Given the level of competition in the cancer market, the high cost of treatment, and the ability to raise an innovative drug's
price tag—the price of Nexavar was increased four times, by a total of 18 percent, between January 2008 and the summer of
2009, Bloomberg reported—it's important to know exactly what kinds of data and endpoints the FDA finds most meaningful in terms of granting
approval. "Oncology is really going the way of cardiology, in terms of evidence-based medicine," says Coles. "In the '90s,
we moved through various clinical proxy endpoints in cardiovascular research until we finally got to a reduction in mortality—overall
survival—as the gold standard. And cancer seems to be following the same order.
"We think it's actually very clear in terms of the endpoints that are useful for FDA. We think progression-free survival and
overall survival are both appropriate endpoints," says Coles. "Overall survival data is desirable and if it can be gathered,
then that's the gold standard." However, progression-free survival is still a "solid" endpoint, and "will likely be acceptable
for approval in most cases," he concludes.
Discussions about the length of survival provided by a given drug, as an approval metric or for a decision on reimbursement,
are fraught with emotion and tough philosophical implications. The primary study that Onyx is using for its NDA filing on
carfilzomib— Phase IIb 003-A1—showed the drug gave patients an additional six months to live, compared with currently available
therapies. "This sounds cliché, but I do mean it: I really don't know how you put a price on additional time for someone's
life, quite candidly," says Coles. On a recent trip, "the woman who was helping us check into the hotel noted that we were
from Onyx, and she said, 'I just want to thank you, because my father had liver cancer, and he took Nexavar, and while he
only had a small amount of time left by the time he was diagnosed, we are so grateful to you, for giving him that additional
time with us.' Speaking in the abstract is one thing, and of course we have to have policies that govern the way we pay for
things and reimburse, but everyone who is a decision-maker in this industry really should have an up close and personal experience
with a life-threatening disease," says Coles.
For everyone at the company, the approval of carfilzomib—or lack thereof—will be a defining moment; Nexavar's patent is good
until 2020, but if Onyx wants to "chart an independent course" based on its proprietary pipeline, as Coles says it does, it
will need to deliver on its proteasome inhibitors commitments in the shorter term.
That said, Nexavar has generated promising Phase II clinical data for thyroid cancer, suggesting improvement in both progression-free
survival and overall survival. In June, however, the drug failed to improve overall survival as a monotherapy for lung cancer,
but it did prolong progression-free survival. Bayer said in a statement that it would continue evaluating Nexavar as a monotherapy,
and in combination with targeted agents, for later lines of lung cancer treatment. In total, Nexavar has seven Phase III trials
under way, including one for patients with metastatic breast cancer that is HER2 negative—a breast cancer representing 75
percent of all cases, according to Coles. Phase II data, published in 2009, demonstrated a 74 percent improvement in progression-free
survival for HER2 negative breast cancer, compared to an active treatment population. Expanding Nexavar's label and maximizing
sales for that drug would go a long way toward providing the funds needed to bring Onyx's next cancer drugs to market.