Gastrointestinal and Cardiovascular Safety Profiles of Neratinib Monotherapy in Patients with Advanced ErbB2-Positive Breast Cancer.
Authors: Burstein H. , Sun Y. , Dirix L. , Jiang Z. , Paridaens R. , Tan A. , Awada A. , Ranade A. , Jiao S. , Schwartz G. , Powell C. , Turnbull K. , Vermette J. , Zacharchuk C. , Badwe R. 
Published: December 2010

Abstract
Background: In a phase 2 study, oral neratinib was administered to patients (pts) with advanced breast cancer in 2 cohorts, those with prior trastuzumab treatment (prior T, n=66) and those with no prior trastuzumab treatment (no prior T, n=70). Neratinib demonstrated robust antitumor activity with objective response rates of 26% and 51%, respectively, and was generally tolerable (Burstein et al. Cancer Res 2009;69:72S). Diarrhea, all grades, occurred in 89% of total pts. Characteristics of the diarrhea and left ventricular ejection fraction (LVEF) measurements are described. Methods: Pts were required to have ErbB2 gene amplification in tumor tissue as measured by fluorescence in situ hybridization by independent assessment. Serial LVEF measurements were made with a multigated acquisition scan or echocardiogram. Pts were ineligible if baseline LVEF was &lt;50%. Adverse events were graded based on the NCI Common Terminology Criteria, v 3.0. Pts received oral neratinib 240 mg daily. Results: Data collected by 18 Mar 2009 are reported; the median (range) duration of neratinib treatment was 4.5 (0.2-23.5) months for pts with prior T and 7.8 (0.5-24.2) months for pts with no prior T. Diarrhea, all grades occurred in 93% of the total population (prior T: 97%, no prior T: 89%); grade 3-4 diarrhea occurred in 21% of the total population (prior T: 30%, no prior T: 13%). Median times of onset were 2 and 3 days after first dose of neratinib, respectively, and median durations of diarrhea were 7 and 5 days. In study week 1, 86% and 73% of pts with prior T and no prior T, respectively, had diarrhea; this decreased to 12-14% in months 3 and 4 (Table). Diarrhea was the cause of dose interruptions in 36% of pts with prior T and 11% of pts with no prior T and of dose reductions in 30% of pts with prior T and 5% of pts with no prior T; only 1 pt (prior T) discontinued treatment due to diarrhea. Pts used anti-diarrheal medications for supportive therapy (prior T: 91%, no prior T: 67%). For LVEF measurements, there was little variation from baseline in most pts during the study. Four pts had at least 1 LVEF measurement &lt;50% (2 of these pts had measurements within the institutional range of normal). None had congestive heart failure. One of these pts had grade 3 atrioventricular block and grade 3 bradycardia, which were considered unrelated to neratinib. Discussion: Neratinib treatment was not associated with clinically significant cardiotoxicity. Pts who developed diarrhea with neratinib monotherapy had early onset, but frequency and severity decreased with time on study. Despite the high frequency of diarrhea with neratinib treatment, it was readily managed with supportive therapy and dose interruptions and/or reductions.Time Course of Diarrhea in ErbB2-Positive Breast Cancer Patients Treated With NeratinibStudy PeriodPrior T: No. on StudyPrior T: % With Diarrhea, All Grades*Prior T: % With Diarrhea, Gr 3-4*No Prior T: No. on StudyNo Prior T: % With Diarrhea, All Grades*No Prior T: % With Diarrhea, Gr 3-4*Week 166861770737Week 2-466611170436Month 260331066152Month 34713060120Month 44312058140*For pts with multiple toxicity grades in a period, the maximum grade was reported.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5096.