medwireNews: Approximately half of patients with anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearranged non-small-cell lung cancer (NSCLC) respond to treatment with lorlatinib, show results of a first-in-human dose escalation study.
Responses to tyrosine kinase inhibitor (TKI) were recorded in patients with central nervous system (CNS) metastases and in those previously treated with two or more TKIs, suggesting that “lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs,” Alice Shaw (Massachusetts General Hospital, Boston, USA) and co-authors remark.
The 54 patients included in the phase I trial received oral lorlatinib at doses ranging from 10 to 200 mg once daily or 35 to 100 mg twice daily, with a minimum of three patients receiving each dose.
The most common treatment-related adverse event was hypercholesterolemia, occurring in 72%, followed by hypertriglyceridemia, peripheral neuropathy, and peripheral oedema, which occurred in 39% each.
The researchers report that one dose-limiting toxicity occurred in cycle 1, at 200 mg, with the patient not taking 16 of the 21 prescribed daily doses due to grade 2 neurocognitive adverse events. The events, specifically slowed speech and mentation and word-finding difficulty, resolved within 48 hours of treatment discontinuation.
The maximum tolerated dose of lorlatinib was not established, but based on the safety profile, pharmacokinetics, and ease of administration, Shaw and team recommended a phase 2 dose of 100 mg once daily.
In terms of efficacy, 46% of 41 ALK-positive patients achieved an objective response, as did 50% of 12 ROS1-positive patients.
In addition, 42% of 26 patients who had previously received two or more ALK TKIs had an objective response, while 46% of 24 patients with measurable CNS target lesions at baseline had an intracranial objective response.
During a median 17.4 months of follow-up, estimated median progression-free survival was 9.6 months in ALK-positive patients and 7.0 months in ROS1-positive patients.
In an analysis of 12 patients who had undergone tissue biopsy, the study team observed tumor regression in all eight patients with ALK resistance mutations, but no regression in the four patients without detectable ALK mutations.
And in line with these findings, mean lorlatinib treatment duration was significantly longer in the patients with ALK mutations than in those without, at 448 versus 42 days, which indicates “that the activity of lorlatinib might be higher in second-generation ALK TKI-treated tumours that have acquired on-target ALK resistance mutations than those tumours without an ALK mutation,” Shaw et al remark.
They conclude in The Lancet Oncology that their study “refines potential treatment options for patients with advanced ALK-positive NSCLC and highlights the potential utility of developing increasingly potent and pan-inhibitory TKIs to overcome drug resistance in oncogene-driven cancers.”
In an accompanying comment, Christine Bestvina and Everett Vokes, both from the University of Chicago Medicine and Biological Sciences in Illinois, USA, say that the trial “provides evidence of the systemic and CNS activity of lorlatinib for ALK-positive and ROS1-positive patients.”
They add: “Lorlatinib could be an excellent therapeutic option for patients with CNS metastases, but additional trials are needed to establish the optimal sequencing of TKIs for patients who have NSCLC with ALK or ROS1 rearrangement.”
By Laura Cowen
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