Can We Reach Brain Metastases of Lung Cancer with Anti-EGFR Targeted Therapy?
Information on the penetration of epidermal growth factor receptor tyrosine kinase inhibitors (anti-EGFR TKIs) through the blood-brain barrier primarily comes from preclinical testing. In clinical studies, its effectiveness in patients with brain metastases can be an indicator of its penetration. However, a truly robust analysis is lacking. Until one is available, we can preliminarily evaluate the available data.
EGFR Tyrosine Kinase Inhibitor Osimertinib
TKIs are used in the treatment of non-small cell lung cancer (NSCLC) with activating mutations in the EGFR gene. Their use is often associated with excellent initial clinical success, but after approximately 10-14 months, many patients progress. The 1st and 2nd generation anti-EGFR TKIs have limited penetration through the blood-brain barrier, creating favorable conditions for metastatic spread to the CNS.
Osimertinib, a 3rd generation representative, is known from animal experiments to penetrate the intact blood-brain barrier in various animal species, including primates. Currently, osimertinib is indicated for the 1st line treatment of patients with locally advanced or metastatic NSCLC with an activating mutation in the EGFR gene and for the treatment of patients with locally advanced or metastatic disease with the presence of the T790M mutation in the EGFR gene, which causes resistance to 1st and 2nd generation anti-EGFR targeted therapy.
What Do We Know from Clinical Trials?
Initial information on the effect of osimertinib on brain metastases is available from clinical trials that were used for drug registration. For example, in the FLAURA study with a population of 128 patients with CNS metastases, osimertinib was shown to improve CNS progression-free survival compared to the comparator, which was gefitinib or erlotinib (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.26-0.86; p = 0.014). In the osimertinib arm, there were also fewer patients with new CNS lesions compared to the comparator arm (3.9% vs 12.3%). A similar comparison in the AURA3 study, this time against pemetrexed/platinum chemotherapy and with a population of 116 patients with CNS metastases, also confirmed improved CNS progression-free survival (HR 0.32; 95% CI 0.15-0.69; p = 0.004).
Meta-Analysis of Available Results
It is useful to compare the results of analyses of small patient groups with other information that has been published about osimertinib. Chinese authors, therefore, conducted a systematic review and meta-analysis, including results from 4 randomized controlled clinical trials, 3 single-arm clinical trials, 2 retrospective studies, and 2 studies from real clinical practice published between 2017 and 2019. A total of 842 patients participated in these studies.
The aggregate results confirmed the high efficacy of the drug. The overall response rate (ORR) reached 70% (95% CI 68-71) and the disease control rate (DCR) was 92% (95% CI 91-94). The median PFS was 10.98 months (95% CI 9.43-12.53). Among patients with CNS metastases treated with osimertinib in the 1st line, the ORR was 71% (95% CI 69-73) and the DCR was 93% (95% CI 90-95). Complete remission was achieved in this group in 3% of patients (95% CI 1-4). The median progression-free survival was 12.21 months (95% CI 9.20-15.23).
Conclusion
Brain metastases negatively affect the survival and quality of life of patients with NSCLC. These lesions in patients with EGFR mutations significantly respond to osimertinib treatment. Although the above meta-analysis included non-randomized and observational studies, which may have some bias, the results regarding efficacy can be considered clinically significant. They should be confirmed by further randomized clinical trials with a sufficient number of participants.
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Sources:
1. Wang N., Zhang Y., Mi Y. et al. Osimertinib for EGFR-mutant lung cancer with central nervous system metastases: a meta-analysis and systematic review. Ann Palliat Med 2020; 9 (5): 3038-3047, doi: 10.21037/apm-20-605.
2. SPC Tagrisso. Available at: www.ema.europa.eu/en/documents/product-information/tagrisso-epar-product-information_cs.pdf
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