New FLT3 Inhibitor Improves Responses in Relapsed AML

An inhibitor of FLT3 known as ASP2215 showed good clinical activity in FLT3-mutated patients with relapsed or refractory acute myeloid leukemia (AML) in a phase I/II trial (abstract 7003) presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting held May 29 to June 2 in Chicago.

“We’ve been studying FLT3 inhibitors for a number of years and we think they show significant clinical promise,” said Mark J. Levis, MD, PhD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore. Previous drugs in this class have had problems, often related to the emergence of tyrosine kinase inhibitor domain mutations that confer resistance. ASP2215 has activity against those mutations.

The new trial was a dose-escalation cohort study; every dose from 20 mg up to 450 mg that showed in vivo FLT inhibition or in which a patient had a clinical response was expanded to include more patients; this occurred in every dose level group, but the 120-mg and 200-mg cohorts were expanded further.

In total, the study enrolled 198 patients, 194 of whom were evaluable for this analysis; 81.4% were white and 53.1% were male, with an average age of about 62 years. Most of the patients-65.5%-were FLT3 mutation–positive. Levis said that at 80 mg and above, effective inhibition of FLT3 was evident.

There were no unexpected safety signals, or adverse events that were unique to this drug, Levis said. The most common serious adverse events were febrile neutropenia (27.3%) and sepsis (11.9%), which are frequently seen in AML. “It is very well tolerated, the patients really don’t complain of side effects in a significant fashion,” Levis said.

As dose levels rose, the responses seen in the trial shifted from more partial responses to more complete remissions with incomplete hematologic recovery (CRi). In the 120-mg dose group (40 patients), 40% had a CRi, 2.5% had a complete remission with incomplete platelet recovery (CRp), 7.5% had a complete response (CR), and 7.5% had a partial response (PR). In the 200-mg group (45 patients), these rates were 42% for CRi, 4.4% for CRp, 4.4% for CR, and 6.7% for PR.

The duration of response, Levis said, “really stood out.” It was over 4 months, which was not seen with other FLT3 inhibitors. That was likely due to ASP2215’s activity against the point mutations.

FLT3–wild-type patients generally did not respond to the drug, while FLT3 mutation–positive patients did. In mutated patients, the overall response rate in all dose cohorts was 52.0%, compared with only 8.8% in the wild-type patients.

Lloyd Earl Damon, MD, of the University of California, San Francisco, the discussant for the session, said that this agent does represent an advance over prior FLT3 inhibitors and it “might result in a low resistance and low relapse rate. This might pave the way for more efficient bridging to stem cell transplant.”