EHA 2019 | QuANTUM-R: quizartinib looks promising for FLT3-ITD mutated AML

Recently the FDA had an ODAC meeting to review the phase 3 results of the QuANTUM-R randomized phase 3 study in relapse refractory FLT3-ITD mutated AML, which randomized patients to receive Quizartinib single agent versus investigator choice treatment, which was high dose chemotherapy or low intensity therapy.

The primary endpoint was overall survival. The study was actually presented at the EHA meeting, exactly one year ago by Dr. Jorge Cortes from our group and it actually showed that the median overall survival improvement was met 6.7 months versus 4.4 months, and it did show that in one year, there were about eight percent more people alive in the relapse setting with Quizartinib, versus chemotherapy.

Also quite importantly, the early mortality, the four week mortality was less than one percent with Quizartinib and was 14 percent with chemotherapy, so even if you look at the number of people who die from the side effects of the treatment, it seemed to be many-fold higher with the chemotherapy than with Quizartinib.

Based on this, we think that the benefit risk profile of Quizartinib actually is quite favorable. We have used this drug now in a few hundred patients across the phase 1, two phase 2 studies, phase 3 studies, and other investigator sponsored studies, and we actually find it to be a very, very well tolerated, safe drug. There has been this question of cardiac issues, which was discussed at the ODAC meeting, and both the FDA cardiologist as well as the sponsor cardiologist basically felt that there was no concern for cardiac signal. There did not seem to be any deaths directly related to QTC prolongation associated deaths, and there was no mandate for having use of beta blockers or other drugs. That’s been our experience, too, that although you can get some numerical increase in QTC, we have not seen active or severe cardiac deaths across a few hundred patients that we have treated.You have to monitor and be careful, but it doesn’t seem to be clinically major cardio toxicity.

The other concerns were related to the magnitude of difference, and I think when you’re in a very, very, very difficult space, like a relapse refractory FLT3 mutated AML, even if you have equivalence with an oral well tolerated drug that gives you manyfold lower early mortality and can be given outpatient, that would, in myself, would be a victory.

Here, you actually see not only equivalence, but doubling of response, improvement of survival, and almost threefold more people going to transplant, which we think indicates that the drug is not only effective in reducing the marrow blast to below five percent, which is usually what we need to consider patient for transplant, but it’s also safe in that people who get to transplant are in a better condition, so the transplanters want to see the blast below five percent, and they want to see the patient in a good performance status, with no major organ dysfunction.

If we can get more people to that transplant, I think that’s actually a meaningful endpoint because it shows the drug is safe and efficacious. What we’re hoping is that eventually, even though the ODAC vote was negative, the FDA will re-review the data and maybe there are some subsets, such as primary refractory FLT3, where we saw the most magnitude of benefit, or the high allelic burden patients, where we see the high degree of benefit, and of course, there is a confirmatory frontline study, the QuANTUM First, which is almost completely enrolled.

Based on all the biology preclinical data, we think that the more potent FLT3 inhibitors Quizartinib and gilteritinib will significantly improve the survival in the frontline setting. We have a number of other studies combining venetoclax with Quizartinib, decitabine with Quizartinib, which were showing very good results and we presented at the ASH meeting this year. I think that most of the expert community is still very keen to have this drug. We still think it’s a huge unmet need. We think that the risk profile is very, very well manageable, and the benefit is clearly there as a single agent, but really, that will be the beginning of the research, and the combinations will probably show more benefit.

If we cannot get the drug as a single agent, that will slow down the combinations, and that’s what we’re really more concerned about.