FDA staff put a damper on Epizyme’s week, raising doubts about the company’s sarcoma drug ahead of an advisory committee meeting Tuesday. Despite questions about safety and efficacy—not to mention the small trial size—the drug walked away from the meeting with an “unusually uniform” 11-0 vote.
Epizyme is seeking approval for tazemetostat in patients with advanced epithelioid sarcoma who can’t undergo surgery to remove their tumors. It is a rare cancer of the soft tissue that can spread to other areas. It is also difficult to diagnose, so it may not be discovered until its later stages. The drug’s application is based on data from about 100 patients who made up two groups—cohorts 5 and 6—in a larger study that tested tazemetostat in other types of tumors.
The drug shrank tumors in 13% of those 100 patients. In briefing documents released ahead of the meeting, FDA staff called the overall response rate a “major issue for discussion” for the advisory committee, asking whether it was good enough to outweigh the risks associated with the drug. They compared tazemetostat to an older drug, doxorubicin, which isn’t approved specifically for epithelioid sarcoma but is used to treat it. It was approved in 1974 to treat soft tissue sarcomas in general based on a response rate that was nearly twice as high at 24%.
Tazemetostat “appears to be relatively well-tolerated," but the documents highlighted the risk of secondary malignancies—that is, developing a new cancer as a result of the treatment. Of the 725 patients in the study’s safety population, six, or 0.8%, developed a blood cancer like acute myeloid leukemia as a result of treatment.
In a previous interview, Epizyme CEO Robert Bazemore and Chief Medical Officer Shefali Agarwal emphasized the 13% figure is not the end of the story. How long tazemetostat keeps patients alive and stops their tumors from growing are also important in an aggressive cancer that has no treatments of its own and is often fatal.
The panelists agreed.
“I was left with the overall impression of a drug that has striking efficacy in an aggressive disease that is hard to interfere with in its natural course,” said Christian Hinrichs, M.D., an investigator and clinical research scholar at the National Cancer Institute. “Despite the number for the response rate being relatively low, I think this reflects a limitation in the way we measure disease responses now.”
“For me, it’s what I perceive to be a clinical benefit and a meaningful benefit to patients. Stable disease is a good thing. There’s certainly a proportion of patients that have a response that is durable,” said Richard Riedel, M.D. an associate professor of medicine at Duke University and associate director of the Duke Sarcoma Program at the university's Cancer Institute.
“I believe that although the response rate is low, I was also impressed as a few others mentioned about the duration of some of those responses,” said Philip Hoffman, M.D., a professor of medicine at the University of Chicago.
Given current survival rates, multiple panelists said the risk of developing a new cancer should not be a worry. More than half of patients diagnosed with epithelioid sarcoma turn out to have metastatic disease, the FDA pointed out in the documents. Most of these patients will succumb to their disease within a year; the five-year survival rate is 0%.
“I was also impressed that this does appear to be safe. While the concern for secondary malignancies is out there, it seems quite rare and the natural history of patients with advanced sarcoma is such that I think the consideration of secondary malignancies is really not very important to that group of patients,” Hoffman added.
“I am impressed by the low rate of discontinuation of the drug—it's really remarkable. And possibly the most concerning safety issue relating to secondary malignancies, I don’t see it as a major problem in the context of this aggressive primary malignancy,” Hinrichs said.
The FDA is expected to make a decision by Jan. 23.