Hope Rugo, MD
Neratinib immediately following adjuvant trastuzumab (Herceptin) plus chemotherapy resulted in a 33% reduction in the risk of disease recurrence in patients with early-stage, HER2-positive breast cancer, but the benefit comes with toxicities in nearly all patients.
In the phase III ExteNET study, 2840 patients who remained disease-free following 1 year of treatment with adjuvant trastuzumab and chemotherapy were randomized to receive either neratinib (n = 1420) or placebo (n = 1420).
A 2-year analysis of the trial found that the invasive disease-free survival (DFS) was 93.9% in the neratinib arm versus 91.6% in the placebo arm (hazard ratio [HR], 0.67; 95% CI, 0.50-0.91; P
= .009). However, 95.4% of patients treated with neratinib experienced all-grade diarrhea, with 39.9% experiencing grade 3 or 4. In the placebo arm, 35.4% of patients had all-grade diarrhea, with a grade 3/4 incidence of just 1.6%.
Other gastrointestinal-related side effects were also observed in the neratinib arm, including nausea (43%), fatigue (27%), vomiting (26.2%), and abdominal pain (24.1%).
To understand how to balance the benefits and risks of neratinib, as well as unanswered questions regarding ExteNET, OncLive
spoke with Hope Rugo, MD, clinical professor, Department of Medicine (Hematology/Oncology), and director, Breast Oncology Clinical Trials Program, at UCSF Helen Diller Family Comprehensive Cancer Center.
OncLive: What did we learn from the ExteNET trial regarding the tolerability of neratinib?
: Neratinib has been met with some difficulty in the metastatic setting, mainly because of its tolerance. The drug was given without any preventive diarrheal therapy and it causes diarrhea in the majority of patients. Unlike some other drugs, including pertuzumab, it causes diarrhea right away. This causes patients to stop the drug early, hold treatment, or reduce the dose immediately. That is one of the reasons why the metastatic trials did not show as good of results as we thought they should have.
However, in the ExteNET trial, they treated a different group of patients. These are patients who completed 1 year of adjuvant trastuzumab and largely received anthracycline and taxane-based chemotherapy. They were randomized to receive either 1 year of neratinib or placebo. Part of the way through the study, a greater understanding of how to manage diarrhea was determined. That resulted in more effective management, even though they were not routinely prophylaxed, which is the standard right now. However, if you prophylax, the rate of diarrhea could go down in these patients. It could really make a big difference.
What questions remain regarding the data from the ExteNET trial?
For the first 700 or so patients included in the ExteNET trial, it was possible to have had a pathologic complete response (pCR) to neoadjuvant chemotherapy and to have stage I disease and node-negative disease and still be enrolled. After approximately 700 patients, they changed the trial to eliminate stage I patients who had node-negative disease and also those patients who had a pCR. That was a really important change because that meant that in the trial, which had over 2000 patients enrolled, the largest number of patients had at least stage II breast cancer and no pCR. That is very helpful.