Jorge E. Cortes, MD, Director, Georgia Cancer Center, Augusta University, presents an analysis of OPTIC, a phase 2, dose-optimization trial of ponatinib, a third-generation tyrosine kinase inhibitor (TKI), in patients with resistant/intolerant chronic-phase chronic myeloid leukemia (CP-CML). These data are being presented at the virtual 2021 American Society of Oncology (ASCO) Annual Meeting.

Transcript

My name is Jorge Cortes. I am a professor of medicine, and I'm the director at the Georgia Cancer Center in Augusta University in Augusta, Georgia.

We had been using ponatinib for a long time, and it was approved on the basis of a study called the PACE trial where patients had been identified as the maximum tolerated dose for 45 mg daily. That's the dose that had been approved on the label.

Very effective at that dose, but we also started recognizing that some patients developed arterial occlusive events. By that, I mean cardiovascular events, myocardial infarctions, angina, cerebrovascular events such as strokes and transient ischemic attacks, and peripheral vascular events.

With that concern, which in sometimes limited the use of these drugs, we explored whether different starting doses, particularly lower-starting doses, could lower the safety concerns but maintain the efficacy and try to find that adequate balance so that the patients could get the maximum benefit.

Design of the study was for patients with chronic myeloid leukemia, only in chronic phase, and they should have received and experienced the resistance or intolerance to at least two prior tyrosine kinase inhibitors or have the mutation T315I. They were randomized to receive a starting dose of 45 mg daily which is a standard, 30 mg, or 15 mg.

The primary endpoint was to achieve transcript levels BCR-ABL1 of one percent or less. An important component of the design was that once patients achieved that response, they have to lower the dose to 15 mg daily. The arms were very well-balanced. Patients were very heavily treated as was the intent on the study.

The main finding of the study is that the primary end point was significantly better. For the patients that received the standard starting dose, the 45 mg daily, the response rate in that group was 44%, whereas for the other two groups receiving lower doses was 29 percent and 23 percent, respectively, so a big difference in terms of efficacy.

I guess the main finding that was somewhat surprising was that although there were some differences in the incidence of arterial occlusive events, the difference was much smaller. Meaning, there was very little to gain by using a lower starting dose than the 45 mg daily dose.

For arterial occlusive events, the incidence with 45 mg was nine percent, whereas were 30 mg was five percent. A little bit of a difference but, clearly, much more to gain in terms of efficacy than to lose in terms of safety by using the 45 mg daily dose.

I think that there's a couple of things that I can think of. Number one, it establishes that clearly 45 mg is the best dose in terms of efficacy. Number two, that that efficacy adjusted dose is very important. This is the first study ever on a tyrosine kinase inhibitor that explores that approach. This has actually been now incorporated into the labels.

That is an important management issue that has to be considered. Number three, it also investigated some of the subsets of patients that may particularly benefit from the higher dose. For example, patients with a T359 mutations, patients with the most refractory disease, those are patients that require particular attention.

I think more globally, the main practice-changing element of the study is that we should use this drug on patients who need it rather than avoid it. We should manage it well. This study provided a guide as to what is the optimal way of managing these patients.

There are many things that we still need to learn. One important question that I have and I want to explore further is the mechanism for these arterial occlusive events. This is not a problem only for ponatinib, it is a class effect. I don't think we understand it well. We need to try to understand it better so that we can minimize those effects further.

Number two, we need longer follow-up because these events can continue occurring in the long-term. We need to make sure that we understand the overall incidence not only after one or two years but after five or even longer periods of time.

Three, there are new tyrosine kinase inhibitors coming along the way. One good example is asciminib, and it will be very important to determine the value of each drug and what specific populations can benefit from one or the other.

The most important message to me is that ponatinib is very useful drug, and there are many patients that can benefit from these drugs. Any patient that has already experienced resistance to a second-generation TKI and whatever line of therapy they use, to me, it's a perfect candidate for ponatinib.

With these results, I feel increasingly comfortable using ponatinib in the right setting, but as important as it is to know how to manage the dose of the drug and the dose reduction by efficacy, it is to assess and manage the comorbidities of the patients so that we can minimize the risk, again, whether we're using ponatinib or any other tyrosine kinase inhibitor.