Abstract
Treatment outcomes in advanced or metastatic non-small-cell lung cancer (NSCLC) remain unsatisfactory, with low long-term survival rates. Palliative chemotherapy offers a median survival not exceeding 1 year. To date, various combinations of cytotoxic drugs have not improved treatment results beyond what has been observed with platinum doublets. By contrast, molecular targeted drugs may block important pathways that drive cancer progression and achieve long-term disease control. Conflicting results have demonstrated marginal benefit with EGFR inhibitors, anti-EGFR monoclonal antibodies and antiangiogenic strategies in unselected populations of patients with advanced NSCLC. However, patients with an EGFR mutation are likely to respond to agents that target this gene. Novel targeted therapies that interfere with insulin-like growth factor 1 receptor, or the EML4-ALK fusion protein have shown promising activity. Aberrations in other key signaling pathways and molecules, such as RAS/RAF/MEK, PI3K/AKT/mTOR, or MET kinase, have been identified as crucial targets, especially in resistant patients. Novel drugs aimed at these abnormalities are already in the clinic. This Review outlines the current state-of-the-art research for targeted therapy in NSCLC.
Key Points
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EGFR tyrosine kinase inhibitors have limited efficacy in an unselected population of patients with advanced NSCLC, but are very effective in patients who have underlying EGFR mutations
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The anti-EGFR monoclonal antibody cetuximab modestly prolongs survival in combination with chemotherapy in an unselected patient population; patients who develop skin rash after treatment initiation have considerably prolonged survival
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Mutated KRAS is not clearly associated with complete resistance to anti-EGFR therapy in NSCLC, but patients with mutated KRAS generally have a poor outcome irrespective of the treatment regimen
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The anti-VEGF monoclonal antibody bevacizumab marginally improves progression-free survival and may improve overall survival when combined with chemotherapy in NSCLC patients with nonsquamous histology
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The product of EML4-ALK constitutively activates RAS, which may confer EGFR resistance; other targets that possibly mediate resistance include the MET kinase receptor and PI3K/AKT/mTOR pathway
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IGF-1R is an interesting target in advanced NSCLC—antibodies have demonstrated promise in phase II trials with chemotherapy, and inhibitors of this target are in early clinical testing
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Change history
01 June 2011
In the version of this article initially published online, the last reference in this article, reference 141, is incorrect. The correct reference is US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00596648 (2010). The error has been corrected for the HTML and PDF versions of the article.
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Janku, F., Stewart, D. & Kurzrock, R. Targeted therapy in non-small-cell lung cancer—is it becoming a reality?. Nat Rev Clin Oncol 7, 401–414 (2010). https://doi.org/10.1038/nrclinonc.2010.64
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DOI: https://doi.org/10.1038/nrclinonc.2010.64
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