T-DM1 plus neratinib was safe and showed preliminary efficacy in HER2-positive breast cancer.

  • Major Finding: T-DM1 plus neratinib was safe and showed preliminary efficacy in HER2-positive breast cancer.

  • Approach: This phase Ib trial enrolled 27 women with metastatic, HER2-positive breast cancer.

  • Impact: A phase II trial of T-DM1 plus neratinib using the dose established in this study is justified.


Treatment of patients with human epidermal growth factor receptor (HER2)–positive metastatic breast cancer with a combination of trastuzumab and pertuzumab typically results in resistance to both agents. In a phase Ib, open-label clinical trial, Abraham and colleagues tested the safety, tolerability, efficacy, and recommended phase II dose of combined treatment with ado-trastuzumab emtansine (T-DM1) and neratinib in 27 women with metastatic, HER2-positive breast cancer whose disease had progressed on trastuzumab plus pertuzumab. This combination was pursued because of the different mechanisms of the two drugs: T-DM1 binds the extracellular domain of HER2, whereas neratinib binds an intracellular ATP pocket. At least one adverse event was experienced by each patient, with the most common being diarrhea, ranging from grade 1 through grade 3, which was noted in 23 patients (93%). Nineteen patients were evaluable for overall response (OR). Of these, 16% (3/19 patients) attained a complete response (CR) for 364, 510, and more than 969 days, 47% (9/19 patients) attained a confirmed partial response (PR), 11% (2/19 patients) experienced stable disease, and 26% (5/19 patients) had progressive disease. Notably, 70% of patients (7/10) with amplification of ERBB2 (encoding HER2) detected in plasma cell-free DNA (cfDNA) exhibited a CR or PR, whereas only 24% of patients (4/17) without ERBB2 amplification attained a PR, and no patients without ERBB2 amplification had a CR. Additionally, the duration of OR in patients with ERBB2 amplification ranged from 18 to more than 132 weeks, whereas the duration of OR in patients without ERBB2 amplification ranged from 12 to 24 weeks. Two patients, both of whom attained a CR, had consented to tissue biopsy upon study enrollment; analysis of these biopsies revealed high levels of total HER2 and truncated HER2 lacking the extracellular trastuzumab binding site. This work provides evidence for safety and tolerability as well as preliminary evidence of efficacy for T-DM1 with neratinib in metastatic, HER2-positive breast cancer and supports proceeding with a phase II trial of the combination.

Abraham J, Montero AJ, Jankowitz RC, Salkeni MA, Beumer JH, et al. Safety and efficacy of T-DM1 plus neratinib in patients with metastatic HER2-positive breast cancer: NSABP Foundation Trial FB-10. J Clin Oncol 2019 Aug 23 [Epub ahead of print].

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