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Neratinib/T-DM1 Combo Shows Promise in HER2-Positive Breast Cancer

Jason Harris
Published: Monday, Jun 18, 2018

Jame Abraham, MD

Jame Abraham, MD

The combination of neratinib (Nerlynx) and T-DM1 (ado-trastuzumab emtansine; Kadcyla) induced an overall response rate of 60% in previously-treated women with HER2-positive metastatic breast cancer, according to results from the phase Ib NSABP FB-10 study presented at the 2018 ASCO Annual Meeting.1

Among 12 of 20 evaluable patients with objective responses, 3 had a complete response and 9 had a partial response. An additional 2 patients had stable disease, and 6 patients had progressive disease.

FB-10 (NCT02236000) is an open-label, single arm study with a dose-escalation phase and an expanded cohort phase evaluating patients who had previously received chemotherapy and the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta). At the time of the data presentation, 27 patients had been enrolled. The target enrollment is 63 patients.

During the phase Ib portion of the study, patients received 3.6 mg/kg of T-DM1 once every 3 weeks and escalating doses of 120 mg, 160 mg, 200 mg, or 240 mg of daily oral neratinib. All patients received high-dose loperamide for diarrhea prophylaxis. Investigators observed activity at all dose levels.

“We are encouraged by these initial findings and we look forward to continuing to enroll patients in the phase II portion of the trial to further evaluate the safety and efficacy of the combination of T-DM1 and neratinib in this patient population,” lead investigator Jame Abraham, MD, director of the Breast Oncology Program at Taussig Cancer Institute and professor of medicine at Cleveland Clinic, said in a statement.

Eligible patients in the FB-10 study had been diagnosed with HER2-positive invasive adenocarcinoma and had measurable disease. Women who had received previous T-DM1 or a HER2-targeting tyrosine kinase inhibitor were excluded.

Among all 27 enrolled patients, the mean patient age was 48.3 years (range, 23-69). Twenty patients had an ECOG performance status of 0 and 7 had a status of 1. Fourteen patients were ER- or PR-positive and 13 were not.

Fourteen patients had received neoadjuvant or adjuvant trastuzumab/pertuzumab and 13 had received the combination in the metastatic setting. Seven patients had brain metastases, 6 had metastases in a single organ, and 21 had metastases in multiple organs.

There was 1 dose-limiting toxicity (DLT) at the 120-mg neratinib dose, 3 at the 200-mg dose, and 2 at the 240-mg dose. There were no DLTs at the 160-mg dose, and the recommended phase II dose was set at 160 mg/daily.

The FDA approved neratinib in July 2017 for extended adjuvant treatment of women with early-stage HER2-positive breast cancer based on results from the phase III ExteNET trial. Patients were randomly assigned to placebo (n = 1420) or 240 mg of daily neratinib (n = 1420) for 1 year. Patients were allowed dose reductions to 200 mg, 160 mg, and 120 mg for toxicity. Diarrhea prophylaxis was recommended but not mandatory.2

At a median follow-up of 5 years, investigators found that the invasive disease-free survival rate was 90.2% for patients assigned to neratinib compared with 87.7% for placebo (HR, 0.73; 95% CI, 0.57-0.92; P = .0083).

However, 40% of patients assigned to neratinib developed grade 3 diarrhea in ExteNET compared with just 2% for those assigned to placebo. The FDA label for neratinib states that antidiarrheal prophylaxis with loperamide should be started with the first dose of neratinib.

Among 27 patients evaluated for safety in FB-10, 6 (22%) experienced grade 3 diarrhea and 25 (93%) experienced any-grade diarrhea. The other most common grade 3 treatment-related adverse events were thrombocytopenia (15%), nausea (11%), and hypertension (11%).

In an email to OncLive, Abraham noted that, with appropriate prophylaxis, the rate of grade 3 diarrhea in FB-10 was about half the rate found in ExteNET.

“It is important to educate the patients about diarrheal prophylaxis and management,” he said. “It is important to modify the dose depending upon the side effects.”

Investigators will continue to evaluate the efficacy of neratinib/TDM-1 in the phase II portion of the study. The combination of budesonide and loperamide—which has been shown to reduce the incidence of grade 3 diarrhea—will also be evaluated.


  1. Abraham J, Puhalla S, Sikov WM, et al. NSABP FB-10: phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DM1) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC). J Clin Oncol. 36, 2018 (suppl; abstr 1027).
  2. Martin M, Holmes FA, Ejertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9.

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