Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis.

Maximilian J Hochmair,Ulrike Setinek,Matthias Urban,Dagmar Krenbek,Elmar Brehm,Peter Errhalt,Gudrun Absenger,Arschang Valipour,Markus Rauter,Helmut Prosch,Oliver Illini,Romana Wass,Hannah Fabikan,Ewald Wöll,Michael Schumacher,Christoph Weinlinger,Tatjana Bundalo

doi:10.3390/ph13110371

Abstract

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-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 ALK 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 ALK- or ROS1-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 ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-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 ALK- and ROS1-positive lung cancer.

Highlights

The anaplastic lymphoma kinase (ALK) fusion gene is a rare driver aberration that occurs only in 2% to 7% of all non-small cell lung cancer (NSCLC) cases, with a predilection in never- or light-smokers and in patients with adenocarcinoma histology [1,2,3,4,5,6]
Five ALK inhibitors including crizotinib, ceritinib, alectinib, brigatinib and lorlatinib have been approved to date for the treatment of ALK-positive lung cancer in the European Union and the United States [7,8,9,10,11,12]
In patients who demonstrated treatment failure on the first-generation agent crizotinib, the main mechanisms of resistance include the expression of other oncogenes, changes in the copy number of the ALK gene, and activation of alternative pathways such as epidermal growth factor receptor (EGFR) or KIT signaling, while secondary ALK rearrangements were only found in 20% to 30% of patients

Summary

Introduction

The anaplastic lymphoma kinase (ALK) fusion gene is a rare driver aberration that occurs only in 2% to 7% of all non-small cell lung cancer (NSCLC) cases, with a predilection in never- or light-smokers and in patients with adenocarcinoma histology [1,2,3,4,5,6]. Tyrosine kinase inhibitors (TKIs) targeting the ALK fusion gene have become the standard of care for these patients. Five ALK inhibitors including crizotinib, ceritinib, alectinib, brigatinib and lorlatinib have been approved to date for the treatment of ALK-positive lung cancer in the European Union and the United States [7,8,9,10,11,12]. ALK resistance mutations represented the major resistance mechanism (50% to 70%) in patients treated with ceritinib, alectinib, or brigatinib. This is thought to reflect the greater potency and selectivity of the next-generation TKIs compared to crizotinib

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Conclusion