Ponatinib Dose-Ranging Study in Chronic-Phase Chronic Myeloid Leukemia

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EP: 1.Ponatinib Dose-Ranging Study in Chronic-Phase Chronic Myeloid Leukemia

EP: 2.Clinical Implications of a Dose Ranging Study of Ponatinib for CML

EP: 3.Optimal Ponatinib Dose Selection for a Given Patient Population

EP: 4.Efficacy and Toxicity Considerations for Use of Ponatinib

EP: 5.Patient Selection and Dosing of Ponatinib

EP: 6.Future Implications for Use of Ponatinib

EP: 7.Ponatinib Dose-Ranging Study in Chronic-Phase CML: Summary

EP: 8.Recap: Finding the Optimal Dose of Ponatinib for Chronic Phase CML

Transcript:

Jorge E. Cortes, MD: My name is Jorge Cortes from the Georgia Cancer Center in Atlanta, Georgia. I’m talking about a manuscript that was recently published in Blood, and it describes a clinical trial called the OPTIC trial. The title of the manuscript is “Ponatinib dose-ranging study in chronic phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial.” This trial was named OPTIC, and was a multi-center study, and there’s a number of authors that work in this study.

Why this study? Ponatinib [Iclusig] is a third-generation tyrosine kinase inhibitor [TKI]. It came many years ago, and it was effective when it started being investigated in the phase 1 and phase 2 setting. Then, the pivotal phase 2 trial, called the “pacing, graded activity, and cognitive behavior therapy [PACE] trial,” showed high levels of efficacy in patients with chronic myeloid leukemia [CML] in all stages of the disease. That study included patients in chronic, accelerated, and blast phase. Patients that had received multiple prior TKIs—more than 90% had received 2 TKIs or more, more than 60% had received 3 TKIs or more, and high response rates. That that was in question, but it worked in T315I mutated patients as well. The problem was that we soon recognized that there was an association over 2 occlusive events that occurred with ponatinib. In those days, this was not recognized for any TKI. Now we understand this is a class effect. If that was something that limited the use of ponatinib, and there were several attempts at trying to use different doses and cutting the doses. Starting different doses unofficially, trying to see if that could reduce the risk of developing those arterial occlusive events, and in practice, ponatinib was not being used because of those concerns.

To try to determine what will be the optimal dose for ponatinib, and whether using different lower doses could have a benefit in reducing the risk of arterial occlusive events, while maintaining efficacy, that’s why this study was designed. For the purposes of understanding, when we talk about arterial occlusive events, we’re talking about cardiovascular events. For example, myocardial infarctions, anginas, cerebrovascular events, strokes, transient ischemic attacks, and peripheral vascular brain gangrene, etc. The design of the study was this study included only chronic phase patients who had been resistant or intolerant to at least 2 prior TKIs or who had the T315I mutation. They could have comorbidities, risk factors for arterial occlusive events, [but] they had to be well controlled at the time of enrollment. The patients were then randomized 1:1:1 to receive a starting dose of 45 mg daily, which is the standard, 30 mg daily, or 15 mg daily.

The primary end point was the achievement of a response defined as 1% or less transcripts…transcripts at 12 months. The important element of the design of the study was that once patients achieved that response, they should lower the dose to 15 mg daily. This was a response directed dose reduction, not a toxicity driven dose reduction. There were guidelines for dose reduction for toxicity as well, but there was a mandatory dose reduction for response. The primary end point, the study, the manuscript describes the primary analysis when all patients had reached the 12-month mark, the follow-up, the overall median follow-up is a bit over 32 months total, to be precise. As I mentioned, this is the primary analysis. In total, there were 94 patients in this manuscript described in each 1 of the 3 cohorts. The median age is in mid-40s to 50s, so well-balanced between the 3 arms. This study shows that there’s all of these arms that were balanced. It does show that some patients had cardiovascular risk factors for arterial occlusive events. Approximately a third of the patients on each 1 of the arms had at least 1 risk factor. Many of them were smokers, about a third, again, and the median body mass index was 26 to 27, in the range of overweight for all of these patients. By design, these patients were heavily pre-treated—more than 95% of patients had received at least 2 prior TKIs, including about 50% or more that had received at least 3 prior TKIs. The patients were resistant to treatment. There were few that were intolerant, only 2 in the whole cohort, and the best response to the prior TKI described in the manuscript, was a hematologic response in about 60% of the patients, and again, well distributed among the 3 cohorts. Not a cytogenetic or a molecular response, only a hematologic response.

The primary end point, as I mentioned, was the efficacy at 12 months, reaching these transcripts for 1% or less, and what the manuscript shows is that this was significantly better in the cohort that received the 45 mg daily. The results that are shown is 44.1% response rate with 45 mg compared to only 29% in the 30 mg and 23.1% in the 15 mg. The responses are seen early on in figure 1. There’s also a description of the responses by 6 months, so early on you see the benefit for the 45 mg cohort. This difference in favor of 45 mg is maintained to 24 months, which is the last time point where data is available, presented in the manuscript. Those differences are equal or larger in favor of the 45 mg. It also presents the dose intensity, and one of the interesting findings is that even though you start with a higher dose, by 12 months, that median dose intensity is lower in the 45 mg cohort. It’s only 15 mg, the dose intensity, the median dose intensity, compared to the 30 mg, which by 12 months, the median dose intensity is 28 mg. That is important even though they started with the higher dose and ended up with a lower dose intensity because of that dose reduction due to the response. There is a subanalysis by mutation status, and it shows that those patients with T315I have a significant benefit with 45 mg. The response rate for those patients is 60% whereas for patients that received 30mg, it’s 25%, and even lower, at 10.5%, for the 15 mg. There’s also a benefit in response rate for patients that have other mutations. For example, the response rate in 45 mg is 56% compared to 40% if they receive 30 mg. For patients with no mutations, the difference is a bit smaller, for 46% for 45 mg treated patients, 37.9% for 30 mg treated patients, and even lower, 28.3%, for 15 mg. According to their response to prior therapy, the response is complete hematologic response or worse, those patients benefit for 45 mg with a response rate of 50% compared to 20.8% with the 30 mg cohort. All along, all these benefits for 45 mg is maintained for the overall population and the subsets that are being presented, there is a presentation of the progression-free survival and the overall survival. None of these differences are statistically significant. The curves for progression-free survival suggest a bit of a starting of a benefit for the 45 mg cohort. Follow-up is short. That’ll need to be presented later.

In terms of the safety profile, the toxicity that is described in the manuscript matches what we know for ponatinib. The most important issue is the discontinuation of therapy and dose reductions, a bit more in the 45 mg cohort. For example, dose reductions were needed in the 45 mg cohort in 45.7%. This is due to adverse events, not due to the response, compared to 35% in the 30 mg cohort. The important issue was these arterial occlusive events. One thing that the manuscript describes is that these arterial occlusive events were prospectively evaluated in a blind way by an independent committee of cardiologists, neurologists, and vascular experts, these are all truly considered arterial occlusive events. They occurred in 9.6% of patients with 45 mg, 5.3% in the patients with 30 mg, and 3.2% in the patients with 15 mg. Some of a higher incidence in the 45 mg cohort, but overall, a low incidence compared to what had been reported in prior studies. The discontinuation rate because of arterial occlusive events was low, 4% in the 45 mg and 3% in the 30 mg cohorts. When the benefit and the risks, particularly arterial occlusive events, are put side to side, and they present these in figure 3, there is an increase in both efficacy and arterial occlusive events with the 45 mg cohort. The change is much greater in terms of the efficacy than it is in terms of the safety. The risk-benefit ratio seems to be favoring the use of 45 mg as the starting dose with that dose reduction after response.

What’s the takeout on this study? This provides several messages that I consider, but one is that 45 mg is most effective, and these are high risk patients that have had a lot of therapy and you need to worry about the leukemia. Forty-five mg provides a greater benefit. What is important is that it shows that you don’t have to maintain that 45 mg all along like we were doing before. When you dose reduce once the patient responds, most patients were able to maintain the response. Seventy-five percent of patients were able to maintain the response, and those who lost it, most of them regained the response with re-escalation. It’s a safe approach and it decreases the dose intensity. It decreases the risk of arterial occlusive events greatly. And it’s an important lesson on how we should manage ponatinib, you could even ask whether we should be doing that with other TKIs? That hasn’t been tested and it’s not the purpose of this manuscript, but it makes you think about that. And finally, the fact that you can minimize the risk of arterial occlusive events in these patients and provide the therapy when it’s indicated, which is important because these patients, when they get to this point, they don’t have too many treatment options. That is my take on the message of this manuscript and why I think this is an important study and manuscript to read. This concludes the presentation of the actual manuscript, the data that’s presented. Please join me now on a conversation with one of my colleagues. We’re going to be talking about what is an impact in practice of these results of this manuscript, how it impacts the clinic, the approach that we take to patients, both in academic institution and in a community setting, and what are the lessons and the implications that we should take and can take to our clinic.

Transcript edited for clarity.