FDA Approves Dose-Escalation Label Amendment for Neratinib in HER2+ Breast Cancer

A dose-escalation schedule for neratinib may help some patients with HER2-positive breast cancer better manage severe diarrhea resulting from treatment.

A dose-escalation label update for neratinib (Nerlynx) as therapy for patients with HER2-positive early-stage and metastatic breast cancer was recently approved by the FDA, according to a press release from the company responsible for the agent, Puma Biotechnology.1

The new dose-escalation schedule examined in the CONTROL trial (NCT02400476) will now be included on the label and for which a new bottle containing 133 tablets will be aligned with a 4-week supply of neratinib. The new schedule will consist of 120 mg of neratinib during week 1, 160 mg for week 2, and 240 mg for the remainder of treatment.

“The inclusion of dose escalation in the prescribing information is a critical road-map for health care providers and patients as they seek to optimize treatment and reduce therapy-related toxicity in the early breast cancer and metastatic settings,” Hope S. Rugo, MD, professor of Medicine at the University of California San Francisco Comprehensive Cancer Center, said in a press release.

CONTROL was an open-label, non-randomized, multi-cohort study designed to look at the severity of diarrhea in patients with early-stage HER2-positive breast cancer who were treated with neratinib and loperamide (Imodium) or other prophylactic measures.

This study consisted or 563 patients who were treated with 240 mg of neratinib daily up to 1 year plus loperamide and additional anti-diarrheal treatment as needed or to dose-escalation of neratinib as described above.

The primary end point was incidence of grade 3 or greater diarrhea. Secondary end points included incidence of serious adverse effects and incidence and severity of diarrhea.

Dose-escalation neratinib coupled with loperamide resulted in a 60% reduction in grade 3 diarrhea at 40% vs 13% for the standard neratinib dose from the ExteNet trial (NCT00878709) where no dose escalation or antidiarrheal was mandated. Patients also experienced a 50% reduction in median cumulative days of grade 3 diarrhea, at 5 days vs 2.5 days, respectively. An 80% reduction in discontinuation rates were noted with dose-escalated (17%) vs standard neratinib from ExteNet (3%).

Follow-up results from the ExteNET trial were recently reported at the 2020 San Antonio Breast Cancer Symposium showing the long-term effects of neratinib after adjuvant trastuzumab (Herceptin) for women with early-stage HER2-positive breast cancer. The 8-year follow-up to the phase 3 trial indicated an overall survival rate of 90.1% in the neratinib group vs 90.2% in the placebo group (stratified HR, 0.95; 95% CI, 0.075-1.21; P= .6916), with no statistical improvement between arms.2

Neratinib is a kinase inhibitor for use in the adjuvant setting following trastuzumab-based therapy for patients with HER2-positive early-stage disease and in adults with advanced or metastatic HER2-positive breast cancer who have received 2 or more anti-HER2 regimens in the metastatic setting.

“We believe that utilizing dose escalation has the potential to improve the overall tolerability of Nerlynx and increase the average length of therapy, with the end result benefiting more patients battling breast cancer,” Alan H. Auerbach, chief executive officer and president of Puma, said in a press release.


1. FDA Approves Dose Escalation Label Update for Puma Biotechnology’s NERLYNX® (neratinib) in HER2-Positive Early Stage and Metastatic Breast Cancer. News Release. Puma Biotechnology. July 1, 2021. Accessed July 6, 2021. https://bit.ly/3wo8vrT

2. Holmes FA, Moy B, Delaloge S, et al. Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: final overall survival analysis from the randomized phase 3 ExteNET trial. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster PD3-03. https://bit.ly/377gMaq