P1-12-09: Safety and Efficacy of Neratinib in Combination with Capecitabine in Patients with ErbB2-Positive Breast Cancer.
Authors: Saura C , Garcia-Saenz JA , Xu B , Harb W , Moroose R , Pluard T , Kiger C , Germa C , Wang K , Kim S-B 
Published: June 2012

Abstract
Background: Neratinib (HKI-272) is an irreversible pan-ErbB receptor tyrosine kinase inhibitor that has shown antitumor activity in patients with ErbB2+ breast cancer. Capecitabine has demonstrated efficacy and tolerability in combination with lapatinib, a reversible dual ErbB1/ErbB2 kinase inhibitor, in patients with ErbB2+ advanced breast cancer. The current study evaluated the safety and clinical activity of neratinib in combination with capecitabine.
Methods: In part 1 of this open-label, phase 1/2 study, the maximum tolerated dose (MTD) of neratinib in combination with capecitabine was determined in adults with advanced solid tumors. Part 2 of the study further evaluated the safety and clinical activity of neratinib plus capecitabine at the MTD in adults with confirmed ErbB2+ metastatic or locally advanced breast cancer (ECOG Performance Status of 0–2). Eligible patients had received prior taxane treatment and ≥1 prior trastuzumab-containing regimen for ≥6 weeks for metastatic or locally advanced disease. The primary endpoint of part 2 was objective response rate (ORR); tumor responses were assessed by investigators using modified RECIST version 1.0 guidelines every 6 weeks.
Results: In part 1 (n = 33), the MTD was determined to be neratinib 240 mg/day plus capecitabine 750 mg/m2 twice daily on Days 1 to 14 of each 21-day cycle. In part 2, as of April 2011, 72 female patients (median age of 52 years [range, 33–79 years]) with ErbB2+ breast cancer were enrolled and treated at the MTD; 7 patients had prior lapatinib exposure and all had prior trastuzumab and taxane exposure. As of the snapshot date, 56% of patients at the MTD were still participating in the study. The most common drug-related adverse events (AEs) in part 2 were diarrhea (89%), palmar-plantar erythrodysesthesia (57%), nausea (33%), vomiting (26%), and decreased appetite (22%). Grade 3/4 drug-related AEs in ≥5% of patients were diarrhea (25%) and palmar-plantar erythrodysesthesia (13%). Eight patients withdrew from part 2 due to AEs, including 4 who withdrew due to diarrhea. Dose interruptions of neratinib and capecitabine, respectively, due to AEs were required by 19 and 29 patients; dose reductions due to AEs were required by 8 and 22 patients. As of June 2010 (interim analysis), 22 patients were evaluable for efficacy in part 2 of the study. Of these 22 patients, 11 achieved a partial response for an ORR of 50%. An additional 2 patients maintained stable disease for ≥24 weeks, resulting in a clinical benefit rate of 59%, and 8 patients had stable disease for &lt;24 weeks. One patient had progressive disease without achieving a response or stable disease. Updated efficacy data will be presented.
Conclusions: The results of this study indicate that neratinib combined with capecitabine is tolerable and has promising antitumor activity in patients with ErbB2+ metastatic or locally advanced breast cancer pretreated with trastuzumab. This study supports further evaluation of this combination in ErbB2+ breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-09.