Second-Generation FLT3 Inhibitors Are Future of Relapsed/Refractory FLT3-Mutant AML Treatment

Kelly Davio
Published: Friday, Jun 14, 2019

Dr. Naval Daver

Naval G. Daver, MD

FLT3-mutated relapsed/refractory acute myeloid leukemia (AML) represents one of the most challenging hematological malignancies to treat and carries a poor prognosis. A novel small molecule FLT3 inhibitor, quizartinib, has been the subject of high hopes among clinicians who treat patients with this disease as it targets AML with FLT3-internal tandem duplication (IDT) mutations, one of the most common molecular aberrations identified in the malignancy.

However, in May 2019, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8-3 against approving quizartinib for adult patients with relapsed/refractory FLT3-ITD–positive AML. Nevertheless, clinicians remain optimistic on the novel agent and the significant impact it could have on patient outcomes. 

In an interview with OncLive during the 2019 European Hematology Association Congress, Naval G. Daver, MD, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discussed the data that support quizartinib thus far, ongoing investigations with this drug in the frontline setting, and the potential for the agent to be approved by the FDA.

OncLive: Could you discuss the data that is available on the QuANTUM-R trial?

Daver: The QuANTUM-R study is a randomized, phase III study in people who have FLT3-mutated relapsed/refractory AML. This is a very high-risk population. Patients who have FLT3-mutated AML, and especially those who have FLT3-ITD–mutated AML, have a very poor prognosis, both in the newly diagnosed setting, as well as in the relapsed/refractory setting.

This has been a major area of research to try to develop targeted therapies. There are multiple FLT3 inhibitors that have been in clinical trials. The only one that was approved by the FDA until recently was a drug called midostaurin (Rydapt), which is a first-generation FLT3 inhibitor. It has reasonable activity, but it’s not as potent at the second-generation inhibitors that we have.

[Data] did show that when midostaurin was added to induction chemotherapy, it improved the overall survival as compared with patients who got induction chemotherapy alone. However, a number of these patients still do relapse.

QuANTUM-R was the first large, phase III randomized study that tried to look at the outcomes in these patients. A total of 450 patients were randomized to receive either quizartinib, which is the targeted therapy, or to receive [either] induction chemotherapy or low-intensity therapy. The comparator arm was basically the investigator’s choice. The primary endpoint was improvement in overall survival (OS), and secondary endpoints included improvement in response rates, including complete response (CR) and CR with incomplete hematologic recovery (CRi), overall response rates, as well as the number of patients who could go on to allogenic stem cell transplant.

The study showed that the primary endpoint of OS had been met; OS was significantly improved with the use of quizartinib as opposed to the investigator’s choice of therapy. What was more impressive and striking was that, if you look at the response rates of CR and CR, which have been the traditional way to look at FLT3-mutated relapsed AML, these were almost doubled with the quizartinib, at around 48% to 50% compared to 25% to 27% with traditional chemotherapy.

This is very good on its own, but it’s even more impressive when we realize that traditional chemotherapy was usually a cocktail of 3 drugs, so we were talking about high-intensity, intravenous 3-drug therapy as compared to oral, single-agent, targeted outpatient therapy.

Even if these would’ve been equal, I think most oncologists and experts would’ve been very excited; they were not equal, and the oral single-agent therapy was in fact showing double response rates with improvement in OS. About 32% of the patients could make it to transplant, as compared to 10% to 12% with traditional chemotherapy.

The study showed 2 things: it showed that in relapsed/refractory FLT3-AML, using traditional cytotoxic or low-intensity therapy is almost futile. You’re looking at OR rates of 20%, CR rates were 1% to 5%, and only 10% to 12% can make it to transplant, which is the only curative hope. If you use a single-agent targeted therapy, you could at least get about 30% to 35% to transplant with a much higher response rate.

Based on this, it is hoped that the quizartinib will actually be approved in the United States, in Europe, in Japan, and in other regions. We think this is just the beginning. Eventually, we hope that development will look at combinations, which we’re already doing at The University of Texas MD Anderson Cancer Center, and seeing if we significantly further improve the efficacy that you get with the single-agent, quizartinib.

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