Neratinib, an Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor: Results of a Phase II Trial in Patients With Advanced Non–Small-Cell Lung Cancer

• Published in: Journal of clinical oncology Vol. 28; no. 18; pp. 3076 - 3083
• Main Authors: SEQUIST, Lecia V, BESSE, Benjamin, ANANTHAKRISHNAN, Revathi, QUINN, Susan, SORIA, Jean-Charles, LYNCH, Thomas J, MILLER, Vincent A, WONG, Kwok K, GITLITZ, Barbara, EATON, Keith, ZACHARCHUK, Charles, FREYMAN, Amy, POWELL, Christine
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20.06.2010
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Female; Humans; International Agencies; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medical sciences; Middle Aged; Mutation - genetics; Pneumology; Prospective Studies; Quinolines - therapeutic use; Receptor, Epidermal Growth Factor - genetics; Receptor, ErbB-2 - antagonists & inhibitors; Survival Rate; Treatment Outcome; Tumors; Tumors of the respiratory system and mediastinum; Young Adult; Antineoplastic agent; Human; Lung disease; Respiratory disease; Lung cancer; trk receptor; Malignant tumor; non-small cell lung carcinoma; Cancerology; Phase II trial; Bronchus disease; Advanced stage; Inhibitor; Irreversible; Neratinib; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2009.27.9414

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 with advanced NSCLC underwent EGFR sequencing of available tumor tissue at enrollment. Those with > or = 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-naïve patients with adenocarcinoma and light smoking histories (< or = 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). 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. Neratinib had low activity in patients with prior benefit from TKIs and in TKI-naïve 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.