Expert Highlights Quizartinib Benefit for Patients With FLT3-ITD+ Relapsed/Refractory AML

Jorge E. Cortes, MD

Jorge E. Cortes, MD

Quizartinib, a FTL3 inhibitor, significantly improved overall survival (OS) for patients withFLT3-internal tandem duplication (ITD)-positive relapsed/refractory acute myeloid leukemia (AML). In QuANTUM-R, a randomized, controlled phase III trial, this agent was compared to standard chemotherapy after patients received first-line treatment with or without hematopoietic stem cell transplantation.

Patients were randomized to receive either a continuous oral, daily dose of quizartinib or salvage chemotherapy. For the chemotherapy arm, patients received either a low dose of cytarabine; a combination of mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or combination fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA).

In results reported at the 2018 European Hematology Association (EHA) Congress, prolonged OS was seen in patients in the quizartinib arm. The toxicity profile for quizartinib was also tolerable, with very little grade 3 or 4 adverse events. At the 1-year mark, 26% of patients in the quizartinib arm were alive compared to 20% in the control arm, according to Jorge E. Cortes, MD, who reported the results at EHA.

Moving forward, other trials are using this agent in different patient populations and in combination with other therapies and novel agents. WhileFTL3-mutated patients with AML are lacking treatment options, quizartinib shows a lot of promise for this patient population. Unlike other FTL3 inhibitors, this agent is highly potent.

In an interview withTargeted Oncology, Cortes, deputy department chair of the Department of Leukemia and director of CML and AML programs at The University of Texas MD Anderson Cancer Center, discussed the results from the QuANTUM-R trial, as well as some other studies investigating the use of quizartinib in different patient populations in AML.

TARGETED ONCOLOGY:Can you share the rationale for using quizartinib in patients with AML? How was this trial designed?

Cortes:Quizartinib is a FTL3 inhibitor. It’s a fairly potent and highly selective FTL3 inhibitor. It does inhibit a few other kinases, but the potency of FTL3 is much higher than the other kinases. There are a few other FTL3 inhibitors that have been investigated, but this is much more selective than the ones we have had to date.

There have been many studies before this, a phase I, of course, and then some phase II studies. They have been looking at different populations, usuallyFTL3-mutated patients. It has shown that it has high levels of activity, high response rates, complete remissions, complete remissions with incomplete hematologic recovery, or what we call CRc, the composite complete remission rate. That led to this study, which was a confirmation of a pivotal trial.

[This trial included] patients withFTL3mutations, specificallyFTL3-ITD in first salvage, so these were patients that had either been refractory to prior chemotherapy or had achieved a remission that lasted less than 6 months. These patients were then randomized to receive either quizartinib orally daily, or standard chemotherapy. The patients could be allocated to either a low dose of cytarabine under the standard chemotherapy arm or a higher dose regimen of either FLAG or MEC.

Patients would receive the quizartinib continuously; the chemotherapy, they would receive in a couple of cycles. For low-dose cytarabine, they could continue indefinitely. In patients who had a good response, they could go to a transplant. Importantly, if the investigator felt that patients in the quizartinib arm wanted to resume therapy with quizartinib after transplant they were allowed to do that, so some patients actually did that.

The primary objective of the study was OS. There were secondary endpoints, event-free survival, and exploratory endpoints, which were response rate, complete remission, overall response rate, and of course, safety was an important objective as well.

TARGETED ONCOLOGY:What were the results?

Cortes:This is the first report of the results. The results just became available very recently. We actually submitted these as a late breaking abstract just because it was so recently that we were able to read the results. We are focusing on the primary objective, which, again, is survival. What we showed was that the median survival was significantly better for the patients that received quizartinib for 26 weeks compared to 20 weeks in the control arm. That is highly statistically significant. The hazard ratio was 0.76, and the percentage of patients that are alive at 1 year is 26% in the quizartinib arm versus 20% in the control arm. Overall, this shows that this was a positive trial and that there is a benefit for these patients.

The other objectives also followed the same trend. There was an improvement in event-free survival, there was also significant improvement in the overall response rate, and in the CRc, favoring the quizartinib arm. Importantly, there were essentially equivalent rates of adverse events and very few grade 3 or 4 adverse events.

One important adverse event of interest is QTc prolongation. That was the dose-limiting toxicity in the phase I, so that was a focus on the quizartinib. Fortunately, it was a little bit more frequent in the quizartinib arm, but it was overwhelmingly grade 1 or grade 2. There were very few patients that had grade 3 toxicities. Nobody had grade 4, nobody had any torsades or any serious arrhythmias or sudden deaths, or anything like that. The safety profile was very favorable in this patient population, so all of these were positive in favor of quizartinib.

TARGETED ONCOLOGY:What is the take home message in regard to quizartinib for community oncologists?

Cortes:I think that this is a very important study because it is the first study to show that the single-agent FTL3 inhibitor improves outcome over standard of care. It’s the first study to show that in the salvage setting you can improve survival compared to standard chemotherapy, in this case, particularly in theseFTL3-mutated patients. We are very hopeful that this will lead to a regulatory approval of this drug, and this offers a very good option for patients with this disease.FTL3-mutated patients already have a poor prognosis, in the salvage setting, it is even more difficult to treat. I think this will give us a great opportunity for these patients.

TARGETED ONCOLOGY:Are there any other ongoing trials that you are excited about in AML?

Cortes:There are many other studies that are happening. An important study is one that is called QuANTUM-First, which is exploring quizartinib versus chemotherapy in the frontline setting compared to chemotherapy. That study is also trying to asses whether we can also improve survival in the frontline setting. This study is still ongoing so we don’t have any data, but we are hopeful that it will prove the same benefit in the frontline setting.

Also, there are many studies that are looking at quizartinib with other combinations. For example, with hypomethylating agents that we use for older patients, there are studies after transplant, and there are studies in combination with other novel agents. There are many, many other studies, and I think little by little, we will see quizartinib expand its reach to other settings.

TARGETED ONCOLOGY: Is there anything else you would like to highlight about QuANTUM-R?

Cortes: