Preclinical evidence for the efficacy of gefitinib exists in mouse models of NSCLC brain metastases with an EGFR mutation (42), and this drug acts as a radiation sensitizer in various cancer cell lines including NSCLC (43). Among the 75 patients with EGFR mutations, EGFR TKI therapy and cytotoxic chemotherapy after diagnosis of LC remained the independent factors predictive of extended survival in the multivariate analysis. We do not retain these email addresses. There is some evidence that CNS disease also responds to newer EGFR-targeted TKIs. Li and colleagues looked at the EGFR mutation status of 110 patients with NSCLC, in whom 14 patients developed brain metastases either at diagnosis (1 out of 14) or during follow-up (41). Takakuwa K, Mogushi K, Han M, Fujii T, Hosoya M, Yamanami A, Akita T, Yamashita C, Hayashida T, Kato S, Yamaguchi S. Sci Rep. 2020 Apr 10;10(1):6214. doi: 10.1038/s41598-020-63200-7. Purpose: Mutations in epidermal growth factor receptor (EGFR) can be used to predict the tumor response of patients receiving gefitinib for non-small cell lung cancer (NSCLC). Mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. The compound is believed to be the first representative from a new structural class of anilinoquinazoline tyrosine kinase inhibitors. A recent clinical trial has demonstrated that EGFRs harboring some of these less common mutations also appear to be sensitive to the third-generation EGFR TKI, osimertinib. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. The epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib have shown efficacy in patients with NSCLC and brain metastases. Dose escalation of afatinib led to a response in both brain and thoracic disease. The CSF levels in such studies are likely to underestimate drug exposure within the tumor in the context of a disrupted BBB (31). Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance. In cases in which there is isolated CNS progression, TKI dose escalation may be of benefit, and even a switch from one type of TKI to another may result in an intracranial response following earlier clinical benefit from an EGFR TKI (62). By contrast, gefitinib in any form is not a PgP substrate and is known to inhibit PgP activity (33). NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. Patients whose metastatic tumors harbor EGFR mutations are expected to live longer than 2 years, … EGFR is a receptor tyrosine kinase that belongs to the EGFR family, consisting of four members: EGFR, ERBB2, ERBB3, and ERBB4. Clinical Cancer Research Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Copyright © 2015 International Association for the Study of Lung Cancer. Gefitinib proved effective in both WBRT-pretreated and WBRT-naïve patients. Boe S. Sorensen MS, PhD . These cases suggest that brain metastases may remain sensitive to EGFR TKIs after progression on TKI therapy, but require a higher CSF concentration to achieve significant BBB penetration. The higher serum concentration of erlotinib compared with gefitinib is thought to lead to higher CSF concentration and, therefore, a response in CNS disease. Subsequently, exploration of alternative schedules and sequencing of EGFR TKI combined with radiotherapy may be warranted. Table 1 summarizes the studies of EGFR inhibitors done in selected and unselected patients with CNS metastases from NSCLC. Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement. Small case series have shown response to gefitinib after failure of standard therapy, including complete response in the brain (48–50). The maximum number of brain metastases for which SRS is considered suitable is controversial, but it is generally used in patients with 1 to 4 brain metastases, less than 4 cm in diameter (14), on the basis of earlier studies showing that patients with 1 to 2 metastases treated with SRS had significantly longer median survival compared with patients with 3 or more metastases (18). HGF, hepatocyte growth factor; IL-6, interleukin-6. 2016 Dec;12(Supplement):C131-C137. This is an important question because improvements in screening techniques are facilitating the identification of patients with uncommon mutations for whom optimal treatment has not yet been clarified.
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