Treatment of Non-Small-Cell Lung Cancer with Erlotinib or Gefitinib

ArticleinNew England Journal of Medicine 364(10):947-55 · March 2011with24 Reads
DOI: 10.1056/NEJMct0807960 · Source: PubMed
A 64-year-old woman receives the diagnosis of metastatic non-small-cell lung cancer (NSCLC), which has progressed during treatment with carboplatin, paclitaxel, and bevacizumab. Erlotinib therapy is recommended.
    • "The activating mutations of epidermal growth factor receptor (EGFR) occur in approximately 10–15 % of NSCLC cases in Caucasian patients and approximately 30–40 % in East Asian patients [1, 2] . The first-and secondgeneration EGFR tyrosine kinase inhibitors (TKI), erlotinib , gefitinib, and afatinib, have been widely used for these advanced NSCLC patients [3][4][5] . However, acquired resistance to these inhibitors frequently develops after a median of 9 to 13 months [5][6][7][8][9][10][11]. "
    [Show abstract] [Hide abstract] ABSTRACT: The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are widely used in patients with non-small cell lung cancer (NSCLC). However, EGFR T790M mutation leads to resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development. These agents include osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Osimertinib (AZD9291, TAGRISSO) was recently approved by FDA for metastatic EGFR T790M mutation-positive NSCLC. HM61713, ASP8237, EGF816, and PF-06747775 are still in early clinical development. This article reviews the emerging data regarding third-generation agents against EGFR T790M mutation in the treatment of patients with advanced NSCLC.
    Full-text · Article · Dec 2016
    • "Small molecule inhibitors of EGFR (epidermal growth factor receptor) have been widely used for lung cancer therapy123456789. A small subset (3–13 %) of non-small cell lung cancer (NSCLC) has been shown to have rearrangements in the ALK (anaplastic lymphoma kinase) gene [10, 11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Crizotinib as the first-generation ALK inhibitor has shown significant activity in ALK-mutated non-small cell lung cancer (NSCLC). Second- and third-generation ALK inhibitors are entering clinical applications for ALK+ NSCLC. In addition, a third-generation ALK inhibitor, lorlatinib (PF-06463922), was reported to resensitize NSCLC to crizotinib. This review provided a summary of clinical development of alectinib, ceritinib, brigatinib (AP26113), and lorlatinib.
    Full-text · Article · Dec 2016
    • "Progress in understanding molecular aberrant pathways of NSCLC has led to the development of agents that specifically target growth factor receptors or their downstream signaling components thereby blocking tumor cell proliferation capacity. The most advanced targets in this respect that are used clinically to combat NSCLC are the epidermal growth factor receptor (EGFR) tyrosine kinase and the fusion protein between EML4 (echinoderm microtubule-associated protein-like 4) and anaplastic lymphoma kinase (ALK) [12, 13]. The insulin growth factor-1 receptor (IGF-1R), is another transmembrane receptor with tyrosine kinase activity found in NSCLC and other tumor types [14][15][16][17][18]. IGF-1R is found in cells as a tetramer with two extracellular localized α domains which are responsible for associating with ligand and two β subunits which apart from ligand binding also harbor the active kinase pocket [14][15][16][17][18]. "
    [Show abstract] [Hide abstract] ABSTRACT: In this work two acetylene alcohols, compound 1 and compound 2, which were isolated and identified from the sponge Cribrochalina vasculum, and which showed anti-tumor effects were further studied with respect to targets and action mechanisms. Gene expression analyses suggested insulin like growth factor receptor (IGF-1R) signaling to be instrumental in controlling anti-tumor efficacy of these compounds in non-small cell lung cancer (NSCLC). Indeed compounds 1 and 2 inhibited phosphorylation of IGF-1Rβ as well as reduced its target signaling molecules IRS-1 and PDK1 allowing inhibition of pro-survival signaling. In silico docking indicated that compound 1 binds to the kinase domain of IGF-1R at the same binding site as the well known tyrosine kinase inhibitor AG1024. Indeed, cellular thermal shift assay (CETSA) confirmed that C. vasculum compound 1 binds to IGF-1R but not to the membrane localized tyrosine kinase receptor EGFR. Importantly, we demonstrate that compound 1 causes IGF-1Rβ but not Insulin Receptor degradation specifically in tumor cells with no effects seen in normal diploid fibroblasts. Thus, these compounds hold potential as novel therapeutic agents targeting IGF-1R signaling for anti-tumor treatment.
    Full-text · Article · Jul 2016
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