PhALLCON Trial: Safety and Efficacy of Ponatinib in Philadelphia-positive ALL

Transcript:

Hagop M. Kantarjian, MD: So this is where, Bijal, I’d like to ask you about the safety results of the [phase 3] PhALLCON trial [NCT03589326], because we are always concerned that ponatinib is the most toxic of the TKIs [tyrosine kinase inhibitors]. And the question is, in this randomized trial…did we see the toxicities that we had seen in the past or…did it show that ponatinib is safe?

Bijal D. Shah, MD, MS: It really demonstrated that it’s safe…we did not see an increase in arterial or venous occlusive events on the study; both the rates were under 5%, if I recall. It was remarkably safe. And I think this is a really, really important point to stress. One, the ponatinib [dose] was at 30 mg, and with that, really no significant arterial occlusive events. I think it was 2% on the study. And when we talk about imatinib, the same rates. I don’t think that we can say any more, particularly at this dose. And…with its use in the up-front setting…venous occlusive and arterial occlusive events need to be the thing that we fear. On the other side…with regard to hematologic toxicities, [there were] very similar rates of cytopenias, very similar rates of grade 3 and 4 cytopenias. No…big differences when we compared imatinib to ponatinib.

What about nonhematologic [adverse] effects? Now I think we’re just kind of trading one for the other. With imatinib, we saw more of the GI [gastrointestinal] [adverse] effects, the nausea, the vomiting…and the like. Whereas with ponatinib we were seeing a little bit more of the constipation [and] dry skin, which wasn’t described in the abstract, but another very common [adverse] effect with ponatinib, a little more hypertension, particularly higher-grade hypertension. But…[the] kind of things that are more typical of ponatinib. Nothing that was really worrisome. And I want to touch on one toxicity in particular, and that is AST/ALT [aspartate aminotransferase/alanine transaminase] elevations, because quite honestly, I see it in almost all of my patients, usually with the first cycle of chemotherapy. And…I’ve begun telling my team to just ignore it…unless it gets really…up there, upwards of 10 times normal. Most of the time this is what I call cosmetic. And if you keep patients on drug, it goes up [and] comes back down and patients do just fine. And so…while we did see more in the way of ALT abnormalities on this trial, it was what I call a cosmetic or laboratory change. I don’t know about for you, but for our CAR [chimeric antigen receptor] T-cell trials we have to actually label, do we consider this laboratory change clinically significant. And in the case of ponatinib, at least in my opinion, I would mark this is not clinically significant, having seen no hepatic compromise or other toxicity along those lines.

And so I really do feel like this is a fairly safe drug. Rates of discontinuation for toxicity were similar between imatinib and ponatinib. So really no signals there. The No. 1 reason why patients came off imatinib was lack of efficacy. And it was significant. It was quite significant. And so you had touched on the EFS [event-free survival] and you touched on the OS [overall survival], but what I really liked in this particular analysis was also the PFS [progression-free survival], which included molecular responses as an end point, where now you really see those curves separate statistically…showing that, really, imatinib patients are just not hitting that end point of molecular remission. And we know that that’s going to correspond with subsequent relapse.

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