FDA Updates Neratinib Label in HER2+ Breast Cancer

The FDA has approved a labeling supplement for neratinib for the extended adjuvant treatment of patients with HER2-positive early-stage breast cancer.

The FDA has approved a labeling supplement for neratinib (Nerlynx) for the extended adjuvant treatment of patients with HER2-positive early-stage breast cancer.1

The labeling supplement includes safety information based on interim results of the phase II CONTROL trial (NCT02400476), in which the addition of prophylactic treatment with loperamide plus budesonide reduced the discontinuation rate of neratinib due to associated diarrhea to 11% compared with 18% for those who received loperamide alone.

“We are pleased to be able to update the label for Nerlynx to include the data on the use of prophylactic loperamide plus budesonide,” Alan H. Auerbach, chief executive officer and president of Puma Biotechnology, the manufacturer of neratinib, stated in a press release. “We believe FDA approval of the labeling supplement will help us to ensure that physicians and patients are better informed in selecting prophylactic therapy that may improve the tolerability of the drug.”

Approximately 20% to 25% of breast cancer tumors overexpress HER2, a breast cancer subtype which is said to be more aggressive than other types of breast cancer with an increased risk of disease progression and death. While trastuzumab (Herceptin) can reduce the risk of early-stage HER2-positive breast cancer recurrence after surgery, up to 25% of those who received trastuzumab experience recurrence.

In July 2017, the FDA approved neratinib for the extended adjuvant treatment of adult patients with early-stage, HER2-positive breast cancer following adjuvant trastuzumab-based therapy. The approval was based on data from the phase III ExteNET trial and the phase II CONTROL trial. In the primary analysis of the ExteNET trial, the 2-year invasive disease-free survival rate was 94.2% with neratinib versus 91.9% with placebo (stratified HR, 0.66; 95% CI, 0.49-0.90; stratified log-rank  P-value [two-sided] =.008).2

However, 95% of patients in the ExteNET trial who received the TKI experienced diarrhea, and 40% reported it as a grade 3 adverse event (AE). Diarrhea also led to study discontinuation for 16.8% of patients. Yet, preliminary results from CONTROL trial suggested that antidiarrheal prophylaxis can control the occurrence and severity of diarrhea among patients receiving neratinib.

The CONTROL trial evaluated antidiarrheal prophylaxis or dose escalation in the reduction of neratinib-associated diarrhea. To be eligible for enrollment, patients had to be ≥18 years of age, have histologically confirmed stage I to IIIC HER2-overexpressed or amplified breast cancer, and have completed trastuzumab-based therapy in the adjuvant setting or experienced AEs that led to early discontinuation of therapy. The last dose of trastuzumab must have been given >2 weeks and ≤1 year prior to study enrollment.

All eligible patients received neratinib at 240 mg daily for 1 year and oral loperamide prophylaxis for 1 or 2 cycles. Loperamide was given at ≤16 mg daily as needed following completion of loperamide prophylaxis (n = 137). Patients enrolled on the budesonide (n = 64) or colestipol (n = 120) cohorts received those respective agents for 1 cycle. The median duration of neratinib in the loperamide, budesonide, and colestipol cohorts was 11.5, 11.9, and 3.7 months, respectively.

An additional two cohorts comprised colestipol plus loperamide as needed (n = 104), and a neratinib dose-escalation and loperamide group (n = 60).

The primary endpoint was incidence of grade ≥3 diarrhea; secondary endpoints included frequency distribution of maximum-grade diarrhea, incidence and severity of diarrhea by loperamide exposure, serious AEs, and AEs of interest. Patient-reported health-related quality of life and exploratory biomarkers served as exploratory endpoints.

Any treatment-emergent diarrhea was managed with dose modifications or reductions of neratinib, and/or dietetic measures and additional pharmacological treatments that were grade dependent. For patients who were unable to tolerate a prophylactic regimen, loperamide was held until the first bowel movement, and was then administered at a reduced dose.

Results showed that in the loperamide/budesonide cohort, the incidence of grade 3 diarrhea was 28.1% compared with 32% in those treated with loperamide alone. The rate of diarrhea that led to treatment discontinuation was 11% in the loperamide/budesonide cohort versus 18% in the loperamide-alone group.

Additional findings presented at the 2019 ASCO Annual Meeting showed that the addition of budesonide or colestipol to loperamide does reduce the rate of neratinib discontinuation due to diarrhea, which permits patients to receive the full 1-year dose of neratinib.3

In the other cohorts, the rates of grade 3 treatment-emergent diarrhea were as follows: colestipol/loperamide (20.6%), colestipol/loperamide as needed (31.7%), and neratinib dose escalation/loperamide as needed (11.7%). The discontinuation rates due to diarrhea in each of these cohorts were 4.4%, 6.7%, and 3.3%, respectively. The authors noted that the data for a neratinib dose-escalation cohort remain incomplete.

There were no fatal adverse events and 2 grade 4 treatment-emergent AEs, which was due to sepsis.


  1. FDA Approves Labeling Supplement for Puma Biotechnology’s NERLYNX® (neratinib) for the Extended Adjuvant Treatment of HER2-Positive Early Stage Breast Cancer. Puma Biotechnology. Published October 2, 2019. https://bit.ly/2pH1Dt4. Accessed October 3, 2019.
  2. Hurvitz SA, Chan A, Iannotti NO, et al. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: the CONTROL trial. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract P3-14-01.
  3. Barcenas CH, Hurvitz SA, Di Palma JA, et al. Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial. J Clin Oncol. 2019;37(suppl; abstr 548). doi: 10.1200/JCO.2019.37.15_suppl.548.