Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: Results of a phase II trial in patients with advanced non-small-cell lung cancer Journal Article


Authors: Sequist, L. V.; Besse, B.; Lynch, T. J.; Miller, V. A.; Wong, K. K.; Gitlitz, B.; Eaton, K.; Zacharchuk, C.; Freyman, A.; Powell, C; Ananthakrishnan, R.; Quinn, S.; Soria, J. C.
Article Title: Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: Results of a phase II trial in patients with advanced non-small-cell lung cancer
Abstract: Purpose Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have had a significant impact on non-small-cell lung cancer (NSCLC) outcomes, particularly for patients with EGFR mutations. Resistance emerges after 9 to 12 months, primarily mediated by the T790M resistance mutation. We studied neratinib, an irreversible pan-ErbB TKI that may overcome T790M. Patients and Methods Patients with advanced NSCLC underwent EGFR sequencing of available tumor tissue at enrollment. Those with <= 12 weeks of prior TKI therapy were placed in arm A if they were EGFR mutation positive or arm B if they were wild-type. Arm C included TKI-naOve patients with adenocarcinoma and light smoking histories (<= 20 pack-years). All patients received daily oral neratinib, initially at 320 mg but subsequently reduced to 240 mg because of excessive diarrhea. The primary end point was objective response rate (RR). Results One-hundred sixty-seven patients were treated: 91 in arm A, 48 in arm B, and 28 in arm C. Diarrhea was the most common toxicity; grade 3 incidence was 50% at 320 mg but improved to 25% after dose reduction. The RR was 3% in arm A and zero in arms B and C. No patients with known T790M responded. Notably, three of four patients with an exon 18 G719X EGFR mutation had a partial response and the fourth had stable disease lasting 40 weeks. Conclusion Neratinib had low activity in patients with prior benefit from TKIs and in TKI-naOve patients, potentially because of insufficient bioavailability from diarrhea-imposed dose limitation. Responses were seen in patients with the rare G719X EGFR mutation, highlighting the importance of obtaining comprehensive genetic information on trials of targeted agents.
Keywords: gefitinib; solid tumors; breast-cancer; gene-mutations; antitumor-activity; growth-factor-receptor; kras mutations; acquired-resistance; molecular predictors; egfr mutations
Journal Title: Journal of Clinical Oncology
Volume: 28
Issue: 18
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2010-06-20
Start Page: 3076
End Page: 3083
Language: English
ACCESSION: ISI:000278883200024
DOI: 10.1200/jco.2009.27.9414
PROVIDER: wos
PUBMED: 20479403
Notes: --- - Article - "Source: Wos"
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  1. Vincent Miller
    270 Miller