Neratinib Global Access Expands for HER2+ Breast Cancer

Global access to neratinib has increased with the drug now being made commercially available in Singapore.

Global access to neratinib has increased with the drug now being made commercially available in Singapore for use as a treatment for patients with HER2-positive breast cancer who have had surgery, chemotherapy, and prior trastuzumab (Herceptin)-based therapy.1

The clinical efficacy of neratinib in this setting was demonstrated in the phase 3 ExteNET trial. In the primary analysis of the trial, the 2-year invasive disease-free survival (iDFS) 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) when used as an extended adjuvant treatment of adult patients with early-stage, HER2-positive breast cancer following adjuvant trastuzumab-based therapy.2

Long-term data showed that at a median follow-up of 5.2 years, neratinib reduced the risk of invasive disease recurrence or death by 27% versus placebo (HR, 0.73; P = .008), with 5-year iDFS rates of 90.2% versus 87.7%, respectively.3 The greatest benefit was observed in patients with HR-positive disease who initiated neratinib within 12 months of completing trastuzumab treatment. Five-year follow-up data with these patients showed a 42% reduction in the risk of invasive disease recurrence or death with neratinib versus placebo (HR, 0.58; 95% CI, 0.41-0.82; P = .002).

"Certain patients with HER2-positive breast cancer may still have a significant risk of relapse, even after being treated with standard chemotherapy and trastuzumab-based therapy. This risk can vary from less than 10% to more than 30% during the first 5 years, depending on the size of the tumor and the number of lymph nodes affected,” ExteNET trial investigator Yap Yoon Sim, MBBS, FRACP, medical oncologist at the National Cancer Centre in Singapore, stated in a press release.

"We know the risk of recurrence continues even 5 years’ post-diagnosis, especially in patients with hormone-receptor positive breast cancer. Nerlynx may now provide additional benefit in terms of reducing this risk of relapse, particularly to women with high-risk disease. Essentially it gives patients another opportunity to remain disease-free," she added.

Despite the efficacy of neratinib shown in the study, diarrhea emerged as an adverse event (AE) that must be managed to successfully implement the treatment. Overall, 95% of patients in the ExteNET trial who received the TKI experienced diarrhea, and 40% reported it as a grade 3 AE. Diarrhea also led to study discontinuation for 16.8% of patients.

To address this issue investigators conducted the phase 2 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.

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

The primary end point 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.4

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 AEs and 2 grade 4 treatment-emergent AEs, which was due to sepsis.


  1. New Early Breast Cancer Drug Available Now In Singapore. Published April 23, 2020. Accessed April 23, 2020.
  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. Gnant M, Martin M, Holmes F-A, et al. Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early-stage breast cancer: Subgroup analyses from the phase III ExteNET trial. Presented at: 41st Annual San Antonio Breast Cancer Symposium; Dec 4-8, 2018; San Antonio, TX. P2-13-01.
  4. 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.


In the ExteNET study, 2840 patients who remained disease-free following 1 year of treatment with adjuvant trastuzumab and chemotherapy were randomized to neratinib (n = 1420) or placebo (n = 1420). Neratinib was administered for 12 months at 240 mg per day. The primary end point was iDFS at 2 years and 28 days from randomization.