This week the Food and Drug Administration (FDA) granted accelerated approval to a new drug produced by Pfizer to treat metastatic hormone positive, HER2 negative breast cancers in post-menopausal women. The FDA granted this approval two months earlier than anticipated. Palbociclib (brand name Ibrance) is a pill that is taken daily along with the aromatase inhibitor letrozole (brand name Femara) daily on a three weeks-on/one week-off schedule.
Until the FDA approves a drug, the main way patients and their doctors access new therapies (besides those used off-market) it is through clinical trials or compassionate use programs. Accelerated approval is granted by the FDA based on promising early study results and allows the drug company, Pfizer in this case, to actively market and sell the drug to doctors and patients. While many are touting palbociclib’s ability to slow tumor growth (measured as progression free survival), there is no data to show that women live longer with the palbociclib plus letrozole combination therapy.
Breast Cancer Action has long held that the FDA should only approve therapies that have been shown to improve overall survival (which means women live longer), improve quality of life (which means they live better), or cost less (so that more women have access and/or aren’t bankrupted by treatment). Palbociclib fails to meet these standards based on available data.
PALOMA-1 (the clinical trial name for the palbociclib study) is an open label (non-blinded) phase 2 clinical trial that enrolled 165 women into one of two study arms. Women in the first arm received the aromatase inhibitor letrozole and the second, or the study arm, received letrozole plus the experimental drug palbociclib. Followed for just shy of two and a half years, the researchers found that women who received both drugs had twice as much time pass before their tumors grew: from an average progression free survival (PFS) of 10.2 months on the letrozole only arm to an average PFS of 20.2 months on the combined arm. While a doubling of PFS is significant, it cannot replace overall survival as an ultimate endpoint.
While some enthusiastic media coverage about this new drug approval suggests that toxicity of this drug is “tolerable” for patients, there are a number of additional side effects for women taking palbociclib, including diminished white blood cells and consequent risk of infection: more than half of patients (54% compared to 1% in the letrozole arm) experienced grade 3 or 4 neutropenia and 19% (compared to 0%) experienced leucopenia. Additional so-called “serious adverse events” include three women (4%) in the palbociclib arm experiencing pulmonary embolism, 2% experiencing severe back pain, and 2% experiencing severe diarrhea. Compared to just 2% of patients on the letrozole only arm, 13% of women taking palbociclib discontinued treatment.
Given these adverse side effects and the failure to demonstrate overall survival benefit for patients, we would hope that in order to earn FDA approval, palbociclib would be cheaper than current therapies. However, it is an add-on treatment used in addition to existing therapy with letrozole, and Pfizer is expected to sell Ibrance for nearly $10,000 a month, totaling close to $120,000 for a year of treatment. Estimates are that the company will earn around $4 billion in just the first year of sales.
By approving a treatment that has not been shown to extend life, reduce side effects, or increase access, the FDA is giving license to Pfizer to make billions of dollars on a drug before its benefit to patients has been adequately demonstrated. While we remain optimistic, like many, that the effects of palbociclib observed so far will result in improved overall survival for women with this form of metastatic breast cancer, we believe it must be demonstrated by the data before the drug is approved.
Some argue that progression free survival is itself a benefit to quality of life. And there is no doubt that a doubling of PFS is promising for this patient group. And while there is logic to the claim that preventing tumor growth can help patients stay out of the hospital, this is a measurable outcome that can be studied, not just asserted without evidence. Those side effects that have been documented in the study show that palbociclib comes with more negative side effects than letrozole alone.
What we have is a short, small study that has not shown that women live longer or that women live better. By pricing the drug at over $100,000/year, Pfizer is ensuring maximum profit on a relatively cheap study to run. And because palbociclib is the first drug of its kind to be approved, we are concerned that full safety data is not yet available. Both normal and cancerous cells depend on cycline-dependent kinases (known as CDKs) and palbociclib works by inhibiting two CDKs. The full effects of this are not yet known in a larger population studied over a longer period of time.
While we desperately want women with metastatic disease to live better and we want to ensure that women with few options have access to promising treatment, full FDA approval of a drug without clear evidence of its benefits is not the way to do that. Once a drug is approved, the gates open to expanded and off-label use.
By approving this drug so quickly, the burden falls on women and their insurance companies to bear the cost of this still-experimental drug. We believe that at this stage in development, Pfizer should retain the cost of providing palbociclib to women, both through clinical trials and through a compassionate access program for all of the women thought to benefit from this experimental drug. If and when palbociclib has been shown to improve overall survival or quality of life, we believe the FDA should then fully approve the drug. By asking Pfizer to ensure that qualifying women have access through clinical trials and compassionate access programs, we are asking them to defer making billions on this drug until we have better assurance as to this experimental drug’s safety and efficacy.