In an interview with Targeted Oncology, Alexander E. Perl, MD, discussed the final results from the ADMIRAL trial and the impact these results have on practice.
Alexander E. Perl, MD
Gilteritinib (Xospata), a FLT3 inhibitor, significantly improved overall survival (OS) in patients with relapsed/refractory acute myeloid leukemia (AML) who harbor aFLT3mutation, according to final analysis findings from the phase III ADMIRAL trial presented at the 2019 AACR Annual Meeting.
Based on interim findings from the trial, the FDA approved gilteritinib in November 2018 for adult patients with relapsed/refractoryFLT3-mutant AML. The co-primary endpoints of the trial, OS and complete response (CR)/CR with hematologic recovery (CRh), were met in the final analysis, where the median OS and CR/CRh were nearly doubled in the gilteritinib arm compared to chemotherapy.
The median OS was 9.3 months in patients randomized to receive gilteritinib (95% CI, 7.7-10.7) versus 5.6 months in patients that received chemotherapy (95% CI, 4.7-7.3). This led to a 36% reduction in the risk of death (HR, 0.637; 95% CI, 0.490-0.830;P= .007). The CR/CRh rate with gilteritinib was 34% versus 15% with chemotherapy.
“On all measures improved survival, better response rates, longer duration of response, and favorable toxicity that can be given with a pill in the outpatient setting – gilteritinib has emerged from this study as the preferred treatment choice for this patient population based on these data,” said Alexander E. Perl, MD.
In an interview withTargeted Oncology, Perl, associate professor in the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania, and member of the Abramson Cancer Center, discussed the final results from the ADMIRAL trial and the impact these results have on practice.
TARGETED ONCOLOGY:What are the latest advancements in the treatment landscape for patients with AML?
Perl:There have been a lot of advances in the therapy of AML patients that have been driven by 2 factors. One is a better understanding of the biology of the disease, and the second is improving therapeutics to meet our understanding of that biology. In the last 40 years, there have been very scant drug development in AML, but a real broad expansion in our understanding of the disease biology. The real trick has been taking that understanding and turning it into therapeutics.
For the last couple of years, we have seen the approval of 9 new drugs for AML, which is a sound thingif you think about it after so many years of really no drug developments, then to see it all happen at once. It’s really been a lot of expansion. Many of the new drugs are actually targeting specific biologic processes that are sometimes driven by the mutations that we see recurrently in AML. The data I presented at AACR is an example of that kind of therapy, a drug called gilteritinib, that targets a mutation that is very common in AML called FLT3.
TARGETED ONCOLOGY:What was the rationale for the ADMIRAL trial?
Perl:The phase III ADMIRAL trial builds on a number of years trying to develop targeted agents for patients withFLT3mutations. The drugs that have been developed are tyrosine kinase inhibitors. They’ve all been variations on a theme in terms of being drugs that turn off the function of what that gene encodes, which is the tyrosine kinase, effectively an enzyme; it’s actually a receptor for cytokines in the bone marrow that help regulate how many blood cells the bone marrow makes every day. In cancer, the tumor cells hijack that mechanism and get uncontrolled growth as well as impaired differentiation; when they should be regulating this, when the mutation gets rid of all this regulation, the cells just continue to divide.It’s a very proliferative disease and grows very quickly. Patients can go from well to sick very fast and often present with very elevated white blood cell count.
The drugs that have been developed turn off that function and inhibit that enzyme, basically stopping that aggressive phenotype dead in its tracks. It can indeed kill off the leukemia cells, markedly reducing the number of bone marrow blasts, which is a measure of the tumor cells.
Now the first FLT3 inhibitors we developed didn’t really do that at all. They could control disease growth, but they couldn’t eliminate leukemia. We didn’t see reductions in bone marrow blasts. We would just see reductions in peripheral blood blasts. It’s not to say those drugs don’t have anti-leukemic effects; some of them are quite effective in the clinic, but in combination regimens, not as single-agents. Midostaurin (Rydapt) is an example of that, which was approved 2 years ago in combination with chemotherapy for newly diagnosed patients. These drugs, like midostaurin, that are not selective inhibitors of FLT3 have a very limited role in the therapy of patients who have relapse of their disease or who don’t respond to chemotherapy. They only seem to be helpful in the frontline for patients with newly diagnosed diseases that have not been treated before.
Since that time, drugs that are more potent and more selective have been developed, including a drug called quizartinib and a drug called sorafenib (Nexavar). Sorafenib is FDA approved to treat different kinds of cancers, but it’s not approved to treat AML. It has been used off-label in that setting, though, because it is an inhibitor of FLT3. Quizartinib was specifically designed to inhibit FLT3 and does so very well. We see a substantial number of patients respond to it. We got very excited about that response rate, but unfortunately the durations have been relatively short. That’s been an issue because we actually looked at the mechanism of why the patients would develop resistance and found that it was due to new mutations inFLT3that were resistant to an inhibitor.
What we really wanted was a new drug that would inhibit FLT3 potently, selectively, and get both the common mutation inFLT3that we see in patients, something we call aFLT3-ITD mutation, and also these mutations that confer resistance to some of the FLT3 inhibitors.
Gilteritinib, the drug we studied in ADMIRAL, is an example of this. It’s kind of a long way to say that this is a drug that is a highly selective, highly potent FLT3 inhibitor that has gone through phase I and phase II testing, had very good tolerability across a wide range of doses, and hit target very well. We did corral the studies to see how potent the inhibition was, and across the board, it was potently inhibiting FLT3 in patients. That was associated with single-agent response rates in about half the patients, which was very good and very promising. We set out to compare its efficacy against best available therapy in the phase III setting, and those are the data I presented on the ADMIRAL study. This is a registration study for gilteritinib, and indeed, the drug was approved based on interim response analysis on the gilteritinib arm. The data I presented at AACR are the final results of this study for the primary endpoint of OS.
TARGETED ONCOLOGY:What were the findings that you presented?
Perl:The ADMIRAL study randomized 371 patients who all had relapsed or refractory AML and all had aFLT3mutation detected at the time of study enrollment. They were randomized 2:1 to either single-agent gilteritinib or investigator’s choice of 1 of 4 different chemotherapy regimens, either high-intensity chemotherapy which is what is most commonly used for this population traditionally or a low-intensity chemotherapy regimen such as low-dose cytarabine or azacitidine (Vidaza).
With high-intensity therapy, and by that I mean mitoxantrone, etoposide, and intermediate-dose cytarabine or fludarabine, cytarabine and GCSF with idarubicin (FLAG-IDA), patients treated with high-intensity chemotherapy are generally hospitalized for at least a month to both receive the chemotherapy and assess for side effects and provide supportive care. Gilteritinib is a pill; we take that once a day in the outpatient setting, again because it has a relatively favorable side effect profile.
Data from this study showed that response rates were substantially higher in the gilteritinib arm, nearly or at least doubling response rates for complete remissions, complete remissions with partial hematologic recovery and OS. The duration of these remissions was also considerably longer. The duration of chemotherapy treatment was also considerably longer in the gilteritinib arm. Patients stayed on study drug for a median of more than 4 months whereas on the chemotherapy arm, the median duration of therapy was less than 1 month, so a substantial difference in terms of drug exposure in these 2 arms.
There were higher transplantation rates for patients treated with gilteritinib also at about 26% versus 15%, and that is important because if we look at long-term outcomes in relapsed/refractory AML, it’s really only the patients that go on to the transplant who have traditionally been associated with long-term survival. We are very excited that not only do we have high response rates, but survival is also better on the study in the gilteritinib arm. The median OS was statistically improved at 9.3 months in the gilteritinib arm versus 5.6 months in the chemotherapy arm. Also, patients treated with gilteritinib had a 36% lower risk of mortality in the gilteritinib arm relative to the standard chemotherapy arm. The 1-year survival was also more than doubled with gilteritinib at 37% versus 17% for chemotherapy. Gilteritinib outperformed chemotherapy pretty much on all measures of response and survival.
TARGETED ONCOLOGY:What was the tolerability of this agent?
Perl:There are side effects with all medications. It’s not to say gilteritinib has no side effects. The most common side effects that we saw were generally quite tolerable in patients; cytopenias, anemia, neutropenia, thrombocytopenia, and also elevation of liver function test (LFT) abnormalities, for the most part, were asymptomatic, so we typically saw grade 1 or grade 2 LFT abnormalities, transaminases, or alkaline phosphatase.We did not see hyperbilirubinemia with any frequency. Yes, we saw infections on both arms. Yes, we saw other toxicities, but really nothing that jumped out in terms of being a really serious or concerning safety issue for gilteritinib relative to chemotherapy.
On all measures improved survival, better response rates, longer duration of response, and favorable toxicity that can be given with a pill in the outpatient setting – gilteritinib has emerged from this study as the preferred treatment choice for this patient population based on these data. The drug, as I mentioned before, is currently approved based on interim analysis response rates in the gilteritinib arm. I should finish by saying that while we had that interim analysis, it did not change the conduct of the study. We did not use that for the purposes of halting the study early. It was purely just to show that the drug had sufficient safety data and efficacy data to get the drug approved. The final analysis is really what shows the superiority of gilteritinib against alternatives.
TARGETED ONCOLOGY:Is there any other research looking at gilteritinib in AML?
Perl:The really exciting thing, we hope, is to not use this to treat relapse or refractoriness but to prevent relapse and refractoriness. [We hope] to improve the efficacy of frontline chemotherapy because while I can be excited that we are improving survival in the relapsed/refractory setting, the number of long-term survivors on ADMIRAL was small, and that’s not something we can be satisfied with by saying “we’ve done our job here.”We really need to move a drug like this earlier into therapy. Honestly, the lack of large number of survivors on this study is not really surprising because we are using a highly selective drug that targets a single mutation and really not a lot else to try to treat AML, which is a multi-hit disease that is biologically quite complex. Using a drug that is really good at what it does but only a part of the whole and integrating it into multi-agent therapy and giving that earlier in the course of therapy is really where a drug like this could have a substantial impact on cure rate, which is ultimately what we care about.
Studies adding gilteritinib to frontline therapy, to both low-intensity therapy for patients who are not candidates for high-intensity therapy and also full-intensity cytarabine and daunorubicin-induction chemotherapy, plus gilteritinib, and post remission therapy have already been initiated. The approach has been feasible, and randomized studies comparing that approach to the current standard using cytarabine and daunorubicin and midostaurin, again a multikinase inhibitor, studies with that randomization approach are already underway.
We also use bone marrow transplantation frequently in the therapy of patients withFLT3mutations who achieve a remission either to frontline therapy or in the case of ADMIRAL, after salvage therapy. We are very interested in adding gilteritinib after transplant to see if that will increase the number of patients that we see that are long-term survivors and are ultimately cured. We think that approach may prove beneficial, and there are randomized studies looking at that option now.
TARGETED ONCOLOGY:What is the take home message from this trial?
Perl:A few things are really important here. One is patients who have relapsed disease do have effective therapy that can be managed in the outpatient setting and can be associated with substantial survival. This is not a situation where if the patient relapses you have to immediately say this patient doesn’t really have good options, we should think about sending this patient to hospice. We should look to see if they are a candidate for targeted therapy whether it is with an IDH inhibitor, because those are very active in this setting, or whether it’s with a FLT3 inhibitor, because drugs like gilteritinib can be quite effective in this setting. Patients who we previously would not have good treatment options now have real treatment options now.I think this is a real game changer, also because we are withholding from these patients more toxic therapies that generally haven’t worked that well; avoiding things that cause harm and giving things that give benefit is really important, especially if the risk-benefit ratio really favors the patient and has a more favorable quality of life in the context of relapsed/refractory disease. We do have long-term survivors from that setting who have been able to respond to the drug and go on to transplant. Again, one approach that I’ve advocated is getting back on these drugs after transplant. Those were actually some of the longest survivals that we saw in the patients treated on ADMIRAL.
That’s really a change in terms of how we approach patients with relapsed disease. We should be testing forFLT3mutations, we should be acting upon those tests, and it’s important because patients can gain aFLT3mutation at the time of relapse and similarly, gilteritinib really doesn’t have much activity if you don’t have aFLT3mutation, so if patients had aFLT3