Neratinib for Metastatic HER2 Breast Cancer

Trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab maytansine have improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. But there is a need for additional agents. Now, investigators have conducted an industry-supported, multinational, open-label, phase I/II trial of neratinib, an oral, pan-HER tyrosine kinase inhibitor that has demonstrated impressive activity in patients with progressive HER2 metastatic disease following trastuzumab and taxane therapy, albeit with a high rate of diarrhea (J Clin Oncol 2010 Mar 10; 28:1301).

Part 1 of the study established the maximum tolerated dose (MTD) of neratinib plus capecitabine in 33 patients with solid breast cancer tumors not curable by currently available therapy. Part 2 evaluated the safety and efficacy of the MTD in 72 patients with confirmed HER2-amplified or locally advanced metastatic disease. Prior treatment with capecitabine, lapatinib (except for a preplanned analysis), other HER2-targeted agents, or anthracyclines (doxorubicin ≥400 mg/m² or epirubicin ≥800mg/m²) was not allowed.

The MTD was determined to be 240 mg/day of neratinib plus 1500 mg/m² per day of capecitabine. In parts 1 and 2, the most common adverse events were diarrhea (88% of patients) and hand-foot syndrome (48%). Of the 65 patients who experienced diarrhea, 15% were managed by dose interruptions, 11% were managed by dose reductions, and 6% withdrew from the study. In part 2, the objective response rate (ORR; the primary endpoint) was 64% in 61 patients without prior lapatinib exposure and 57% in 7 patients with lapatinib exposure; median progression-free survival rates in these two groups were 40.3 and 35.9 weeks, respectively.