Pan-Kinase Inhibition Key to Midostaurin Benefit in AML

Mark Levis, MD, PhD

FLT3 targeted agents are emerging in the treatment of acute myeloid leukemia (AML), and which specific agent will be most effective is highly dependent on whether a patient has been previously treated, said Mark Levis, MD, PhD.

“FLT3 should probably be used throughout every component of the patient’s treatment,” said Levis, associate professor at Johns Hopkins Medical Center. “You will have totally different outcomes from treatment depending on if they are newly diagnosed versus relapsed.”

Levis highlighted the role of the FLT3 targeted-agent midostaurin (PKC412) in newly diagnosed AML patients as part of a focus group held at the European Congress on Hematology: Focus on Lymphoid Malignancies, an event hosted by Physicians' Education Resource (PER) in Paris, France, from November 4 to 5, 2016.

During the discussion, Levis noted that midostaurin may be the best option for newly diagnosed FLT3-positive AML patients because it is a pan-kinase agent that inhibits FLT3 as well as other targets. More selective inhibitors like quizartinib, may not have the same benefit in this patient population, he said.

“I’d like to see what happens if a selective inhibitor like quizartinib is approved and someone pulls that drug out for a newly diagnosed older FLT3 patient that has FLT3 disease and decides to give it to them alone,” said Levis. “I would predict that it won’t work, it will slow down a few of the cells, but it won’t bother most of the disease. However, at relapse, which is where all the trials are, molecularly the cells are different and you can kill them in-vitro with a single agent—just about any FLT3 inhibitor you want. There is this evolution between diagnosis and relapse.”

During the discussion, Levis described his experience examining a selective agent like quizartinib in the lab with cells from diagnosis and cells from relapse. In doing this, he could kill off the relapsed cells in culture. However, the diagnostic cells were unfazed. When he did the same using a pan-kinase inhibitor, he could kill off the diagnostic cells. His conclusion was the pan-kinase is hitting multiple targets, which may suggest midostaurin would work better in the newly diagnosed FLT3 patient.

The FDA granted a priority review to a new drug application (NDA) for midostaurin for adult patients with newly diagnosed FLT3-mutated AML in November 2016. The NDA was based on the phase III RATIFY trial, which found that the addition of midostaurin 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 benefit with midostaurin remained steady at 25%. The survival curve in the RATIFY trial suggests a benefit seen early in treatment, within the first month, with midostaurin, said Levis.

“What was striking to me about the RATIFY trial was that patients that got midostaurin and then went to allotransplant in remission clearly did better, and as a transplanter, I’ve learned that the single most important thing is that depth of remission going into transplant,” he said. “The curve from the RATIFY trial tells me that the midostaurin-treated patients were in deeper remissions.”

Levis believes these remissions were mainly due to pan-kinase inhibition early on with midostaurin, not just FLT3 inhibition.

“Midostaurin is a relatively poor FLT3 inhibitor compared to some others, but as a pan-kinase inhibition it is best during that first month of therapy, and the event-free survival curves really separate early on during those first months of therapy. So I would argue that the main benefit is hitting during that first month of treatment.”

Analysis has shown that by day 15 of treatment with midostaurin, even in the best of circumstances, there is only partial FLT3 inhibition, said Levis.

“The main benefit of midostaurin is pan-kinase inhibition early on,” said Levis. “It can cause deep remissions, and better survival, particularly for those patients that were transplanted in CR1.”