Expert Highlights FLT3 Inhibitors in AML

Mary-Beth Percival, MD

With FLT3 Inhibitors and other emerging agents, Mary-Beth Percival, MD, says it is an exciting time for investigators seeking to improve outcomes for patients with acute myeloid leukemia (AML).

“There have been a lot of new drugs approved in the past year-and-a-half,” said Percival. “They come with some caveats, because we don't have a lot of information that we still need to gain from clinical trials with more patients. [We need] to figure out if some of the drugs that have been approved in the relapsed/refractory setting can be moved into the upfront setting, and whether some of them should be combined with chemotherapy or not, but it's an exciting time in AML right now.”

The FDA approved the FLT3 inhibitor midostaurin (Rydapt) in April 2017 for the treatment of adults with newly diagnosed FLT3-positive AML. The indication is specifically for use in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

The approval was based on the phase III RATIFY (CALGB 10603) trial, which showed that the addition of midostaurin to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone in patients who harbor FLT3 mutations. After censoring for those who received stem cell transplants, the overall survival (OS) benefit with midostaurin remained stable at 25%.

Newer FLT3 inhibitors are also moving through the pipeline. In May 2018, the FDA granted a priority review designation to a new drug application for gilteritinib for the treatment of adult patients with FLT3 mutation—positive relapsed or refractory AML. Additionally, the FDA granted a breakthrough therapy designation to the FLT3 inhibitor quizartinib in August 2018 for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive AML.

OncLive: What novel therapies in AML are you interested in right now?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Percival, an assistant professor of medicine at the University of Washington and assistant member in the Clinical Research Division with Fred Hutchinson Cancer Research Center, discussed the ongoing development of FLT3 inhibitors and other current research in patients with AML.Percival: The most significant therapy is the FLT3 inhibitors. The only one that's approved right now for the treatment of AML is midostaurin. It's a poster child for the treatment of patients with AML because it was evaluated in a very large randomized study with more than 700 patients and they had to screen more than 3000. It was a true labor to get the study underway, and then to show a 10% survival advantage is huge. It's also paved the way for other FLT3 inhibitors. There is a lot of interest in some of the second-generation inhibitors that are more potent and selective, such as gilteritinib and quizartinib. How those are going to end up comparing with midostaurin and whether they'll be used in slightly different settings remains to be seen.

What toxicities are associated with FLT3 inhibitors?

It's also interesting to think about whether there's application outside of FLT3-positive disease. For example, midostaurin is being studied in a trial right now for patients who don't have FLT3 mutations. It is one of the arms for a new study of older patients with AML. There may be beneficial effects with FLT3 inhibitors, even in patients without FLT3 mutations.That's a huge issue because we know that there can be off-target effects or toxicities that we need to manage. For midostaurin, it seems like it's primarily mild cytopenias in patients who achieve a remission and go on to the maintenance phase. Also, there is rash in the early phase. It's sometimes hard to tease out whether that's related to chemotherapy or to midostaurin, but it was an increased rate in that arm of patients that received midostaurin [in the RATIFY trial], so I think that is a real effect.

There is potentially gastrointestinal toxicity as well. Many patients have said midostaurin does not smell good, they do not like taking it, and it's much better tolerated with food. That is something to watch out for.

What do you expect to learn from the results of the QUANTUM-R trial?

What are you working on currently?

The different tyrosine kinase inhibitors have nonoverlapping toxicities. For quizartinib, there is been a lot of focus on cardiac toxicity, particularly with the Corrected QT interval. The toxicities may change with the different drugs.We will get more information from the QUANTUM-R study. There are still some questions about what to do with some of the relapsed/refractory patients. Are we going to use quizartinib as a bridge to allogeneic transplant or something else that might be curative? Right now, while there is definitely an improvement in OS, it's not leading to cure as a single agent. That's our goal, even with our relapsed patients.An area that needs a lot of work is measurable residual disease (MRD). We know that it's clinically and prognostically important and that our current therapies really fail patients. Standard chemotherapy doesn't seem to be effective at getting rid of MRD, and allogeneic transplant is not effective in all patients, and we don't seem to have a good way to predict which patients are going to benefit. I am working on opening a trial with single-agent gemtuzumab ozogamicin in patients with MRD to see if it's able to eradicate MRD. That should open in the next few months. We're really excited to see whether there is a benefit for that clinical population.

Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Eng J Med. 2017;377:454-464. doi: 10.1056/NEJMoa1614359.