Efficacy of Lorlatinib in Patients with ROS1-Positive NSCLC in Clinical Practice
Interesting real-world data have been brought by a study on the efficacy of lorlatinib in patients with non-small cell lung cancer (NSCLC) with a mutation in the ROS1 gene.
Therapeutic Options for ROS1-Positive NSCLC
Mutations in the gene for the ROS1 receptor tyrosine kinase, leading to its permanent activation, occur in only 1-2% of patients with NSCLC, mostly in lifelong non-smokers. Several tyrosine kinase inhibitors (TKIs) are active against ROS1. According to current recommendations from the European Society for Medical Oncology (ESMO), crizotinib, ceritinib, or entrectinib are administered in the first line for metastatic ROS1-positive NSCLC, with a median progression-free survival (PFS) on this therapy ranging from 6 to 20 months. However, resistance to the treatment and disease progression eventually occur in all patients.
Lorlatinib is a third-generation TKI with good blood-brain barrier penetration, showing efficacy against several mutations leading to resistance to crizotinib. In a clinical study in patients pretreated with crizotinib, lorlatinib achieved an overall response rate (ORR) of 35% with a median PFS of 8.5 months. However, there are currently few data available to evaluate its efficacy in real-world clinical practice. The presented study describes the results of French patients treated under an expanded access program.
Study Methodology
The analysis included data from medical records of all patients treated with lorlatinib at a daily dose of 100 mg for at least 7 days from October 2015 to June 2019 in one of 49 centers for advanced or metastatic ROS1-positive NSCLC. Patients could be included in the expanded access program if they had failed at least one TKI. 69% had undergone prior chemotherapy.
The primary objective of the study was PFS, measured as the time from the first administration of lorlatinib to disease progression according to RECIST 1.1 criteria or death from any cause. Secondary objectives included ORR, disease control rate (DCR), overall survival (OS), and other parameters.
Results
A total of 80 patients were included in the analysis (median age 58.2 years, 59% women, 62% lifelong non-smokers). 85% of patients had stage IV disease, with adenocarcinoma being the most common histological finding (95%). At the start of lorlatinib therapy, 64% of patients had brain metastases. Lorlatinib was administered as the second line of treatment in 29% of patients, 28% were treated in the third line, 18% in the fourth line, and 26% in the fifth and further lines.
The median follow-up period from the start of lorlatinib treatment was 22.2 months. A median PFS of 7.1 months (95% confidence interval [CI] 5.0-9.9) was achieved, with a median OS of 19.6 months (95% CI 12.3-27.5). The median duration on lorlatinib treatment was 7.4 months (95% CI 6.5-13.1). An ORR of 45% was achieved, with a disease control rate (complete or partial response or stable disease) of 82%. The central nervous system response rate was 72%.
The safety profile was consistent with previous observations. Treatment was discontinued due to excessive toxicity in 10 patients (13%).
Conclusion
In real-world clinical practice, lorlatinib represents a significant therapeutic option for patients with advanced ROS1-positive NSCLC as part of a sequential treatment strategy. Further studies are needed to evaluate options post-progression on treatment and to detail the mechanisms of resistance, which would help to better choose the optimal therapeutic sequence.
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Source: Girard N., Galland-Girodet S., Avrillon V. et al. Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study. ESMO Open 2022; 7 (2): 100418, doi: 10.1016/j.esmoop.2022.100418.
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