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PURPOSE: Based on promising predinical 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 HER2(mut) nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2(mut) detection. EXPERIMENTAL DESIGN: Tumor tissue positive for HER2(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 HER2(mut)). RESULTS: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2(mut) (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2(mut) cases were identified locally. Twenty-one of these 22 HER2(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 HER2(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 HER2(mut) variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. CONCLUSIONS: Neratinib is active in HER2(mut), nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2(mut) cancers for clinical trial participation.

Advances in DNA sequencing provide the potential for clinical assays that are timely and affordable and use small amounts of clinical material. The hypothesis has therefore been raised that marked improvements in patient outcomes will result when DNA diagnostics are matched to an armamentarium of targeted agents. While this may be partially true, much of the novel biology uncovered by recent sequencing analysis is poorly understood and not druggable with existing agents. Significant other challenges remain before these technologies can be successfully implemented in the clinic, including the predictive accuracy of pathway-based models, distinguishing drivers from passenger mutations, development of rational combinations, addressing genomic heterogeneity, and molecular evolution/resistance mechanisms. Developments in regulatory science will also need to proceed in parallel to scientific advances so that targeted treatment approaches can be delivered to small subsets of patients with defined biology and drug reimbursement is available for individuals whose tumor carries a mutation that has been successfully targeted in another malignancy, as long as they agree to participate in an outcome registry. Clin Cancer Res; 19(23); 6371–9. ©2013 AACR.