Comments to FDA About Neratinib to Prevent Breast Cancer Reccurance

Stephanie Fox-Rawlings, PhD, National Center for Health Research: May 24, 2017

Thank you for the opportunity to speak today. My name is Dr. Stephanie Fox-Rawlings. I am a Senior Fellow at the National Center for Health Research. Our research center analyzes scientific and medical data to provide objective health information to patients, providers and policy makers. We do not accept funding from drug or device companies so I have no conflicts of interest.

The pivotal study that is the basis of today’s review only demonstrated a small improvement in the primary efficacy endpoint. After 2 years, about 2.3% more patients were without invasive disease if they took the drug compared to placebo. This difference was statistically significant, likely because the large number of patients in the study. However, such a small difference could be specific to this particular sample of patients and trial and might not be generalizable for all women with early-stage breast cancer.  It is impossible to say, since after 2 years over 90% of patients were free of invasive disease whether they received the drug or placebo.

Patients followed for 5 years had a similar result – about 2.5% were more likely to be cancer-free, while almost 90% of patients taking placebo were also cancer-free.   There are no data yet on overall survival, so the results aren’t compelling.

This small difference should be considered in the context of adverse events that are typical of cancer drugs: diarrhea, nausea, vomiting, and fatigue were common. However, some were categorized as serious events. Adverse events were so unpleasant that they caused 28% of patients taking the drug to drop out of the study, compared to just 5% of patients taking placebo.

The sponsor also presented data from an ongoing, open-label, single armed study aimed to reduce adverse events due to diarrhea with prophylactic treatment. However, there were still a high occurrence of diarrhea, and the treatment for diarrhea caused a different set of adverse events.  

Patients should not be exposed to adverse events if the drug isn’t proven to provide a real improvement.   The 2.3% difference between 91.9% and 94.2% is not impressive.  And with only one pivotal study, there is no way to know if that result would be replicated in a second study.

A recent study published in JAMA Internal Medicine found that when FDA approved cancer drugs based on a surrogate endpoint, such as cancer-free survival, later studies have not found a benefit in overall survival.  And yet, these drugs cost an average of $100,000 – often more – and can harm quality of life.

We see that neratinib’s benefit compared to placebo is similar to that of a previously approved drug.  That does not mean that it should be approved. Patients do not benefit from more new drugs on the market unless the new drugs are more likely to have benefits that outweigh the risks.

The FDA should be sure that new treatments provide a real benefit to patients before they are approved.   We recommend that the FDA not approve neratinib for breast cancer unless a clear benefit can be replicated, or a benefit for overall survival is demonstrated.

The Cancer Prevention and Treatment Fund is the major program of the National Center for Health Research, and can be reached through Stephanie Fox-Rawlings at