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Novel Targeted Therapies on Horizon in AML

Greg Kennelty
Published Online:9:25 PM, Mon April 11, 2016
Multiple targeted therapies have shown promising signs of efficacy for patients with acute myeloid leukemia (AML), including the FLT3 inhibitor midostaurin and novel IDH inhibitors, with the ongoing potential for combination strategies in the future, according to Eytan M. Stein, MD.
In February 2016, the FDA has granted midostaurin a breakthrough therapy designation as a potential treatment for adult patients with newly diagnosed FLT3-mutated AML. This designation was based on the phase III RATIFY study, in which the addition of midostaurin to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone. Findings from this study are currently being discussed with the FDA for a potential approval.
In addition to midostaurin, other novel agents are in development. On March 30, 2016, a phase I/II study was initiated to explore the IDH inhibitors AG-221 or AG-120 in combination with azacitidine for patients with newly diagnosed IDH-mutant AML. These agents have each shown promising signs of efficacy in early phase studies.
In an interview with Targeted Oncology, Stein, hematologist/oncologist, Memorial Sloan Kettering Cancer Center, discussed the possibilities of combining midostaurin with similar agents along with exciting clinical trials that have the potential to alter the standard of care for patients with AML.
TARGETED ONCOLOGY: Where is the treatment paradigm currently for AML?
STEIN: We're very excited about our ability to now think about how to target specific biological pathways. In the past we've been giving induction chemotherapy and consolidation chemotherapy, which is relatively non-specific. Although it does an all right job at getting rid of leukemia initially, many patients will relapse.
We're excited that we now have the ability, number one to identify mutations that we think may be driving acute myeloid leukemia, and number two that there are now drugs that are coming into the clinic that can target those biological mutations and they actually improve overall survival. One of the most exciting things that has happened in the past 6 months is this big phase III trial of a drug called midostaurin, which is an inhibitor of FLT3, in combination with chemotherapy versus chemotherapy alone.
What that trial shows is that there is a survival advantage for giving midostaurin, the FLT3 inhibitor, with combination chemotherapy. The overall survival advantage is about 7% at 5 years, and that's really exciting because it's proof of principle that we can target a biological pathway and it will lead to an overall survival advantage.
TARGETED ONCOLOGY: Is there any possibility of combining agents like midostaurin?
STEIN: We're very excited about that kind of work. As you can imagine, all patients with AML have a multitude of mutations that are causing their disease. One of the things we think needs to happen is that it's not enough just to target FLT3 or just enough to target IDH. You really need to target the whole panel of mutations that are causing the disease. Speaking to that, we are interested in developing a clinical study where we combine IDH inhibitors with FLT3 inhibitors, and there are a variety of other combinations that one could consider doing.
That's probably the future of AML therapy – not only combining the inhibitors together, but also combining them with our current standard of care, which although it's not great, does have a response rate and does cure some people. So our goal would be to combine all these things together to make the cure rate higher.
TARGETED ONCOLOGY: Are there particular studies investigating this?
STEIN: There are a lot of studies that are really interesting. There are phase I trials of a variety of inhibitors that people can find on ClinicalTrials.gov, but the ones I'm most interested in are the ones which are now taking these targeted therapies and moving them to the upfront setting.
An example of that is there's now a clinical study of an IDH1 inhibitor or an IDH2 inhibitor in combination with induction chemotherapy. There's also a clinical study of an IDH1 inhibitor or an IDH2 inhibitor in combination with a hypomethylating agents for older patients who might not be candidates for induction chemotherapy. There are a variety of new FLT3 inhibitors that are going to be tested, both in the relapsed/refractory setting and in the upfront setting, and those include crenolanib and ASP2215. Those are all agents I'm really excited about.
Another agent I didn't talk about that I'm excited about is this antibody-based therapy, this anti–CD33 conjugate called SGN-CD33A. That's something that has already been combined with hypomethylating agents and showed a fairly robust overall response rate of about 65% at the earliest look at the clinical data.

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