Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 9

Sequencing of FLT3 Inhibitors in AML

February 8, 2021
Harry P. Erba, MD, PhD, Duke University School of Medicine

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Alexander E. Perl, MD, University of Pennsylvania

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Eunice Wang, MD, Roswell Park Comprehensive Cancer Center

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Adam Bagg, MD, University of Pennsylvania

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Corey S. Cutler, MD, MPH, FRCPC, Dana-Farber Cancer Institute

Harry P. Erba, MD, PhD: Before we get to the combination, let’s talk about sequencing because we now have more data looking at sequential use of FLT3 inhibitors or a second-generation drug like gilteritinib following the first-generation drugs, midostaurin/sorafenib. I know you presented on this, Sasha, at the 2020 ASH [American Society of Hematology] Annual Meeting. Do you want to summarize some of that data?

Alexander E. Perl, MD, MS: I presented data that came from the ADMIRAL study and the CHRYSALIS study for the phase 1/2/3 development of gilteritinib, recognizing that the phase 1/2 study was designed for anyone with relapsed and refractory disease, the vast majority of whom were FLT3 mutated, but it did not have any restrictions in terms of prior therapy. About a quarter of the patients on that study had a prior FLT3 inhibitor. By the time gilteritinib was brought to the phase 3 setting, midostaurin was approved in many places, and sorafenib was commonly used post-transplant, so there were patients who were treated with these drugs, but you could not have had prior salvage therapy when you went on the ADMIRAL study. In general, there were relatively few people who had had a prior FLT3 inhibitor based on when the study enrolled. Only 12% of patients in the ADMIRAL trial had a prior FLT3 inhibitor, and the question comes up: should we be giving gilteritinib in somebody who has progressed after a regimen containing midostaurin with sorafenib now that these are commonly used in frontline therapy, either with induction and consolidation or post-transplant.

We did not have a lot of data to guide that from what we got out of the ADMIRAL trial, so we pooled the analysis of those 2 studies, the phase 1/2 CHRYSALIS trial and the phase 3 ADMIRAL trial, among the patients treated who had had prior FLT3 inhibitor, either midostaurin or sorafenib. We then looked at the outcomes of patients who had not had that on both of the arms for the ADMIRAL study—because there was a chemotherapy arm—what we basically found was this: the response rates to gilteritinib were still quite robust if you had prior midostaurin or sorafenib without much of a difference between the 2 of them. There was not a finding of pan-resistance if you had progressed after prior therapy. The response rates were a bit lower, more like about 40% composite CR [complete response] rate rather than 50%, but both of these were certainly better than the chemotherapy arm comparator. Even when we did a statistical comparison of the survival of those treated with gilteritinib on the gilteritinib TKI [tyrosine kinase inhibitor] arm vs the placebo arm, that was still highly statistically significantly better.

We can at least say that, when we looked at patients who had had prior FLT3 inhibitor midostaurin or sorafenib, responses were fairly comparable, and survival may be a bit lower than that seen in patients who had not had a prior FLT3 inhibitor, but it is still superior to alternatives. I would not recommend anything other than what you would ordinarily do for these patients: Use the data that say that gilteritinib is a superior option than salvage chemotherapy. It does not change the directive to use gilteritinib as the preferred salvage agent in patients with relapsed and refractory disease.

Harry P. Erba, MD, PhD: At this year’s meeting, Keith Pratz from your institution, the University of Pennsylvania Perelman School of Medicine, presented data from the phase 1b study of gilteritinib in combination with standard intensive chemotherapy, 7+3 and high-dose cytarabine, with a high response rate of 80%. It was basically a study that was large enough to say that this can be done safely.

What we are getting at here is sequencing. Should we start with a first-generation or a second-generation drug, first? We do not know. The PrECOG study that is being led by Selina Luger and Keith Pratz as well will be looking at intensive chemotherapy with either midostaurin or with gilteritinib in previously untreated patients with FLT3 mutations. We have to wait for the results of that type of trial. A similar study with crenolanib vs midostaurin is also ongoing at this point. We await the results of those studies that look at the benefit of a type of a second-generation drug in combination with chemotherapy vs the first-generation drugs.

Transcript Edited for Clarity