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Ponatinib Advances as Frontline Therapy in Ph+ ALL: PhALLCON Study Highlights
Author(s):
Bijal Shah, MD, MS, and Hagop Kantarjian, MD, discuss promising results and regulatory progress for ponatinib in frontline Philadelphia-positive acute lymphoblastic leukemia treatment.
Transcript:
Hagop M. Kantarjian, MD: What I want to ask you, Bijal, is to comment on how the regulatory authorities view ponatinib and how [we can] bring ponatinib to become an acceptable, approved, established standard of care in Philadelphia-positive ALL [acute lymphoblastic leukemia]. What are the approaches to get ponatinib to be a legitimate TKI [tyrosine kinase inhibitor] therapy in Philadelphia-positive ALL?
Bijal D. Shah, MD, MS: I think that’s a great question. I think the reality is until very recently, we just didn’t have comparative trials. We…can compare across studies: hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, methotrexate, cytarabine, and dexamethasone] imatinib versus hyper-CVAD dasatinib [vs] hyper-CVAD ponatinib and try to…use propensity score analyses and other analyses to show the broader-acting TKI is really a better agent to use up front.
It reinforces what we see clinically. We know that when we enrich for the T315I when we use a less broad-acting TKI, it’s often not in isolation. We’re getting these compound mutations, E255 and others. And then when we try to bring ponatinib into that space, we get limited if any activity. And…we’re all scratching our heads asking what to do next. So moving the broader, better-acting TKI up front has helped us tremendously. We’re seeing less of this compound mutation issue emerge in practice and what we’re seeing clinically, again, comparing across studies, supports that rate with improved survival rates of 3 years relative to what we were seeing from the other clinical trials. And it’s been outstanding to see. But getting to your point, what do the regulators want to see? Comparative data. And we finally have that with the [phase 3] PhALLCON study [NCT03589326]. And…for those who aren’t familiar, the PhALLCON study took imatinib 600 [mg]—so [a] reasonable dose of imatinib—vs ponatinib 30 [mg] and built it on a low-intensity chemotherapy backbone. So this was a …[dexamethasone] backbone for 3 cycles, followed by a methotrexate Ara-C [cytarabine] backbone for another 6 cycles and asked…which one is likely to be better?
I guess I can cut to the chase and say ponatinib really seems to have performed very, very well in this analysis. And I think we’ve already now seen this impact [on] the National Cancer Center Network guidelines, where imatinib has been deprioritized. For those who aren’t aware, it’s only recommended now for patients who cannot tolerate any of the other TKIs. So we no longer recommend it outside of that single scenario, which I hope would be very rare in clinical practice. Before I go any further, Dr Kantarjian…I know that MD Anderson was very heavily involved in the study. Can you tell us a little bit about the primary end point? You can tell I’m excited, but why should those who are listening today also be excited about this trial?
Hagop M. Kantarjian, MD: So when we approached this trial design, we wanted primarily to be able to show that ponatinib is superior to imatinib in the frontline setting in Philadelphia-positive ALL because this is what the single trials were showing. Now in Europe, still, imatinib was considered reasonable frontline therapy and in fact many people still consider imatinib as a reasonable standard with chemotherapy.
So what we said is, let’s take patients who are older. We randomized them to imatinib 600 mg, which is accepted by many as a standard [dose], or ponatinib. And then we’ll do low-intensity chemotherapy, and the end point of the treatment will be the incidence of molecular response at 3 months. Now, at 3 months patients could cross over from imatinib to ponatinib. And this is what happened quite commonly. When the study was done, we found that the primary end point would show us the incidence of 3 months [of] complete molecular response, which was the end of the induction therapy. So they call the 3 months the induction therapy.
So the incidence of complete molecular response was significantly higher with ponatinib compared to imatinib. And we are hoping that this will give the regulatory approval for ponatinib in the treatment of Philadelphia-positive ALL. But I think this is only the first step because next what we need to do is see what we can do to improve on those results. Because even in that trial, the 3 months’ incidence of complete molecular response, even though it was higher with ponatinib, it was not very high. And that relates to some of the designs of the trial, the point at which the FDA approved the testing of the BCR, and so on. But nevertheless, this was the first step for us to be able to consider this as a new standard of treatment.
So in terms of the efficacy end point, the incidence of 3 months [of] molecular response, this was accomplished. The secondary end points were event-free survival, relapse-free survival, and [overall] survival. In terms of event-free and relapse-free survival, the results were better with ponatinib, but because many of the patients on the imatinib crossed over to ponatinib, with this early follow-up, the survival is still the same. So this is where we are now, and I think we have to move on from here to better combination regimens. And my view is that the better combination regimens are perhaps with ponatinib-blinatumomab or dasatinib-blinatumomab.
Transcript is AI-generated and edited for clarity and readability.
