Neratinib Efficacy and Circulating Tumor DNA Detection of <i>HER2</i> Mutations in <i>HER2</i> Nonamplified Metastatic Breast Cancer

Abstract

<b>Purpose:</b> Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in <i>HER2</i>^mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) <i>HER2</i>^mut detection.<b>Experimental Design:</b> Tumor tissue positive for <i>HER2</i>^mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor <i>HER2</i>^mut).<b>Results:</b> Nine of 381 tumors (2.4%) sequenced centrally harbored <i>HER2</i>^mut (lobular 7.8% vs. ductal 1.6%; <i>P</i> = 0.026). Thirteen additional <i>HER2</i>^mut cases were identified locally. Twenty-one of these 22 <i>HER2</i>^mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same <i>HER2</i>^mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA <i>HER2</i>^mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.<b>Conclusions:</b> Neratinib is active in <i>HER2</i>^mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with <i>HER2</i>^mut cancers for clinical trial participation. <i>Clin Cancer Res; 23(19); 5687-95. ©2017 AACR</i>.