Osimertinib Improves Overall Survival in Patients With EGFR-Mutated NSCLC With Leptomeningeal Metastases Regardless of T790M Mutational Status

Abstract

Introduction: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, efficiently penetrates the blood-brain barrier. This study explored whether treatment with osimertinib leads to improved overall survival (OS) for patients with EGFR-mutated NSCLC with leptomeningeal metastases (LM) compared with those not treated with osimertinib. Methods: From October 2008 to October 2019, patients with EGFR-mutated NSCLC and cytologically confirmed LM were retrospectively analyzed for OS according to osimertinib treatment and T790M mutational status. The OS was defined as the time from the diagnosis of LM to death. Results: For the 351 patients with LM included in the analysis, the median OS (mOS) was 8.1 months (95% confidence interval [CI]: 7.2-9.0). T790M mutation was detected in 88 of 197 patients tested, and a total of 110 patients were treated with osimertinib after LM. No difference in mOS according to T790M mutational status (10.1 mo [95% CI: 4.31-15.82] versus 9.0 [95% CI: 6.81-11.21], p ¼ 0.936) was found. Nevertheless, patients treated with osimertinib had a superior OS of 17.0 months (95% CI: 15.13-18.94) compared with those not treated with osimertinib who had a mOS of 5.5 months (95% CI: 4.34-6.63), regardless of T790M mutational status (hazard ratio: 0.36 [95% CI: 0.28-0.47], p < 0.001). This was also considerably longer even than the mOS of 8.7 months (95% CI: 7.01-10.39) of those who were never treated with osimertinib but had firstor second-generation EGFR tyrosine kinase inhibitors. Conclusions: Osimertinib is a promising treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status.

Multiple combination therapy based on intrathecal pemetrexed in non-small cell lung cancer patients with refractory leptomeningeal metastasis

“…High-dose erlotinib (200 or 300 mg every 2 days, or 300 or 450 mg every 3 days, or 600 mg every 4 days) and pulsatile high-dose erlotinib (median dose 1500 mg, weekly) achieved radiographic responses of 30% and 67%, respectively, compared with standard doses of erlotinib or gefitinib in patients with EGFR mutant NSCLC with rLM (9,22). Osimertinib is a third generation EGFR-TKI that effectively penetrates the blood-brain barrier (23), and a previous study had reported that osimertinib improves OS in NSCLC patients with rLM regardless of T790M mutation status (24). The BLOOM study demonstrated a meaningful treatment effect of highdose osimertinib (160 mg daily) in patients with EGFRmutant NSCLC with rLM (positive CSF cytology) and a manageable safety profile (11).…”

Development of Liposomal Vesicles for Osimertinib Delivery to EGFR Mutation—Positive Lung Cancer Cells

“…In patients with EGFR mutation-positive advanced NSCLC, there is an unmet need for EGFR-TKIs with improved central nervous system (CNS) penetration and activity against CNS metastases, either at initial diagnosis or time of progression [ 30 ]. OSI was shown to have a good brain exposure in human subjects [ 31 ] and to be active against CNS brain metastases or leptomeningeal disease, regardless of T790M status [ 30 , 32 , 33 ]. Patients with brain metastasis may benefit from treatment with liposome-based OSI delivery due to favorable blood-to-brain penetration of the drug and additionally by brain targeting route of administration.…”

Osimertinib for Leptomeningeal Disease in EGFR-Mutated NSCLC

“…In conclusion, Lee et al 22 reveal that osimertinib significantly prolongs OS in patients with EGFRm NSCLC and LMD irrespective of the sequence of the therapy. This is a significant improvement in survival for patients with LMD who have thus far been excluded from clinical trials, lack standardized response assessment methods, and treatment guidelines.…”

“…Throughout this study period (October 2008-October 2019), the treatment paradigm for metastatic EGFRm NSCLC has evolved, with osimertinib becoming the standard-of-care first-line (1L) therapy irrespective of EGFR T790M mutation status. Lee et al 22 found no OS advantage with a higher dose of osimertinib. This study further reinforces the excellent CNS bioavailability of osimertinib, and CNS failure seems to be less common with osimertinib.…”

“…In this issue, Lee et al 22 report the OS of patients with EGFRm NSCLC and LMD treated with osimertinib compared with other therapies. This was a singlecenter retrospective analysis of 351 patients, most receiving firstor second-generation TKIs before LMD detection.…”