Yesterday the FDA granted accelerated approval to
The FDA’s decision on palbociclib immediately expands treatment options for a large fraction of people living with metastatic breast cancer. While in recent years several new types of drugs and antibodies have been approved for Her2+ breast tumors, dramatically new treatments for hormonally-sensitive breast cancer subtypes that lack Her2 have been slow to enter the clinic.
The drug’s approval is exciting, first because its effect was pronounced: In a randomized trial, Palbociclib nearly doubled progression-free survival in women with metastatic breast cancer, from 10.2 to 20.2 months. And second, because it’s a new kind of medication, a CDK inhibitor. What limits enthusiasm is how much this oral drug will cost. Also, it has not been shown to extend overall survival.
The drug’s use in advanced breast cancer was approved based on results of an open (non-blinded) Pfizer-sponsored phase 2 trial called PALOMA-1. The results, published recently in Lancet Oncology, look at two patient cohorts with median follow-up of 27-30 months. The 165 patients, all postmenopausal women with stage 4, ER+/Her2- breast cancer, enrolled between December 2009 and May 2012. So this is current data. The women were randomized to receive either letrozole (an aromatase inhibitor) alone or in combination with palbociclib, taken once daily for 21 days out of every 28. Both drugs are pills.
The main finding was that for women who took the combination of letrozole and palbociclib, median progression-free survival was 20.2 months. For those who were randomized to take only the aromatase inhibitor, progression-free survival was 10.2 months. This difference is highly significant from a statistical standpoint (one-sided p-value 0.0004) and from a clinical standpoint. There has not yet been a benefit shown in overall survival.
The potential to delay the progression of disease by most of a year, overall – and in half the cases for longer – is very good news for people living with metastatic breast cancer. Survival with this condition averages only 3 years, although this may be improving. In that context, a drug that delays the tumor’s growth without major toxicity may be beneficial, in terms of improving the quality of life. Of course prolonging life and eradicating the tumor would be better than just improving progression-free survival, as this drug appears to do.
Keeping a tumor in check can help patients stay out of the hospital, among other advantages. That's because most symptoms arise from progression of the disease. For instance, patients may experience shortness of breath when breast cancer affects the lungs, pain when it grows into the bones, jaundice and metabolic problems when it spreads to the liver, anemia and bleeding when it invades the bone marrow and other problems.
Toxicity from palbociclib is a bit hard to tease out from the reported findings. In general, it appears that the regimen was tolerated by most of the 165 women enrolled. In this open-label study just 13 percent (11 women) of 84 taking both the experimental drug and letrozole dropped out early. A few patients experienced low white blood counts and fatigue. Serious toxicity in the combination group included blood clots in the lung (3 patients), back pain and diarrhea, which can be limiting.
The number of patients in the U.S. and elsewhere who may benefit from Ibrance is unknown. As was outlined in the Landscape Analysis released last fall, the number of people living with metastatic breast cancer goes untallied. It surpasses 150,000 and may approach 200,000 in the United States. Over 99.5 percent of breast cancer patients are women. Among those with early-stage disease, ER+/Her2- negative tumors constitute the largest fraction of cases.
So this drug may be useful to tens of thousands of women in the United States, today.
Like most chemotherapy and small molecule drugs, palbociclib does not appear to have much activity on its own. How much Ibrance will cost, and how much patients will bear out-of-pocket expenses for this oral medication, may unfortunately limit this agent’s use in those living with metastatic disease, nearing the end of life.
Future and ongoing trials seem likely to identify a role for this and other CDK inhibitors, in combination with other medications, in other types and stages of breast cancer, and in other malignancies.
