Third Generation Targeted Therapy for ROS1-Positive NSCLC
The potent third-generation tyrosine kinase inhibitor, lorlatinib, has shown activity in preclinical studies against nearly all known mutations in the ALK and ROS1 genes that lead to resistance to crizotinib treatment. Moreover, lorlatinib crosses the blood-brain barrier, offering hope for patients with CNS metastases. The results of a clinical evaluation of the efficacy and safety of lorlatinib in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) were published in The Lancet Oncology.
Tyrosine Kinase Inhibitors in NSCLC Treatment
Approximately 1−2% of patients with NSCLC present aberrations in the ROS1 gene, which encodes a receptor tyrosine kinase (TK). Targeted treatment with crizotinib, recommended as the first-line therapy for these patients, leads to responses in 65−72% of patients, with a median progression-free survival (PFS) of 19 months. However, most treated patients eventually develop resistance and disease progression. This resistance typically arises either through mutations in the ROS1 gene or through progression in the CNS (in 30−50% of patients), as crizotinib poorly penetrates the blood-brain barrier.
ROS1-positive patients progressing on crizotinib have very limited therapeutic options, usually resorting to chemotherapy or radiotherapy. Several potential candidates for targeted therapy are currently being tested in clinical studies. Lorlatinib is an oral macrocyclic TK inhibitor that selectively targets ALK and ROS1 kinases. The drug molecule was structurally designed to penetrate the blood-brain barrier. In patients with ROS1-positive advanced NSCLC, most of whom had already been treated with crizotinib, lorlatinib demonstrated anti-tumor activity in the study presented below.
Study Methodology
From January 2014 to October 2016, 69 patients with cytologically or histologically confirmed ROS1-positive advanced NSCLC participated in a phase I/II clinical study: 21 had not previously been treated with a TK inhibitor, 40 had undergone prior crizotinib treatment, and 8 had been treated with at least one other TK inhibitor.
Patients were given lorlatinib at a dose of 100 mg once daily in 21-day cycles until disease progression, unacceptable toxicity, or death. The primary evaluation goals were the overall response rate to treatment and the intracranial response in patients with CNS metastases.
Results
The median follow-up period was 21.1 months. An objective response to treatment was achieved by 13 patients (62%; 95% confidence interval [CI] 38−82%) in the previously untreated group and 14 (35%; 95% CI 21−52%) after prior crizotinib treatment. Intracranial responses were seen in 7 of 11 (64%; 95% CI 31−89%) previously untreated patients and 12 of 24 (50%; 95% CI 29−71%) patients post-crizotinib treatment.
The most frequently observed grade 3−4 adverse events were elevated triglycerides (in 13 patients) and hypercholesterolemia (in 10 patients). Serious adverse events occurred in 5 patients, with no deaths reported in connection to the treatment.
Conclusion
Lorlatinib showed clinical efficacy in patients with advanced ROS1-positive NSCLC, including those with CNS metastases. For patients refractory to crizotinib, it represents a promising next line of treatment.
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Sources:
1. Shaw A. T., Solomon B. J., Chiari R., et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 1−2 trial. Lancet Oncol 2019; 20 (12): 1691–1701, doi: 10.1016/S1470-2045(19)30655-2.
2. Duruisseaux M. Lorlatinib: a new treatment option for ROS1-positive lung cancer. Lancet Oncol 2019; 20 (12): 1622–1623, doi: 10.1016/S1470-2045(19)30716-8.
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