Dr. Cortes Discusses Approval of Ponatinib for Adults with Chronic-phase CML

Jorge Cortes, MD, Director of the Georgia Cancer Center, talks about the approval of ponatinib for adults with chronic-phase chronic myeloid leukemia (CML), and why it’s important to continue research into ponatinib for chronic-phase CML.

DocWire News: Can you discuss the study or studies that led to the supplemental new drug application for ponatinib for adults with chronic-phase chronic myeloid leukemia (CML)?

Dr. Cortes: Sure. It’s one study, but I’ll describe two because the first one provides a background of why we needed to do this new study. The original study that brought the ponatinib to be approved some years ago, it’s called the PACE study. That study was just a straightforward study of patients with CML that had received multiple prior therapies and needed additional therapy, that were refractory or intolerant to prior therapies.

That study showed that ponatinib was very active. We had response rates of 60% to 70%, and that led to the approval. Unfortunately, and this was not very obvious at the beginning, but over time, we started seeing that more patients were having what we call arterial occlusive events… some of them cardiovascular, like heart attacks and anginas and things like that; others cerebrovascular, like strokes and transient ischemic attacks; and others were peripheral vascular, like gangrene and things like that.

So the drug was approved. The standard dose was 45 milligrams, but because these events started happening… they occur over time. Some had them early, and some had them later… and it continued happening as the patients were exposed to the drug, we started seeing that there was a concern about the use of the drug. Certainly, patients that have other risk factors for these events, like diabetes, and hypertension, and obesity, those were the patients that were having most of these events. But unfortunately, you have those patients, so you cannot just not treat those patients. They need the drug as well.

So we did some analysis, and we thought that perhaps there was a correlation with the dose. That led to the design of this study, which is called the OPTIC study, where we wanted to explore whether using lower doses could decrease the concerns about the incidence of these events but maintain the efficacy. We’re treating cancer, so we wanted to make sure that we didn’t compromise in the efficacy.

The study was designed in a way that patients, again that had CML, that had received multiple prior therapies, that were resistant or intolerant to these prior therapies, they were at random allocated to receive a starting dose of 45 milligrams, which is again the standard, or 30 milligrams or 15 milligrams. The patients who responded based on the criteria that was put in the study to qualify as a response, another thing that was unique on this study was that they were mandated to then reduce the dose to 15 milligrams so that they wouldn’t continue the exposure to higher doses after their response. So that’s the genesis of the study and how the study was designed.

What we found was that 45 milligrams provided the best response. Approximately 38% of the patients responded at the 45 milligrams, whereas at the 30 and the 15 milligrams, it was about 27%. So there was a significant difference in terms of the response in favor of the standard dose.

In terms of the safety, we found two interesting things. The first one was that the difference was not that much between the standard dose and the lower doses. So the standard dose, we had 5% patients having these events. Now granted, this is an interim analysis, so we need to continue seeing if they don’t increase over time, but so far, it’s 5%. And with the 30 milligrams, it was 4%. So there was a drop, but a very small drop, in the incidents. Then at the 15 milligrams, it was 1%.

The other interesting thing is that these rates seemed to be lower than we would have expected based on what we had seen in the prior study. One of the explanations, we think, is that the decrease in the dose, once you get the response, is important because it minimizes the exposure. You do want to be aggressive at the beginning. The patient has active disease. Again, it’s cancer. But once the patient responds, it seems to be that many patients can be maintained with good response at lower doses, and that probably decreases the risk and that’s why we see a much lower rate.

DocWire News: What makes ponatinib different from other treatment options for patients with chronic-phase CML?

Dr. Cortes: Well, there’s some things that make it unique. Number one, for patients who have received prior therapies, it provides by far the highest response rate of the drugs that are available today. They’ve never been compared head to head in a study, but if you just look at the different experience and other studies, et cetera, it certainly provides a higher response rate.

In addition, it is the only drug that we have today that is able to work when the patients develop these mutations that we call T315I. None of the other drugs works against this mutation. Ponatinib does. So that also makes it very unique, very different. That means that there’s many patients where ponatinib is either the only option if they have this mutation or by far the best option if they have received, for example, two prior inhibitors or more.

DocWire News: Are there any future research plans for this area?

Dr. Cortes: Well, first, we want to continue the study. The analysis, as I mentioned, was an interim analysis, and it is important to continue the follow-up of the patients because the arterial occlusive events can happen later. So we want to make sure that we understand the full extent of the safety and the risks of this drug.

I think that it is important then to consider exploring this drug as a second-line therapy. The studies that I’ve described are mostly using them after two or more prior inhibitors. But when you have received an initial therapy with a second-generation TKI, using another second-generation TKI doesn’t really give you much of a benefit. So I think that that’s a perfect setting for ponatinib, using it earlier in the disease and not just when you’ve received three or four prior therapies.