Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Non-amplified Metastatic Breast Cancer

Purpose: 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 HER2^mut non-amplified metastatic breast cancer (MBC).  Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2^mut detection.  <p>Experimental Methods:  Tumor tissue positive for HER2^mut was required for eligibility.  Neratinib was administered 240mg daily with prophylactic loperamide.  ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2^mut). </p> <p>Results:  2.4% (9/381) tumors sequenced centrally harbored HER2^mut (lobular 7.8% vs ductal 1.6%; p=0.026).  Thirteen additional HER2^mut cases were identified locally.  21 of these 22 HER2^mut cases were estrogen receptor positive.  Sixteen patients (median age 58 [31-74] years and 3 [2-10] prior metastatic regimens) received neratinib.  The CBR was 31% (90%CI 13-55%), including 1 CR, 1 PR and 3 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%).  Additionally ctDNA HER2^mut variant allele frequency decreased in 9 of 11 paired samples at week four, followed by an increase upon progression.</p> Conclusions: Neratinib is active in HER2^mut, non-amplified MBC.  ctDNA sequencing offers a non-invasive strategy to identify patients with HER2^mut cancers for clinical trial participation.

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