Q: How commonplace is testing for FLT3 in newly diagnosed AML patients?
Dr. Wang: So FLT3 mutations are found in up to 37% of patients with newly diagnosed AML, slightly more common in the younger patients than the older patients. We currently have FLT3 inhibitor therapy, which is FDA approved for the treatment of FLT3 mutant AML in both the newly diagnosed and the relapsed setting. So for many of us over the last couple years, we have considered FLT3 testing as a standard test that needs to be done at the time of diagnosis, and needs to be done at the time of relapse, because of the therapeutic options that could be available for the patients that have that type of mutated acute myeloid leukemia.
Many of us will do a single PCR test to look for FLT3 mutations. There's two types. There's FLT3 ITD or internal tandem duplication, which is more common, found in about 20% of patients. And then there are patients that have rare mutations in the tyrosine kinase domain, and that's probably about seven to 10%. So you have to have an assay that can pick up both of those. Many clinicians will actually order next-gen sequencing now to look at an array of myeloid gene mutations, and the pitfall of doing next-gen sequencing is that it can be very good at picking up, for example, the tyrosine kinase domains, but can miss the internal tandem duplications. So we do recommend that people consider still doing a targeted PCR for FLT3 ITD as well as TKD, and not just rely upon the next-gen sequencing for those results.
Q: What is the typical frontline regimen for newly diagnosed FLT3+ AML patients?
Dr. Wang: So, in patients who are younger or considered fit for intensive chemotherapy, they don't have comorbidities, they're typically under the age of 60, 65 years old, sometimes 70, the standard therapy offered to those would be intensive chemotherapy with the cytarabine and anthracycline base regimen over seven days. And then that is followed by incorporation of the FLT3 inhibitor midostaurin, which is taken for 14 days of that induction chemotherapy, and then also is incorporated into consolidation chemotherapy with high doses of cytarabine.
Q: Tell us about the design and outcomes of the LACEWING study presented at ASH 2021 investigating newly diagnosed FLT3+ AML patients who are ineligible for intensive induction chemotherapy.
Dr. Wang: Sure. So, for individuals who are unable to, or ineligible, for intensive chemotherapy due to age, for example, age greater than and equal to 65 or 70, and/or who have comorbidities or other organ dysfunction of any age, that just makes them not able to tolerate or survive intensive chemotherapy, the options for those patients are fairly limited. We know that venetoclax-azacitidine is approved for the management and treatment of older individuals, 75 years and above, and who have comorbidities, but recent data presented at ASH 2020, and in retrospective fashion, as well as in the VIALE-A trial, suggested that there's really no overall survival benefit for older unfit patients with FLT3 mutant disease, particularly FLT3 ITD disease, when they get venetoclax-azacitidine. So that has led us to say, can we use FLT3 inhibitors as part of that upfront regimen? Now gilteritinib is a newer generation potent FLT3 inhibitor, which is already approved for treatment of patients with relapse and refractory FLT3 mutant disease based on the results of a Phase III trial, the Admiral trial a few years ago.
So, the Lacewing trial was really examining, could you combine gilteritinib with the backbone azacitidine to treat older unfit patients who had newly diagnosed FLT3 mutant disease? Now, preclinical studies had demonstrated that the combination of gilteritinib and azacitidine can be synergistic and can result in greater anti-tumor activity than either agent alone. So in the LACEWING trial, what we did is we randomized older patients or unfit patients to receive either gilteritinib monotherapy, gilteritinib plus azacitidine, or azacitidine alone. And the initial design was a one plus one plus one. So there were patients were randomized 33%, 33% and 33%. However, over the course of the trial duration, the gilteritinib monotherapy was removed, and patients were subsequently randomized two to one to get gilteritinib-azacitidine versus azacitidine alone.
So in the final analysis, we looked at about 123 patients, two-thirds randomized to gilteritinib, one third to azacitidine alone, not the combination of gilteritinib-azacitidine, and we looked at the primary endpoint, which was overall survival, secondary endpoint, event-free survival, response rate, et cetera. So the results were somewhat disappointing in that, in the interim analysis of the trial, there was no statistically significant difference in overall survival between gilteritinib azacitidine versus azacitidine alone. However, it wasn't, I would have to say, a completely negative study because, as with any of these studies, we learn a lot about the disease population and the potential to move forward with these targeted therapies.
So what was noted was that there was a significant difference in overall response rates. So patients receiving gilteritinib-azacitidine had a 58% overall response rate, and that was largely due to significantly different rates of complete remission with incomplete count recovery, complete remission with incomplete platelet recovery, as well as CR, as opposed to patients getting azacitidine alone, who had an overall response rate of 26%. So the absolute difference in overall response was 31%.
There was also as a suggestion that patients who had FLT3 ITD, and FLT3 ITD high disease burden, as demonstrated by allelic ratio greater than 0.5, seemed to have better or improved median overall survival with the combination arm, and patients who had good performance status, who could tolerate the drug longer, also seemed to have improved median overall survival.
So there was a suggestion that there could have been some subgroups which benefited from the therapy, and as to why that didn't translate into the entire population, we have to remember that over the course of this study, which is a very dynamic thing, right, doesn't happen in isolation, gilteritinib was actually approved in the United States for treatment of relapsed and refractory AML. So if you look at the patients treated in the azacitidine only arm, out of those patients, 22 of the 29 patients got subsequent therapy after they got azacitidine. And 14 of those patients got FLT3 therapy after azacitidine, and 10 of those 14 patients actually got gilteritinib. So there certainly could have been a confounding factor that subsequent FLT3 therapy in terms of altering the overall survival outcomes that we originally were planned with just azacitidine alone.
Q: The LACEWING study didn’t demonstrate an overall survival advantage, but there are subgroups that benefited from the therapy, so is this study practice changing?
Dr. Wang: So in terms of changing practice, I would say that certainly gilteritinib-azacitidine was not significantly more toxic than azacitidine alone. So the safety and tolerability of the combination was good and was proven in this study. And there were particular subgroups of people, both FLT3 ITD mutation alone and a high disease burden, that may have really benefited from this. So I think that this could be an option that people could consider if they have an older unfit patient who meets that criteria.
Now, is this study going to go head to head with something like venetoclax-azacitidine, I'm not sure. Venetoclax-azacitidine is really approved agnostic of any mutations in the older unfit population. Where I see this study going is in future combination regimens. So I know that there's active studies right now looking at triplet therapy, which is combining a FLT3 inhibitor like gilteritinib with venetoclax and azacitidine, adding it on, to seeing whether you could merge the benefits of the FLT3 inhibitor with the benefits of ven aza.
And some people are thinking about doublet therapy or sequential therapy. Could you get venetoclax-azacitidine followed by a FLT3 inhibitor? I think that this data suggests that there is potentially a role, and that it's well tolerated in these older unfit patients. And I think it's likely that these results, although technically negative, will end up supporting incorporation of FLT3 inhibitors for these older, unfit or ineligible for intensive chemotherapy patients in the near future.
Q: Please provide perspective on the latest clinical news from ASH 2021 concerning combining venetoclax with gilteritinib in relapsed/refractory FLT3+ AML.
Dr. Wang: It is known that patients who get treated with gilteritinib in the relapsed refractory setting have improved outcomes, as opposed to those getting salvage chemotherapy, either high dose or low dose chemotherapy, but the overall response rate of patients getting gilteritinib in that setting is still low, about 30%. And those patients will have a limited overall survival, less than a year on average. So clearly, although gilteritinib is superior to chemo, we still have ways to go. So it turns out that again, in preclinical studies, that you can combine BCL-2 inhibitor with venetoclax, with gilteritinib, and get again, synergistic anti tumor effects. So this has led to the results of a fairly large Phase IB examining venetoclax and gilteritinib, a dual oral therapy in patients with relapsed and refractory disease.
So I think in this setting, we see extremely potent activity. The overall response rate in that particular relapsed refractory FLT3 mutant population is in excess of 80, 85%. And the drugs together, both oral drugs, are well tolerated overall, with the caveat being that both of them lead to a significant amount of myelosuppression.
So I think that when we start looking at doublet therapies, of targeted therapies, venetoclax based therapies, or even what we saw a lot at this meeting, triplet therapies, we start to get into questions of how to combine three things together, how to manage the side effects, which one of those three things is really important, and is sequence going to be an important issue.
So I think for right now, venetoclax-gilteritinib really is being examined very closely in this population of patients as an alternative or as an improvement upon gilteritinib alone. And triplet therapy, I think, is coming down the pike, but really isn't ready for prime time yet until we work out some of these adverse event monitoring and management.
