Maurie Markman, MD
Historically, FDA approvals of oncologic agents have occurred as a result of positive phase III trial results. However, Maurie Markman, MD, proposes that in this era of precision medicine, phase III trials with the endpoint of overall survival (OS) should not be the be-all and end-all in respect to drug approvals—particularly in ovarian cancer.
“There is a risk that we might discard potentially valuable drugs because of this irrational endpoint,” says Markman, president of medicine and science, Cancer Treatment Centers of America, and editor-in-chief of OncologyLive
. Instead, he suggests allowing other endpoints and earlier-phase or basket studies as the basis for future regulatory decisions.
In a lecture during the 35th annual CFS®
, Markman discussed the need to change the paradigm of clinical trials and FDA approvals for ovarian cancer.
OncLive: Can you discuss your presentation on the treatment paradigm of ovarian cancer?
My talk at this meeting was to basically challenge the existing paradigm in clinical trials in the United States and worldwide in ovarian cancer. There has been so much progress with new drugs and new strategies, and as a result, phase III randomized trials looking at OS as a primary endpoint is simply no longer rational.
The reason for that is if you conduct a trial with “regimen A” versus “regimen B,” patients progress, then go off of the trial, that would be progression-free survival (PFS) or disease-free survival as an endpoint—which was what the trial endpoints have to be now. However, if you looked at OS as an endpoint, that would assume that what happens to a patient after they go on that trial is going to be the same on either arm of the trial—and that is a completely irrational endpoint.
We are not talking about patients who might live 2 or 3 months after they finish a trial; we have patients who are living 1 to 3 years or longer after they finish a trial. Therefore, holding that drug or combination—which a patient would have received 2 or 3 years ago—hostage to a survival endpoint when all of the things that might have happened to the patient population during the interim is not controlled simply makes no sense. Stating that doesn't mean that an individual drug or strategy can't improve OS—that is not what I am saying. If we had this wonderful new drug or strategy and we do a trial and hit a “grand slam” with survival, that would be wonderful. That is not the point. The point is that we could see an enormously positive outcome.
The other very important issue that I want to comment on is not just the issue of PFS in phase III trials, but in fact the new paradigm that we have, which is basically precision cancer medicine. When you have a situation where you are dealing with a relatively uncommon cancer, such as ovarian cancer, the likelihood of completing a phase III randomized trial is low. Therefore, we have to come up with other strategies to evaluate efficacy. We don't have to do clinical trials, but is it the only way to move a drug forward into the non-research domain with phase III randomized trial in the era of precision cancer medicine?
We need to come up with a novel approach. That could be looking at high objective response rates (ORRs), or time to disease progression compared with a well-categorized historical control. It could potentially be having patients’ own natural history of disease characterize their time to progression. For example, [they could go] on this novel therapy and the time to progression was 50% to 100%. There are a variety of ways we could look at this, but the point is that we need to come up with strategies that are acceptable to the regulatory agencies, insurers, and ultimately, the patients.
Are there any steps being taken toward this?
There is no question that what I am describing and advocating for is happening. The extraordinary poster child for that is the approval of a checkpoint inhibitor [pembrolizumab (Keytruda)] based on robust phase II trial data with microsatellite instability-high (MSI-H) tumors, and I applaud the FDA for this. What they have done is extraordinary important for patients.