Jorge Cortes, MD, Reviews Positive Phase 3 Quizartinib Data for AML Treatment

Results from the phase 3 QuANTUM-R clinical trial evaluating investigation therapy quizartinib for the treatment of patients with FLT3-internal tandem duplication (FLT3-ITD)—mutated relapsed/refractory acute myeloid leukemia (AML) were presented at the 60th ASH Annual Meeting & Exposition in San Diego, California.

As AML is entering an exciting time in which a number of therapies are being developed, lead investigator, Jorge Cortes, MD, deputy chair in the Department of Leukemia at MD Anderson Cancer Center, sat down with Rare Disease Report^® (RDR^®) to highlight the trial’s key results and explain their clinical implications on the rare blood cancer.

[Editor’s note: Transcript is slightly modified for readability.]

RDR^®: Can you provide some background on the phase 3 QuANTUM-R clinical trial?

Cortes: “Quizartinib is a FLT3 inhibitor. It's what we call a type 2 FLT3 inhibitor. It's very potent [when] orally administered. Based on preclinical work, it's the most potent inhibitor that we have available to date. It is also the most selective inhibitor, meaning it inhibits very few other kinases compared to any of the others that are available in the clinic or in clinical research at the moment.

[Quizartinib] has gone through phase 1 and phase 2 studies, and it has shown very significant activity with high levels of response in patients with FLT3 ITD-mutated AML. In the range of around 50%, patients have a response that we call a composite complete remission, meaning complete remission or a complete remission with incomplete hematologic recovery.

In the QuANTUM-R study, we had patients that had refractory or relapsed acute myeloid leukemia that had the FLT3i mutation. They were randomized to receive either quizartinib or the standard of care. The physicians had to choose—at the time of randomization—between 1 of 3 options. [Two were] intensive regiments. One is called MEC [mitoxantrone, etoposide, and intermediate-dose cytarabine], the other one is called FLAG-IDA [fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin]. A less intensive regimen, LoDAC [low-dose cytarabine] was for patients that were thought unable to get the intensive chemotherapy.

Very importantly, these patients were selected to have a very poor prognosis. Not only had they relapsed or were refractory to therapy and had the FLT3i mutation, which is already a bad thing, but they also should have received an intensive chemotherapy regimen in the past that contained an anthracycline, and if they had relapsed, they should have relapsed within 6 months. That makes it a very difficult population.”

RDR^®: What were the highlights presented in the data from the phase 3 QuANTUM-R clinical trial?

Cortes: “The primary objective of the study was overall survival. The results showed that it was a positive study, meaning it improved the survival, it was a significant improvement in survival. At 1 year, for example, there were 27% of patients alive compared to 20% with a standard chemotherapy.

The median survival was equally significant. This also came with an improvement in some of the secondary endpoints. For example, the composite complete remission rate was around 48%, which was almost a doubling of the static chemotherapy, which was 27%. There were also some partial responses they didn't count as a success. They counted as a failure, but they were partial responses, which is a benefit for the patients. The event-free survival was also in favor of quizartinib, particularly when we look at the population of patients per protocol, meaning those who met eligibility and received treatment, etc.

All in all, the efficacy endpoints were favorable for quizartinib. In terms of safety, it was a very well-tolerated drug, and it's oral. That's already a benefit compared to these intensive chemotherapies. There was not much toxicity.

The 1 concern with this drug has been QTcF prolongation. That has been seen as the dose-limiting toxicity. We used a lower dose than was done in the initial studies, so the starting dose was 30 milligrams, and if the patients didn't have a QTcF prolongation, we escalated to 60 milligrams. With that, only 3% of patients had a great QTcF prolongation; there was no Grade 4. None of these patients had any clinical consequences of the prolongation. It was very well managed.

Overall, the results were very favorable and suggest that this is a very active drug and a very safe drug. It’s the first study ever that has demonstrated a survival benefit in the context of salvage treatment for acute myeloid leukemia. [These are] very exciting results.”

RDR^®: What are some traditional challenges in treating this patient population that quizartinib helps address?

Cortes: “The most important challenge is that the treatments we have used have been highly ineffective. In addition, it has been toxic [since] we use these high-intensity chemotherapy regimens. These regiments tend to have to be done in the hospital at least for some part of the time, and they have a lot of side effects. Patients feel very tired and fatigued with lots of nausea, etc.

You have very toxic regimens that don't work very well. In this context where patients end up spending most of the time in the hospital, and yet they don't live too long, unfortunately, that was something that we have—for years—been unable to overcome.

This drug seems to be helping with that because for 1, you can take the treatment outpatient. It's oral, so it's self-administered. [It’s] much less toxic, and therefore, the patients live longer. There was no actual measure of quality of life, but in general and from years of my experience, these patients feel much better by being treated out of a hospital and being able to be at home and eat their food rather than hospital foods.”

RDR^®: What are the clinical implications from this phase 3 data of quizartinib?

Cortes: “This this drug is currently under review by the regulatory authorities. We hope and we expect that the drug will be approved so that we can start using it in the clinic not—just in clinical trials.

In addition, there are other trials ongoing. For example, this study was for patients who already had relapsed or did not respond to the initial therapy. Ideally, you would want to use these from the time of diagnosis. There are studies ongoing that are addressing combining chemotherapy with quizartinib and comparing that to the chemotherapy alone.

There are other studies looking at the use after transplant and all the different combinations, so there's a lot of other approaches that you can imagine. The study that we are discussing today is an important one, but it has many implications on other potential uses of the drug.”

RDR^®: What are the clinical implications from this phase 3 data of quizartinib?

Cortes: “This is a very exciting time. For many years, we did not see much improvements in the outcome, which was perhaps not a big surprise because we really didn't have any new drugs. We were mixing different types of chemotherapy and giving higher doses for more days and things like that, but we really were not changing—substantially—the approach.

Now, we are having much better therapies on targeted and immunotherapies, and things of the like. We have had a lot of new drugs approved, and many others that we saw at this meeting. For example, new antibody-drug conjugates, bispecific monoclonal antibodies, and other targeted therapies that are very promising.

I think that our approach to leukemia is finally changing in the refractory/relapsed setting. Of course, from then, you can extend them to the frontline setting, but I think that finally, we are starting to break that impasse where we were not making any progress, and now, we clearly are.”