The FDA has approved the small-molecule inhibitor midostaurin in combination with chemotherapy to treat acute myeloid leukemia. It is the first approved drug for the disease that specifically targets FLT3 mutations, which occur in about a quarter of all AML cases and are associated with particularly poor outcomes.
The FDA has approved the small-molecule inhibitor midostaurin (Rydapt; Novartis) in combination with chemotherapy to treat acute myeloid leukemia (AML), making it the only new treatment for AML in more than two decades. Midostaurin is the first drug that specifically targets AML harboring FLT3 mutations, which occur in about a quarter of all cases and are associated with particularly poor outcomes.
The approval was based on data from the phase III RATIFY trial, in which 717 previously untreated adult patients with FLT3 mutation–positive AML were given either midostaurin or standard chemotherapy during the induction and consolidation phases of treatment. Those in the midostaurin group had a 23% reduced risk of death (25% among those who received stem cell transplants) compared with the control arm, and significantly longer median overall survival (74.7 vs. 26.0 months). The findings were presented at the American Society of Hematology meeting in December.
The FDA also approved a companion diagnostic, LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies), to help identify patients most likely to benefit from treatment. In addition to AML, midostaurin was approved to treat the rare blood disorder aggressive systemic mastocytosis with mutations in KIT, based on findings from a phase II trial.
“Patients with FLT3 mutations typically have a more aggressive form of the disease and much worse survival rates than other AML patients,” says Soheil Meshinchi, MD, PhD, a pediatric oncologist at the Fred Hutchinson Cancer Research Center in Seattle, WA. “We've known this since the late 1990s, but until recently, we have not had an effective way of targeting this gene.”
FLT3 mutations can be classified into two major types: internal tandem duplication (ITD) and tyrosine kinase domain mutations, says Meshinchi. Notably, midostaurin targets both types of mutations, whereas other FLT3 inhibitors, such as sorafenib (Nexavar; Onyx Pharmaceuticals)—which is approved for kidney cancer—target only FLT3-ITD mutations.
The trial leading to midostaurin's approval should be interpreted with some caution, notes hematologist-oncologist Derek Stirewalt, MD, who is also affiliated with Fred Hutchinson and specializes in treating leukemia. Many patients underwent stem cell transplantation, and it remains to be determined whether adding midostaurin will lead to many more patients with FLT3-ITD mutations being “cured” without a transplant.
“Nevertheless, this approval suggests that the FDA is willing to move toward more targeted approaches to treating AML,” he says. “It has the potential to significantly improve how we treat a subpopulation of patients with this devastating disease.” –Janet Colwell