Assessment of Effectiveness and Safety of Osimertinib for Patients With Intracranial Metastatic Disease

Abstract

IMPORTANCE Intracranial metastatic disease (IMD) is a serious and life-altering complication for many patients with cancer. Targeted therapy may address the limitations of current treatments as an additional agent to achieve intracranial disease control in some patients with IMD. Given the paucity of evidence regarding effectiveness, current guidelines have not made recommendations on the use of targeted therapy. Osimertinib mesylate is a mutant epidermal growth factor receptor (EGFR) inhibitor that can penetrate the blood-brain barrier and inhibit tumor cell survival and proliferation in patients with non-small cell lung cancer (NSCLC) with specific EGFR alterations. OBJECTIVE To assess the effectiveness and safety of osimertinib in the management of IMD. DATA SOURCES Studies were selected from MEDLINE and Embase databases from their inception to September 20, 2019, using the following search query: (osimertinib OR mereletinib OR tagrisso OR tamarix OR azd9291) AND (brain metastases OR intracranial metastatic disease OR cns). STUDY SELECTION Studies reporting intracranial outcomes for patients with metastatic EGFRvariant NSCLC and IMD treated with osimertinib were included in this systematic review and metaanalysis. Among 271 records identified in the systematic review, 15 studies fulfilled eligibility criteria for inclusion in the meta-analysis. DATA EXTRACTION AND SYNTHESIS Data were extracted from published studies and supplements. These data were pooled using a random-effects model. Risk of bias was assessed using the Cochrane risk of bias tool and the modified Newcastle-Ottawa Scale. MAIN OUTCOMES AND MEASURES Information extracted included study characteristics, intracranial effectiveness measures, and safety measures. Meta-analyses of proportions were conducted to pool estimates for central nervous system (CNS) objective response rate and CNS disease control rate. RESULTS Fifteen studies reporting on 324 patients were included in the meta-analysis. The CNS objective response rate was 64% (95% CI, 53%-76%; n = 195), and CNS disease control rate was 90% (95% CI, 85%-93%; n = 246). Included studies reported complete intracranial response rates of 7% to 23%, median best decrease in intracranial lesion size of −40% to −64%, and Common Terminology Criteria for Adverse Events (version 3.0) grade 3 or higher adverse event rates of 19% to 39%. Subgroup analyses did not reveal additional sources of heterogeneity. CONCLUSIONS AND RELEVANCE Findings reported herein support a potential role for osimertinib in the treatment of patients with metastatic EGFR-variant NSCLC and IMD treated with osimertinib.

Systematic review and meta-analysis of lung cancer brain metastasis and primary tumor receptor expression discordance

“…EGFR amplification was observed in BM samples but not in lung lesions, suggesting that those patients were resistant to EGFR TKI. Osimertinib a third generation EGFR-TKI has demonstrated excellent CNS response of 91% in patients with EGFR-mutant NSCLC in both first and second-line setting [ 17 ]. For example, in the phase III FLAURA trial, the CNS efficacy of osimertinib was demonstrated in the first-line setting with fewer patients in the osimertinib arm developing new brain lesions compared with the control arm (12% versus 30%) [ 18 ].…”

Integration of Systemic Therapy and Stereotactic Radiosurgery for Brain Metastases

“…Osimertinib, a third-generation EGFR TKI, has high CNS penetration [47] (Figure 1). In a retrospective study of NSCLC BM patients, Xie et al compared the outcomes of patients treated with RT and osimertinib versus osimertinib alone [48].…”

A Case of Five-Year Survival After Combined-Modality Treatment for Non-Small Cell Lung Cancer With Intraspinal Metastasis

“…One of the factors responsible for limited long-term survival rates is the development of central nervous system (CNS) metastases, which typically are located in the brain or meninges. Their multidisciplinary treatment involves different radiotherapy modalities, surgical resection, and systemic therapy [2][3][4][5][6][7][8]. Defined subtypes of NSCLC, e.g., those with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations, may respond to targeted agents; however, wild-type NSCLC (negative EGFR, ALK, and other common alterations) is the prevailing tumor type in the authors' geographical region [9].…”