Intracranial Activity of Lorlatinib in Patients with Metastatic ALK-Positive NSCLC
Lorlatinib is a potent third-generation anaplastic lymphoma kinase (ALK) inhibitor with significant antitumor activity against non-small cell lung cancer (NSCLC). According to the results of an international clinical study published in the Annals of Oncology, it shows very good efficacy in treating intracranial metastases in patients who experienced disease progression during therapy with second-generation ALK inhibitors.
NSCLC and Metastases in the Central Nervous System
The development of resistance to treatment and the progression of CNS metastases remain issues despite the advancements brought by second-generation ALK inhibitors in the treatment of patients with advanced NSCLC. Lorlatinib is a drug with good blood-brain barrier penetration, specifically developed for a broad range of action against mutations inducing resistance to ALK inhibitor treatment.
Based on the favorable preliminary results from pilot studies, lorlatinib received approval for the treatment of patients with metastatic ALK-positive NSCLC after progression on alectinib or ceritinib in the first line of treatment, or after progression on crizotinib and at least one other ALK inhibitor. Recently, an updated analysis focusing on extracranial and intracranial activity in patients treated with at least one second-generation ALK inhibitor was published.
Study Course and Objectives
The ongoing phase I/II clinical study involves patients with ALK-positive advanced NSCLC who were treated with ≥ 1 second-generation ALK inhibitor and possibly chemotherapy. Patients were enrolled in the study expansion cohorts according to the number of prior therapy lines. All patients received lorlatinib at a dose of 100 mg daily in 21-day cycles until disease progression or unacceptable toxicity.
The primary objective of the study was to assess the objective response rate (ORR) and intracranial response according to the modified RECIST v1.1 criteria through independent central radiological review. Additionally, response duration, progression-free survival (PFS), overall survival (OS), and safety profile were evaluated.
Results
The analysis included a total of 139 patients, with 28 treated with one second-generation ALK inhibitor before entering the study, 65 treated with 2 inhibitors, and 46 treated with 3 inhibitors. The achieved ORR across all patients in the expansion cohorts was 39.6% (95% confidence interval [CI] 31.4–48.2) with a median response duration of 9.6 months (95% CI 5.6–16.7), while the intracranial ORR (IC-ORR) in 57 patients with measurable CNS metastases at baseline was 56.1% (95% CI 42.4–69.3). The extracranial ORR (EC-ORR) across all patients was 36.7% (95% CI 28.7–45.3). The median PFS was 6.6 months (95% CI 5.4–7.4) and the median OS was 20.7 months (95% CI 16.1–30.3).
In patients pretreated with 1 ALK inhibitor, the IC-ORR was 66.7% (95% CI 29.9–92.5) and the EC-ORR was 32.1% (95% CI 15.9–52.4). For patients where lorlatinib was the 3rd or higher line of treatment, the IC-ORR was 54.2% (95% CI 39.2–68.6) and the EC-ORR was 37.8% (95% CI 28.8–47.5).
Conclusion
Lorlatinib demonstrated clinically significant intracranial and extracranial antitumor activity in patients with NSCLC who experienced disease progression on at least one second-generation ALK inhibitor, with higher intracranial activity, particularly in patients at lower lines of treatment.
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Source:
Felip E., Shaw A. T., Bearz A. et al. Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs. Ann Oncol 2021; 32 (5): 620−630, doi: 10.1016/j.annonc.2021.02.012.
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