progression after treatment with second-generation ALK tyrosine kinase inhibitors, for whom there is little data for the use of an additional drug of the same class,” because the objective response rate with lorlatinib “is probably similar to that achievable with chemotherapy,” without the additional side-effects.
By Laura Cowen
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