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Lead Researcher Discusses Midostaurin in AML

Shannon Connelly
Published: Friday, May 05, 2017

Richard M. Stone, MD

Richard M. Stone, MD

The recent FDA approval of midostaurin (Rydapt) has excited the field of acute myeloid leukemia (AML). Midostaurin was granted approval for the treatment of adult patients with newly diagnosed FT3-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

This approval was based on the results of the phase III RATIFY trial (CALGB 10603), which reported that midostaurin, in addition to standard chemotherapy, reduced the risk of death by 23% compared with chemotherapy alone in patients with AML who harbored a FLT3 mutation. After censoring for patients who received stem cell transplants, the overall survival (OS) benefit with midostaurin remained steady at 25%.

The median OS was 74.7 months with midostaurin versus 25.6 months with chemotherapy alone (HR, 0.77; 95% CI, 0.63-0.95; P = .016). The 5-year OS rate for patients in the midostaurin arm was 50.9% versus 43.9% in the chemotherapy-alone cohort.

Although midostaurin has the ability to improve the cure rate of this disease, it will not benefit all patients with AML, says Richard M. Stone, MD, the lead author on the RATIFY trial.

In an interview with OncLive, Stone, director of the Adult Leukemia Program, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School, discussed the impact that midostaurin could have for patients with AML, as well as ongoing research with the agent.  

OncLive: What impact do you see midostaurin making in the AML community?

Stone: AML is a devastating disease that affects about 15,000 people in the United States annually. Unfortunately, about 40% to 50% of the people who get this disease die of it. It is particularly difficult in older adults who get this disease, and the median age is about 68 to 70, so it is a disease of older adults. But, young people do get it as well. Even in young people, a lot of patients die of it.

We have not really done much to change or improve the care of people between the ages of 18 and 60 who have AML, and we have done even less, frankly, for those with AML who are over the age of 60 over the last few years. We are desperately looking for drugs to improve the outcome. There have not been any drug approvals for AML in several decades, so any new drug in AML that is going to improve the cure rate is going to be heralded with some degree of excitement.

With midostaurin, when added to chemotherapy, one has a better outcome in the long run, and in the short run, for that matter, than if one added placebo to chemotherapy. That is why we are excited about this. I wish I could say that we cured everybody who was eligible to get midostaurin by adding it to chemotherapy. That is not the case, but it is an advance compared to chemotherapy alone for people with FLT3-mutant AML.  

What benefit was seen with midostaurin in the phase III RATIFY clinical trial?

This trial had a simple design with the control group getting standard induction chemotherapy, which was daunorubicin and cytarabine, and if those individuals achieved remission, they got standard high-dose post-remission therapy.

The experimental arm got the same chemotherapy, but instead of placebo being added to it, which was the case in the control arm, they got midostaurin at a dose of 50 mg twice daily orally given on days 8 through 22, which is 14 days after the chemotherapy completed. They got the midostaurin during induction during each of the post-remission courses, and there was also randomization to placebo or midostaurin for 12 months after the chemotherapy was concluded. It was not a re-randomization—the people who got midostaurin got it all along.

With any trial, the important thing to think about is what is the endpoint, so what was the most important finding we were looking for, because that primary endpoint determines the number of patients that had to be enrolled on the trial. The primary endpoint we chose was overall survival—would more people on midostaurin plus chemotherapy survive than people who had chemotherapy plus placebo.

The trial was based on seeing a risk reduction of at least 22% in the risk of dying for those randomized to midostaurin plus chemotherapy versus placebo plus chemotherapy. The trial met its primary endpoint, meaning that indeed the risk of dying was lower by about 24% if you were randomized to midostaurin than if you were randomized to placebo. It took 714 patients to see that difference.


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