EHA 2019 | Improving outcomes in FLT3-mutated AML patients

So, to start with, we have to know that FLT3 mutated patients have a very bad outcome. This is true in the frontline setting, as well as in the relapse setting. And a number of papers, both from European groups, US groups, MD Anderson, we’ve all published this. So, from the last 15 years, we’ve known that we need drugs that improve the outcome in FLT3 mutated patients. The first thing we did is what we always do in

So, to start with, we have to know that FLT3 mutated patients have a very bad outcome. This is true in the frontline setting, as well as in the relapse setting. And a number of papers, both from European groups, US groups, MD Anderson, we’ve all published this. So, from the last 15 years, we’ve known that we need drugs that improve the outcome in FLT3 mutated patients. The first thing we did is what we always do in acute leukemia is to use transplant as kind of the blanket that will improve outcomes. And indeed, it did bring our five year survival from 15% to 20%, in the front line, to about 35%-40%, but we were still below the bar for the non-FLT3 patients.

The next step, was to develop a drug called Midostaurin which actually was done in a phase three study in the front line setting in combination with 3+7. And it showed that the 3+7 with Midostaurin versus 3+7 Placebo, did have a beneficial effect, the overall survival endpoint, which is the primary endpoint was met, but also the response rates were improved. And this led to the approval of Midostaurin in the frontline setting. And indeed, if you do give Midostaurin the frontline setting, and you do get the patient to transplant, which we can do both these things, in about 50% of patients, you could have about a 65%, four to five year survival.

But about half the patients, you’re either not able to give them Midostaurin, either because of access, because of toxicity, because of cause. And then there are a lot of patients who will not go to transplant: donors not available, patient preference, economic issues, transplant centers not in the area. And in those patients, we are still seeing 50 to 70% response rates. So, there remains a huge unmet need where at least 50% of all FLT3 mutated new patients, in the next three to four years, will still relapse. The other thing we’re seeing is, when they relapse after Midostaurin, they may be relapsing with more aggressive clones, including things like TP53, RAS, and so, these patients are going to require more intensive, as well as improved therapies.

So, there are now two FLT3 inhibitors that are in this space. One of them is a drug called Gilteritinib, which is a potent, second generation FLT3 inhibitor. It has both FLT3-ITD and DA35. They completed phase three study in the relapse refractory setting where they compared Gilteritinib to investigator choice treatment, which could include low-intensity therapies like low-dose cytarabine, hyperventilating agents or high-intensity cytotoxic therapy, like FLAG-Ida and MEK. And they showed that both the overall response rate including CR/CRi, as well as the median overall survival were significantly improved with Gilteritinib. In fact, it’s amazing to see that you could get with a single agent oral therapy, response rates in the marrow for up to 45%-50%, which were double of what you would get with three or four drug IV high intensity inpatient chemo. So, the study actually showed doubling a response and improvement in survival, but even if it was equivalent, I think a lot of us would argue that would you like to take an oral pill, outpatient, low toxicity versus a three drug, IV chemo, hair loss, mucositis, and in this one actually it showed benefit.

So, that drug was approved recently. And even though the single agent, we do see the median survival improved. At two years, we still see that only 5% to 10% are alive. So, this is the beginning of the research, but now we’re doing combinations of Gilteritinib with Venetoclax, Azacitidine, chemo, and hopefully these will further improve the outcome. At the end of the day, there’s still a huge unmet need. 50% of the patients will relapse after the frontline setting, and of the relapse, 5% to 10% are alive at two years. So, we still need new drugs, and that’s where we think the other drug that’s being developed is going to be extremely important. Quizartinib, which is a second generation FLT3 inhibitor. This one also recently completed a phase three study: the quantum-r study. It met its primary endpoint of overall survival. And interestingly, even also showed that the response rates were about double of what you would see with chemotherapy.

So, we think the future is going to be using both of these drugs in combinations with HMAs, with chemo, or even more so, with venetoclax, MCL1 inhibitors, BET inhibitors, MEK inhibitors. And just like we’ve done in CML, where it wasn’t one drug or two drugs, but all four or five drugs being used in sequence in many patients, making them stay alive, whereas many of these would not have been alive if the 3rd and 4th TKI care were not available. I absolutely think that these drugs, when used in sequence after each other in combinations, could bring that survival up to 30%, 40%, 50% in relapse, and they’re both going to be very critical, hopefully to the future development in the FLT3.