BCR-ABL1 TKIs in Relapsed/Refractory CML - Episode 9

Bosutinib Versus Ponatinib in R/R CML

June 24, 2019

Harry Erba, MD, PhD:Jorge, can you, discuss some of the risks and benefits, the toxicity profiles, of bosutinib versus ponatinib in patients with relapsed-refractory disease.

Jorge Cortes, MD:The third person becomes relevant when we consider that in the third-line setting, those are the 2 drugs that have prospective data from clinical trials. In the bosutinib study that led to the approval in the salvage setting, there was a cohort of patients who had received prior imatinib and either dasatinib or nilotinib—resistance or intolerance. And of course, the ponatinib study was specifically for patients who had received at least 2 tyrosine kinase inhibitors [TKIs] or more. There were a few patients who had received only 1 because they had theT315I, but overwhelmingly it’s 2 or 3 or more tyrosine kinase inhibitors.

That’s where that comparison becomes important. I think what you see there is that in terms of efficacy, just look at the raw data. Of course these are different studies and you can look at differences in population, but just looking at the raw data, the response rate with ponatinib is much higher. The major cytogenetic response is 60% to 70%, even if you take away theT315I, because we know bosutinib doesn’t work there. But even then, it’s a good 60% to 65%. With bosutinib it’s about 40%. It’s nice to have that, but there is a difference there.

I think in terms of efficacy the third line—let’s not forget that the ponatinib has a number of patients who have seen 3 or more tyrosine kinase inhibitors. Here we’re talking about 2 prior tyrosine kinase inhibitors—prior only with the bosutinib study. Efficacy-wise, there’s clearly an advantage there.

There have been some statistical comparisons. We can see that difference, both in putting these studies side to side and clinically, I think it is fair to say.

You asked about the safety, and the big difference there are the arterial occlusive events.… That’s where we started seeing those risks, and then we recognized that it happens with other tyrosine kinase inhibitors. But ponatinib probably has it more than others, and if anything, of the second-generation TKIs, bosutinib has the lowest risk, although we have seen them reported at least.

Obviously what’s important here is that I mentioned ponatinib is a great drug, and I use it. I’m not afraid of using ponatinib in the right patient. For a patient who has had 2 or 3 TKIs, if I have to use ponatinib, I’m going to use it. I would start with a lower dose. If they have comorbidities, I’ll manage them.

There are patients who have way too many comorbidities. It’s good to have bosutinib, and there are patients for whom I’m going to use bosutinib. But I think that in the right context, in that third-line setting and certainly more, ponatinib is the most effective drug.

Harry Erba, MD, PhD:That’s what I hear you saying—patients who do not have cardiovascular risk factors, based on the efficacy, you would use ponatinib or bosutinib. As long as I’m on that topic, let me ask you 1 other thing. Have you ever used ponatinib in order to get a patient into a deeper remission for treatment-free remissions?

Jorge Cortes, MD:No, I have not. But what I’ve done is, some of my patients on the PACE study have gotten such a good response that I have 3 or 4 patients for whom I had stopped therapy. They had a great response, and it’s 3 or 4 patients, but they’re maintaining their response. It’s definitely doable because you can get to those responses.

Harry Erba, MD, PhD:What I heard you saying there then, if there was a clinical indication for switching to ponatinib, such as in the PACE trial, then that might actually become an option. But for a patient who’s meeting all the milestones and is just interested in a treatment-free remission, you think there might be other options to get them there besides ponatinib.

Jorge Cortes, MD:We haven’t done it, but it probably would work. We’ve seen it with nilotinib. There’s been an intentional study…for patients on imatinib. You put them on nilotinib, and some of them—not everybody, but some of them—do get to that milestone. I’m sure that if we did the same thing with ponatinib, we’ll get that many or more. We haven’t done it—and again, you always have to calculate that risk-benefit ratio—but certainly I think that it could happen.

Transcript edited for clarity.