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.
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)).
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.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.
View details for PubMedID 28679771