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

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.

Can you also discuss the QuANTUM-First study, and whether it has been impacted by the recent ODAC vote?

The QuANTUM-First study is a study that is looking at frontline, newly diagnosed, FLT3-AML. This study is trying to see whether the addition of quizartinib to standard induction therapy, which was selected to be 3 plus 7, improves the OS, event-free survival (EFS), and hopefully remission rates.

This is a large, multinational study that is open at about 100-plus centers across the world. We plan to look at about 500 patients who will be randomized in a blind fashion to receive standard induction therapy of 3 plus 7, or induction with quizartinib added on.

In general, QuANTUM-First is enrolling very, very well. There was concern about a year ago that the enrollment [would slow] because of the approval of midostaurin in the frontline FLT3 space. Enrollment has not only kept pace with what was anticipated, but is also about 10% to 20% ahead of schedule. At this time, almost 90% of the enrollment is complete.

We do not think there’s going to be any direct impact of the ODAC vote at this time; QuANTUM-First is moving ahead of schedule, and we hope that that data will also become available next year. That’s a very important data set, because it’s the first time we’re using a second-generation FLT3 inhibitor in combination with induction chemotherapy and have those results.

Can you discuss the efficacy and the potency of quizartinib?

Among the FLT3 inhibitors, the way we think of them are as first-generation drugs which were the ones that entered clinical development about 15 years ago. These included drugs like lestaurtinib, midostaurin, sorafenib (Nexavar), sunitinib (Sutent)—a lot of these are what we call repurposed FLT3 inhibitors. These were not developed as FLT3 inhibitors. They were developed to target other pathways, and later, it was found that they are multikinase inhibitors, and the kinases they inhibit include FLT3. They were tried in FLT3-AML when we started realizing that FLT3 was associated with adverse prognosis.

Then, there was a second generation of FLT3 inhibitors. These include quizartinib, which was the first among the second generation, gilteritinib (Xospata), and crenolanib. Gilteritinib and quizartinib were specifically designed to be FLT3 inhibitors. So these were not repurposed drugs; they did have other targets, but the main key is they were developed to be very potent inhibitors FLT3.

When you look at the single-agent studies of the first-generation FLT3 inhibitors like sorafenib or midostaurin, you see the response rate is about 5% to 10% as a single agent in relapsed/refractory AML. Very modest or negligible response. The only way these drugs work is if you combine them, either with azacitidine or induction [therapy].

But when you look at the second generation, both quizartinib and gilteritinib, you see that the marrow remission rates are almost 50%. This is 10 times higher than you would get with sorafenib or midostaurin. These are very potent as single agents in clearing out the marrow, killing the leukemiablasts, and giving patients an opportunity to go to transplant.

Whichever assay you do, if you look at just the potency of inhibiting FLT3, quizartinib is by far the most potent. Gilteritinib is probably the second most potent.

One of the things, though, with quizartinib is that although it works extremely well in the ITD mutation, it does not cover the D835 mutation, which is potentially one of the mechanisms of escape. That’s the difference: gilteritinib may not be as potent per se, but it does cover the D835.

In AML, I absolutely believe that the availability of 2 or 3 or 4 second-generation FLT3 inhibitors will be a great bonus to patients. If we can sequentially treat patients with second-generation FLT3 inhibitors, ideally in combination, we could then dramatically improve survival.

Can you address the unmet need in the FLT3-ITD—mutated patient population?

We still have a number of patients who are relapsed and refractory. At this time, we do have gilteritinib, which is a great improvement compared with chemotherapy, which has 10% to 20% response rates and very few true CRs.

If you look at the long-term outcome with gilteritinib, even if [patients] go to transplant or no transplant, at 2 years, only about 10% to 15% are still alive. We still have a huge unmet need, where 80% to 85% of patients will still need subsequent therapy.

As single agents, these drugs are good at achieving marrow remission, but durations are short, and the curative potential is low. We think a lot of these drugs will require combination. We feel there’s a lot of room for gilteritinib, quizartinib, potentially even drugs like crenolanib.

Can you discuss the recent ODAC vote on quizartinib and share your thoughts on getting this drug into the treatment paradigm?

The recent ODAC vote was based on the FDA’s review of the QuANTUM-R study. The study’s primary endpoint is OS, and this primary endpoint was met, with quizartinib showing an improvement in OS at 6.5 months versus 5 months with traditional chemotherapy. More importantly, key secondary endpoints, which were remission, CR, and CRi were also met, with quizartinib showing about a 50% CR/CRi compared with 27% with traditional chemotherapy.

When we saw this data, we were impressed that the phase II data that we saw with quizartinib were actually replicated in the phase III, which almost never happens. We almost always see that the phase II study is done in 8 or 9 major academic centers that usually have a better expertise of management, and response rates and outcomes are better, and you get a little bit of drop out when you go to 120 centers that may not be as proficient or see as much volume of [patients with] leukemia.

Here, actually, the response rate, the OS, the EFS in phase I, phase II, and phase III were almost exactly the same over 8 years of development. This is a very good, consistent signal.

In the ODAC vote, there was a lot of discussion about therapeutic equipoise and whether there was a clear signal of benefit. I think that, in most drugs in oncology, we rarely have that clear signal where we can absolutely say that a drug is superior, because we all know that when we [conduct] clinical trials, there are inherent biases and issues.

One of the key concerns in the ODAC vote was the number of patients who were randomized into the investigator therapy arm but did not get treatment. This is something that is impossible to control because of the pace of development.

For example, we [were aware] of many patients who were seen at smaller centers who were randomized, but once it was found out that they would be going on the standard chemotherapy arm, they asked their physician, “What would you do if you were a patient?” Most of the physicians said, “we would do a FLT3 inhibitor.” We actually got a lot of these referrals for patients who decided, after knowing that they would not get quizartinib, that they wanted to go off trial.

The other issue [cited] in the ODAC [review] was about the cardiac signal, QT/QTc. Luckily, both the ODAC cardiologist and the cardiologist from the sponsor found that there were no clinically significant cardiac concerns.

In general, when you look at the ODAC reading, we feel that a lot of the things that people were concerned about were actually found not to be major issues. I think it’s a bit of a surprise that we did not get a positive vote. The FDA still has time to deliberate on this, and a lot of the experts in the community are trying to analyze the data and find the subsets that have the best efficacy.

While QuANTUM-First is ongoing, one of the hopes is that, at least for these subsets where we have a very clear benefit and high impact, we’d be able to try and get [quizartinib] approved. More analysis and more data collection from QuANTUM-R and QuANTUM-First could further support this.

Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681-3687. doi: 10.1200/JCO.2013.48.8783.