Second-Generation FLT3 Inhibitors for Acute Myeloid Leukemia

, , , ,

Peer Exchange | <b>Acute Myeloid Leukemia: 2021 Perspectives on Testing, Systemic Therapies, and Transplantation</b>

A panel of thought leaders in AML examines single-agent and combination-based approaches using the second-generation FLT3 inhibitors gilteritinib, quizartinib, and crenolanib.

Harry Erba, MD, PhD: There are 3 second-generation drugs, or FLT3 inhibitors, being used up front with chemotherapy in randomized phase 3 studies. The study of quizartinib may be the 1 that can really address the potent and specific targeting of FLT3 compared with nothing because that study was designed before the approval of midostaurin. Patients have a randomized HDAC [high-dose cytarabine] with either quizartinib or a placebo. It will be interesting to see if we see a positive effect there and we’re expecting the survival readout of that study later this year. The other 2 studies were of gilteritinib and crenolanib in the up-front setting with chemotherapy. The comparator arm is what we would use now, midostaurin.

Dan Pollyea, MD, MS: What will we do if the quizartinib study is positive? How will we put that into clinical practice? That’s going to be difficult.

Harry Erba, MD, PhD: What I will do is call up Mark and ask him what to do. For me, it would be about the magnitude of the benefit and the toxicity and if there’s something there. We all love what we can do now with midostaurin, but let’s face it, the improvement in the survival of 4 years was from 44% to 51%, and the benefit was for patients meant to have a transplant, so I still think we have a long way to go in that regard. Mark, what would you do?

Mark Levis, MD, PhD: I’m going to be very interested in the MRD [minimal residual disease] results from that study. They actually are getting legitimate MRD. I believe a deeper remission is a good thing. I’ll be very curious to see if, in fact, there may be a big gap in survival. It’s still hard to judge between drugs, but if I see a distinct change in MRD, that—to me—is important. I want to see post-transplant survival as well. With deep remission, those patients are going to transplant. I want to see the whole spectrum of data. Obviously, the drug is only good against ITD as well, not TKD.

Courtney DiNardo, MD: I was going to make that point, and we just need to make sure there would still be a role for midostaurin for the FLT3 D835 or other TKD mutations since quizartinib is not effective against those.

Harry Erba, MD, PhD: That’s a good point. Thanks. How do you use gilteritinib in the treatment of patients with refractory relapse? When I look at the data from the ADMIRAL trial, there’s a 20% CR [complete response] rate, and then you throw in all these other CR wannabes: CRh [CR with partial hematologic recovery], CRi [CR with incomplete hematologic recovery]. God forbid there’s a morphologic leukemia-free state and you can get it up to 50%—but is that adequate, and are you starting to dabble with combinations?

Vinod Pullarkat, MD: I’ve used only gilteritinib as a single agent. For a patient who has failed initial therapy who relapses, I like to use ivosidenib-venetoclax because the response is much quicker and my goal, at that point, for patients who are transplant eligible is to take them to transplant. I’ll drop any remission and go to transplant. When using gilteritinib as a single agent, the responses are slower, so I like to use it in combination if it’s possible to do that. That would be my approach. The goal in that setting for a transplant-eligible patient would be to quickly push them to transplant.

Harry Erba, MD, PhD: Is that a combination with intensive therapy or less intensive therapies?

Vinod Pullarkat, MD: I would do less intensive therapy.

Harry Erba, MD, PhD: We do have some data there to guide us. Courtney, do you want to talk about gilteritinib and the venetoclax experience?

Courtney DiNardo, MD: Yes. I was going to make the statement—people are going to feel differently about it—that when we get drugs approved in the relapsed setting, the approval pathway is using a monotherapy and showing that it’s safe. You see responses. With gilteritinib as a single agent, absolutely we see responses, as you said, with up to 50% in the CR-like responses without full count recovery.

Then you add venetoclax to the gilteritinib—as Jessica Altman just updated us—and we’re getting responses in the 70%-to-79% range, so the context of the patient is really important. If you’re a post-transplant patient with a low level of disease coming back and you’re afraid of graph failure, gilteritinib as a single agent makes perfect sense. If I have a patient who has just failed intensive chemotherapy with a FLT3 ITD and I’m trying to get them to that first transplant, gilteritinib-venetoclax is a good combination. We have data showing that’s a very effective combination, and I’d think about it for that.

Harry Erba, MD, PhD: That’s a good point, trying to get them to transplant. Clearly, for patients with FLT3 ITD mutations who are eligible for transplant, they should go in first for remission and not be waiting for relapse. The 1 concern I have about any combination of venetoclax with gilteritinib, at least in my experience, has been the myelosuppression. What do you do? Do you drop back the venetoclax? Do you drop back the gilteritinib? It’s a great regimen to get a deep response in the transplant, but for the 80-year-old patient who just needs counts? Getting to your point, Courtney, it depends on your patient and what you want to do with them. My approach has been, for unfit patients—those whom I don’t think I am going to get to transplant—I’ll start with single-agent gilteritinib, but I admit I’ve had to add in venetoclax with or without a hypomethylating agent to get them to respond but enough to see some count recovery. I saw that patient yesterday, actually.

Vinod Pullarkat, MD: The sooner you get count recovery, the less you have complications and other issues. With single-agent gilteritinib, that’s a major drawback—the time it takes to get them into remission.

Harry Erba, MD, PhD: Another thing: we’re targeting a very late event in leukemogenesis, so of course the primary end point of the ADMIRAL trial was reached with an improvement in median survival. But none of us on the Zoom gallery here wants to be on either of those Kaplan-Meier curves that meet at less than 10% to 20% at 2 years. Those survival curves come together, so these patients clearly need something more than just a FLT3 inhibitor. More work needs to be done there. The landscape has changed recently too, with the development of gilteritinib because now many of our patients are being exposed to first-generation drugs like midostaurin or even sorafenib as part of their initial therapy. We do have some data from the ADMIRAL trial, but also a multicenter retrospective study looking at patients who received midostaurin or sorafenib with initial therapy, and then, those who relapsed received gilteritinib. The good news—I’ll point to Sasha’s [Alexander Perl] data from the ADMIRAL trial—is the overall response rate was around 50% in patients who had been exposed to midostaurin and sorafenib. That multicenter trial showed a very similar response rate in the second line. However, with each successive use of a FLT3 inhibitor—I think your group, Courtney, has published or presented data showing that the response rates are successful and FLT3 inhibitors keep going down.