Acquired resistance to therapy with tyrosine kinase inhibitors (TKIs) is common in patients with ALK or ROS1-rearranged non-small-cell lung cancer (NSCLC). Lorlatinib is a novel TKI of both ALK and ROS1 specifically designed to inhibit mutations driving resistance to other ALK TKIs, and to penetrate the blood–brain barrier. A phase I dose-escalation study of this TKI was conducted in 54 patients with NSCLC and disease progression after receiving other TKIs. An objective response was observed in 46% of patients with ALK rearrangements, 50% of patients with ROS1 rearrangements, and 42% of patients who had received two or more TKIs. The most common treatment-related adverse events were hypercholesterolaemia (72%), hypertriglyceridaemia (39%), peripheral neuropathy (39%), and peripheral oedema (39%). Lorlatinib is currently being compared with crizotinib in the frontline in a phase III randomized trial in patients with ALK-rearranged NSCLC.
References
Shaw, A. T. et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. http://dx.doi.org/10.1016/S1470-2045(17)30680-0 (2017)
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Romero, D. First-in-man phase I trial with lorlatinib. Nat Rev Clin Oncol 15, 7 (2018). https://doi.org/10.1038/nrclinonc.2017.201
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DOI: https://doi.org/10.1038/nrclinonc.2017.201