Significant progress has been made in the treatment of stage iv non-small-cell lung cancer (nsclc); however, the prognosis of patients with brain metastases remains poor. Resection and radiation therapy remain standard options. This issue is an important one because 10% of patients with nsclc have brain metastases at diagnosis, and 25%-40% develop brain metastases during their disease. Standard chemotherapy does not cross the blood-brain barrier. However, there is new hope that tyrosine kinase inhibitors (tkis) used in patients with identified targetable mutations such as mutations of and rearrangements of could have activity in the central nervous system (cns). Furthermore, immunotherapy is increasingly becoming a standard option for patients with nsclc, and interest about the intracranial activity of those agents is growing. This review presents current data about the cns activity of the available major tkis and immunotherapy agents.
Somatic epidermal growth factor receptor (EGFR) mutations are present in around 50% of Asian patients and in 10–15% of Caucasian patients with metastatic non-small cell lung cancer (NSCLC) of adenocarcinoma histology. The first-generation EGFR-tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have demonstrated improved progression-free survival (PFS) and response rates but not overall survival (OS) benefit in randomized phase III trials when compared with platinum-doublet chemotherapy. All patients treated with EGFR-TKIs will eventually develop acquired resistance to these agents. Afatinib, an irreversible ErbB family blocker, has shown in two randomly controlled trials in patients with EGFR-activating mutations, a significant improvement in PFS and health-related quality of life when compared to platinum-based chemotherapy. Afatinib improved OS in patients with Del19 mutations. In patients having progressed on first-generation EGFR-TKIs, afatinib did lead to a clinical benefit. A randomly controlled trial showed that PFS was significantly superior with afatinib vs. erlotinib in patients with squamous NSCLC in the second-line setting. A phase IIb trial comparing afatinib and gefitinib in first-line EGFR positive NSCLC showed significantly improved PFS with afatinib but OS was not significantly improved.
Despite recent advances in the systemic therapy of non-small-cell lung cancer (nsclc), the prognosis for stage iv disease remains poor. The discovery of targetable mutations has led to new treatment options. The most common mutations, the activating mutations, are present in about 50% of Asian patients and up to 15% of white patients. First-generation reversible epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) have led to improved survival in patients positive for activating mutations, but resistance eventually leads to disease progression. The irreversible egfr tki afatinib was developed to counter such resistance. The clinical efficacy of afatinib has been shown in first-line studies comparing it with both cytotoxic chemotherapy and first-generation egfr tkis. Afatinib has also shown continued benefit beyond progression while a patient is taking an egfr inhibitor. Furthermore, its toxicity profile is both predictable and manageable. The results of the principal clinical trials assessing afatinib are reviewed here.
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