Midostaurin in FLT3-Mutated AML: Results of the RATIFY Trial

Richard Stone, MD

As part of our coverage of the 57th Annual American Society of Hematology (ASH) Meeting and Exposition held December 5–8 in Orlando, Florida, we are speaking with Richard Stone, MD, director of the adult leukemia program at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School in Boston. Dr. Stone presented results of the Cancer and Leukemia Group B (CALGB) 10603 RATIFY trial of midostaurin for acute myeloid leukemia, or AML.

Cancer Network:The trial tested the efficacy of midostaurin in patients with FLT3-mutated AML. Dr. Stone, are there distinct characteristics of FLT3-mutated AML? What is the frequency of this mutation among patients?

Dr. Stone: AML is a heterogeneous disease, which means it varies both biologically and according to the type of patients that get it. FLT3-mutated AML can occur at any age but is a bit more common in younger adults. Having a mutation in this transmembrane tyrosine kinase occurs in about 30% to 35% of all AML patients. A distinct characteristic of patients with FLT3-mutant AML is that most of them have an adverse prognosis compared with those without a FLT3 mutation. I say “most” because there are two subtypes of FLT3-mutant AML: One is an internal tandem duplication, or ITD, which accounts for about three-quarters of those with a FLT3 mutation and does have an adverse prognosis due to a high relapse rate. And the other one-quarter of those with mutations-about 5% to 10% of all AML patients-have a point mutation in the tyrosine kinase domain of this particular enzyme.

Both of these types of mutations in the test tube cause growth of leukemic cell lines transfected with [the mutations] and don’t require binding of the cognate ligand for activity, and can also create a myeloproliferative disease in mice. These mutations are relatively common and relevant pathophysiologically, and, as I mentioned, the most common subtype of the mutations confers an adverse prognosis.

Cancer Network:Could you tell us about the design of the phase III RATIFY trial?

Dr. Stone: Sure. The design of the RATIFY trial was based on the desire to deal with this unmet need in AML treatment, mainly that patients with FLT3-mutated AML generally don’t do well. Since the pathophysiological abnormality is a gain of function in this mutated enzyme, it was thought that we could inhibit the function of this activated, mutated enzyme with the small molecule midostaurin. It was known from preclinical and early clinical studies that midostaurin can inhibit the activity of the FLT3 enzyme, both the ITD and the point mutation subtypes. The experimental models that generate FLT3-mutant AML can be inhibited by the drug as a single agent. By the same token, we knew that giving the drug as a single agent in those with advanced AML caused reductions in the leukemic burden but didn’t cause disease-remitting activity. So, it is biologically active but not sufficiently clinically active as a single agent.

We also knew that combining the drug with chemotherapy worked in a test tube, and we also did a clinical trial in which we combined the drug with standard induction and post-remission chemotherapy for AML patients and showed that it can be given safely at a dose of 15 mg orally twice a day. That generated the design of the trial, which was a multi-national, prospective, placebo-controlled, double-blind trial in which we randomly assigned half the patients to standard chemotherapy in the induction and post-remission settings given with a placebo and the other half to standard chemotherapy in the induction and post-remission settings with the active agent midostaurin. Additionally, patients received midostaurin for 12 months after they finished all of their chemotherapy or placebo according to their initial randomization.

In summary, it was a simple trial design of standard therapy with placebo or with midostaurin, and the design of the trial indicated that the primary endpoint would be overall survival, uncensored for transplant, which means that we looked at patients from the start of enrollment onto the study until death or the last available data point, regardless of what other therapies the patient may have received. The study would have met its primary endpoint if therapy reduced the risk of dying by at least 22%, with a hazard ratio of 0.78.

Cancer Network:What were the major results of the study?

Dr. Stone: The most important result of the study was that indeed the primary endpoint of the study was met. The risk of dying if you were randomized to the midostaurin arm was 23% less than if you were randomized to the placebo arm, and this was very significant on a P-value test. We did reduce the death rate and improved the 4-year survival rate. We improved the median survival and also event-free survival, with events being either no remission, relapse, or death, whichever occurred first. We improved disease-free survival and we did this regardless of whether patients had transplants or not, although the effect of midostaurin seemed to be greatest if the patient had a transplant at first remission rather than waiting until they relapsed or had a transplant beyond the first remission.

Cancer Network:What have we learned about midostaurin and FLT3-targeted agents from this and other trials in AML?

Dr. Stone: I think that this trial is unique. It is the only trial done with a FLT3 agent in the upfront setting that was a randomized trial. This agent doesn’t just inhibit FLT3; it’s a multitargeted inhibitor and inhibits FLT3, PDGFR, c-KIT, VEGFR, and protein kinase C, so if there is a beneficial effect, which there seems to be, it may be due to something that is not just FLT3 inhibition. This drug has not been tested in this context in wild-type patients. It does tell us one specific thing: that adding this drug for patients with this leukemia who are getting standard chemotherapy between ages 18 and 60 was a benefit.

Now, it doesn’t tell us whether it should be used in the relapsed setting with or without chemotherapy and it doesn’t tell us if it should be used in the frontline setting in patients that don’t have a FLT3 mutation but who could potentially benefit from it. It doesn’t tell us anything about other FLT3 inhibitors, except that it’s a fertile ground for more study. Certainly, one would expect that addition of a FLT3 inhibitor to chemotherapy would be better than chemotherapy alone, but every FLT3 inhibitor is different and we have to carefully watch the study design and particularly the patient subgroup that is under assessment in a given trial.

Cancer Network:Thank you so much for joining us today, Dr. Stone.

Dr. Stone: Thank you.