Putting this trial into context, Mark J. Levis, MD, of the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, said: “Six different FLT3 inhibitors have advanced into phase III trials. Midostaurin in the only one that has made it to the ‘station.’”

“The fact that midostaurin is multitargeted limits its in vivo potency against the FLT3 target and causes off-target effects, but the drug is active against both the internal tandem duplication and TKD-FLT3 mutations,” he continued.

Knowing that AML is a polyclonal disease, it makes sense that multitargeted agents would have better effects in newly diagnosed patients, such as the patient population of the ­RATIFY trial, he continued.

“It has taken RATIFY almost a decade from conception to results. We have had no new drugs for AML for many years, and we lost one—Mylotarg [gemtuzumab ozogamicin]. While we waited for this trial to accrue, allogeneic transplant has become a favored approach. Now it is time to ask whether overall survival is the best endpoint for clinical trials that are so time-consuming. Another endpoint might be more suitable, given the time it took to accrue patients to RATIFY,” Dr. Levis commented.

Future Directions

“It was a monumental accomplishment to design and complete an intergroup study involving multiple countries and nine different laboratories,” said Mark Litzow, MD, Professor, Mayo Clinic, Rochester, Minnesota, and Chair of the ECOG-ACRIN Cancer Research Group Leukemia Committee, which is planning the next generation of FLT3 AML studies.

Dr. Litzow was optimistic about midostaurin and its role in treating FLT3 AML. “The data looked like the drug was of most benefit to the patients with FLT3-TKD mutations but did also benefit patients with FLT3-ITD mutations.”

“The study does have the potential to be practice-changing, and midostaurin should be considered as part of the control arm of future studies. ECOG-ACRIN is now discussing the design of future trials,” said Dr. Litzow. “A major question now is to see how other FLT3 inhibitors stack up as compared with midostaurin.” ■

Disclosure: Drs. Levis and Litzow reported no potential conflicts of interest.