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      Current progress and outcomes of clinical trials on using epidermal growth factor receptor-tyrosine kinase inhibitor therapy in non-small cell lung cancer patients with brain metastases

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          Abstract

          Non-small cell lung cancer (NSCLC) continues to be one of the major causes of cancer-related deaths worldwide, and brain metastases are the major cause of death in NSCLC patients. With recent advances in understanding the underlying molecular mechanism of NSCLC development and progression, mutations in epidermal growth factor receptor ( EGFR) have been recognized as a key predictor of therapeutic sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Using EGFR-TKI alone or in combination with standard treatments such as whole-brain radiotherapy and surgery has been an effective strategy for the management of brain metastasis. Particularly, a newer generation of EGFR-TKIs, including osimertinib and AZD3759, has been developed. These new EGFR-TKIs can cross the blood–brain barrier and potentially treat EGFR-TKI resistance and improve prognosis. In this article, current progress and outcomes of clinical trials on the use of EGFR-TKIs for treating NSCLC patients with brain metastasis will be reviewed.

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          Most cited references 59

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          Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity.

          Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.
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            Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer.

            Brain metastasis (BM) is a leading cause of death from non-small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety. Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility. Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations. Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.
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              Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.

              Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harboured EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouring EGFR mutations was 11.7 (7.9-15.5) months, compared to 5.8 (5.2-6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2-19.7) months and 3.1 (2.5-3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed. Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.
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                Author and article information

                Contributors
                Journal
                Chronic Dis Transl Med
                Chronic Dis Transl Med
                Chronic Diseases and Translational Medicine
                Chinese Medical Association
                2095-882X
                2589-0514
                12 December 2017
                December 2017
                12 December 2017
                : 3
                : 4
                : 221-229
                Affiliations
                [a ]Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, China
                [b ]Key Laboratory of Radiation Oncology of Shandong Province, Shandong Academy of Medical Sciences, Jinan, Shandong 250001, China
                Author notes
                []Corresponding author. Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, China.Department of Radiation OncologyShandong Cancer Hospital Affiliated to Shandong UniversityJinanShandong250117China xinglg@ 123456medmail.com.cn
                Article
                S2095-882X(17)30076-2
                10.1016/j.cdtm.2017.11.001
                5747498
                © 2017 Chinese Medical Association. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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