Last week the FDA approved neratinib as a so-called “extended therapy” for early-stage HER2-positive (HER2+) breast cancer to be used after the standard of care, which includes surgery and treatment for a year with trastuzumab (brand name Herceptin). Despite the fact that neratinib comes with additional side effects and women treated with the drug have not been shown to live longer, Puma Biotechnology, Inc. is reportedly planning to sell the drug (brand name Nerlynx) for $10,500 a month.
Rather than marking a breakthrough in breast cancer treatment, the approval of neratinib marks an eroding of FDA standards. Puma received accelerated approval for neratinib based largely on a single phase III clinical trial, which showed that women with early stage HER2+ breast cancer were slightly less likely to experience a recurrence of their disease. But this minimal reduction came at a cost of high rates of severe diarrhea.
The ExteNET trial, which was the basis for the FDA’s approval, randomized 2,840 women to receive either neratinib or a placebo after receiving the standard of care (surgery plus a year of trastuzumab) for early-stage HER2+ breast cancer. Researchers hoped to lower the risk of disease returning after standard treatment and were able to show a minor improvement in the length of time before a recurrence (what the researchers term “invasive disease-free survival”) by giving neratinib to patients who had completed treatment. More than nine in ten patients in the ExteNET trial, regardless whether they received the experimental treatment, did not have a breast cancer recurrence after two years: 91.6% of patients were free of disease after two years on the placebo group, compared to 93.9% on the neratinib group.
Neratinib’s ability to slightly reduce the risk of recurrence by half in just a month is not the same as showing that women live longer with treatment. A so-called “surrogate endpoint” like invasive disease free survival that is not clinically significant may be useful in guiding the development of experimental treatments, but it cannot replace the outcome that patients and doctors ultimately care about: women actually living longer, or at least living better with fewer side effects.
Meanwhile, 40% of patients taking neratinib experienced grade 3 diarrhea, which led 17% of patients to stop taking the experimental drug. Grade 3 diarrhea can require treatment in a hospital or clinic. With such severe side effects, and no demonstrated overall survival benefit, it is hard to justify adding neratinib to treatment protocols for a group of patients who are just as likely to do well with the existing standard of care. Survival rates for early stage HER2+ breast cancer patients are fairly high with current treatments, with 84% of patients with mostly node-positive disease living 10 years after treatment.
Often described as “controversial,” neratinib’s approval was viewed as a long shot by many journalists covering biotechnology who predicted that Puma’s request would not be approved by the FDA. After following fewer than 3,000 women for just two years, the drug has been shown to have a small possible benefit through a surrogate endpoint and comes with known toxicity. Neratinib’s approval is a win for Puma, but not for patients.
Desperately needed breakthroughs in treatment are all too rare. The last one for breast cancer was nearly twenty years ago in 1998, when the Food and Drug Administration (FDA) approved trastuzumab for use in women with metastatic HER2+ breast cancer. Several years later, the FDA also approved the use of trastuzumab for early-stage HER2+ breast cancer. Despite the risk of heart problems associated with the drug, trastuzumab can help reduce the risk of recurrence and death for the 20-30% of women diagnosed with this aggressive subtype of breast cancer.
Unfortunately, trastuzumab doesn’t always work for all patients, and some HER2+ breast tumors are either inherently resistant or develop resistance to trastuzumab. Researchers have attempted to overcome this barrier by combining treatments in an effort to block multiple pathways and prevent resistance through drugs like neratinib.
This landmark approval of a targeted therapy for a specific (HER2) cancer-related molecular marker sparked a lot of excitement that we are on the cusp of a new era of targeted life-saving therapies. But the reality is, subsequent drugs developed to treat breast cancer have not been shown to clearly benefit patients by extending overall survival or improving quality of life. And yet companies are selling these add-on treatments for well over $100,000/year.
At Breast Cancer Action, we believe the best way to ensure more truly breakthrough treatments is to incentivize innovative research by preserving approval standards. If drug companies know their treatments must do one of the following three things in order to get approved, they’ll focus on developing treatments that:
- Help patients live longer (improving overall survival)
- Help patients live better (reducing side effects and lowering toxicity)
- Help people access treatment (lowering costs)
Too often, the FDA puts speed before safety and efficacy, allowing companies to sell drugs that have not been proven to do just one of these things to benefit patients. In recent years, a majority of cancer drugs have been approved by the FDA based on surrogate endpoints and follow up studies in subsequent years have shown that half of these do not help patients live longer.
With the approval of neratinib, the FDA has once again approved an experimental drug that has not been shown to lengthen or improve breast cancer patients’ lives—either by helping them live longer or live better, with fewer side effects. The decline of standards at the FDA over the last decade is alarming and means that thousands of cancer patients each year are exposed to expensive, toxic treatments that don’t actually help them live longer.
After two decades of waiting for the next breast cancer breakthrough, many of us in the breast cancer community are frustrated and fatigued. And the reality is we haven’t actually gotten a breakthrough by lowering approval standards. Instead of letting drug companies profit from our desperation, let’s call on the FDA to uphold high standards of safety and efficacy that incentivize true innovation.