Global Perspectives: FLT3 Inhibitors for AML - Episode 6
Naval G. Daver, MD: The RATIFY study was a large, phase III, multinational cooperative group—led study. The primary goal was to see if the overall survival was improved when we added an FLT3 inhibitor, namely midostaurin, to standard induction, which was 3+7, in patients with newly diagnosed FLT3 ITD [internal tandem duplication] or FLT3 D835-mutated AML. The study enrolled a total of 750 patients in about 100 sites, taking about 8 to 9 years to complete because 3500 patients had to be screened to find 700 FLT3-mutated patients, since the incidence is only in about 25% to 30%.
The study results were released about 1.5 years ago, and showed that the study did meet the primary endpoint where the addition of midostaurin to 3+7 in FLT3 ITD-mutated as well as FLT3 D835-mutated patients was associated with improved overall survival and was associated with an improved response rate when all responses were observed together. Based on this, the FDA approved midostaurin to be used in combination with 3+7 induction in all newly diagnosed FLT3 AML cases. This is now considered to be a standard approach, so we do recommend all of the academic and community physicians in the United States as well as in Europe wait for the results of the FLT3 testing and use midostaurin as an add-on to standard induction to improve the overall survival of their patients.
The second study is QuANTUM-First, a large phase III study looking at relapsed/refractory patients. The population of focus was people of varying age with acute myeloid leukemia, who had received induction therapy and had either refractory disease—meaning they did not respond at all or had relapsed. These patients will usually be treated with standard chemotherapies, so one could use regimens like FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin], azacitidine, or low-dose cytarabine; but the outcomes have usually been dismal in the relapsed FLT3 ITD patients. The goal of the QuANTUM-First study was to see whether we could use the single-agent oral drug quizartinib, which is a potent FLT3 inhibitor, as opposed to using the traditional chemotherapies, such as the low-dose cytarabine, decitabine, etc. The primary endpoint, again, was overall survival.
The QuANTUM-First study was multinational, opening at about 80 sites. A total of 380 patients were admitted, who received, at random, either quizartinib or the investigator choice, which included a low-dose of cytarabine, azacitidine, decitabine, or chemotherapy. The study was released a few months ago, and it showed that both the overall survival and the response rates were significantly improved with quizartinib. The overall survival was 30 weeks with quizartinib compared to 20 weeks with traditional chemotherapy. The response rate, which I think is the most striking, was 50% when we included all bone marrow remission rates with quizartinib, compared to only 25% with chemotherapy.
A lot of people say, “Well, the survival improvement is modest, it’s only 8 to 10 weeks,” which I agree with. But I think the key factor here is that we’re using 1 oral agent, which is very well tolerated in comparison to 3-drug chemotherapies like FLAG-IDA] or IV [intravenous] chemotherapy, such as azacitidine. Even if I was told as a patient that I could be given 1 oral drug that is very well tolerated compared to a 3-drug IV chemotherapy regimen that will have all the [adverse] effects—mucositis, diarrhea, nausea, infection—I think most of us would say, “I will go for the oral drug,” even if they were equivalent. So here you’re not only seeing equivalence, but superiority.
We at MD Anderson, and a lot of the other big centers, believe that eventually these drugs—quizartinib, like midostaurin—will be used optimally in conjunction, and a number of these studies are ongoing. Today, as a single agent for a relapsed FLT3 ITD-mutated disease, this is probably going to be our primary choice over high-dose chemotherapy.
Richard F. Schlenk, MD: The implication of the current trials of FLT3 inhibitors in daily clinical practice is a disparity of age. For example, the RATIFY study was focused on patients between 18 and 59 years old; whereas, in the QuANTUM-First study, there were patients between 60 and 70 years old.
The second difference is a matter of permutation inclusion. For example, in the QuANTUM-First trial, only patients with an FLT3 internal tandem duplication were included; whereas, in the RATIFY trial, patients with a tyrosine kinase domain mutation were included, especially those patients who benefit best from midostaurin if we look at the different results and the hazard ratios for the different mutation types. The hazard ratio for tyrosine kinase domain mutation was much better than those for FLT3 internal tandem duplication, whether low or high allelic burden.
There will be other trials coming up where crenolanib and gilteritinib are compared in the first-line setting to midostaurin and crenolanib, the only drug so far approved for the treatment of patients with FLT3 and activating FLT3 mutations.
Transcript Edited for Clarity