Second-Generation FLT3 Inhibitors in AML

Harry Paul Erba, MD, PhD: Let’s move on to second-generation drugs. Mark, I’m going to come back to you on the development of both quizartinib and gilteritinib in this setting. And of course there’s crenolanib if we have time.

Mark J. Levis, MD, PhD: Yes. Actually the 3 drugs were coming in parallel. Quizartinib is the older 1 that was designed specifically as a FLT3 inhibitor. It had a bumpy regulatory course, but they finally emerged with this QuANTUM-R trial. Now quizartinib is a type 2 inhibitor. It does not inhibit the TKD mutations. It’s very specific for the ITD. Very potent, very selective, and for patients with relapsed or refractory FLT3 ITD AML [acute myeloid leukemia], they were randomized to receive a conventional MEK, or vicious salvage, or LoDAC [low-dose cytarabine], or quizartinib as a single agent.

Although that trial met its primary end point of overall survival, and the Japan regulatory agency thought that was fine, Europe and the United States did not. There was wringing of the hands over well QT prolongation. This drug seems very toxic, which is startling to any of us who have given it compared with MEK chemotherapy. Their point was it wasn’t a big enough improvement and that it really looked good only against LoDAC. But we can quibble over that. The simple truth is that it is an effective agent, and it is being studied in a different context as well in something called QuANTUM-First trial, which is up front. We can talk about that. But that’s quizartinib for the relapsed-refractory setting, a type 2 selective potent inhibitor.

The other 1 is gilteritinib. Gilteritinib was developed, and I like to use this analogy: The developers of gilteritinib watched all the mistakes made, and we were doing quizartinib. They just waited for us to spring all the traps and find all the screwups. Then they just marched on through very rapidly and casually developed a very good drug, which is in fact a type 1 inhibitor. Less potent but still very potent in vivo and really quite selective for the FLT3 mutation. It got approval for the relapsed-refractory setting and is now being studied up front versus midostaurin in combination with chemotherapy.

Finally, crenolanib is still back there. We’re waiting to see what’s happening with that drug. Really the focus, for practical purposes, is still on quizartinib and gilteritinib.

Transcript Edited for Clarity