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In clinical practice, patients with <i>anaplastic lymphoma kinase (ALK)</i>-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of <i>ALK</i> resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced <i>ALK</i>- or <i>ROS1</i>-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for <i>ALK</i>-positive and 12.2 months for <i>ROS</i>-positive patients. <i>ALK</i>-positive patients showed a response rate of 43.2%, while 85.7% percent of the <i>ROS1</i>-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the <i>ALK</i>- and <i>ROS1</i>-positive groups, respectively. In the <i>ALK</i>-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced <i>ALK</i>- and <i>ROS1</i>-positive lung cancer.