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Emerging Targeted Agents in AML

Insights From: Hervé Dombret, MD, Institut Universitaire d’Hématologie; Richard M. Stone, MD, Dana-Farber Cancer Institute
Published: Friday, Apr 28, 2017


Transcript:

Richard M. Stone, MD:
I have a lot of experience with midostaurin because I participated in the initial single-agent trial in relapsed/refractory patients. I participated in the trial in which we combined the drug with chemotherapy, and I obviously participated in the RATIFY trial, which was a randomized trial.

I think it should be a new standard of care for those patients who fit the approved indication: those who are between ages 18 and 60, maybe older, who are getting chemotherapy and who have a FLT3 mutation. There are plenty of other issues that need to be explored. Can we improve upon the results with chemotherapy plus a FLT3 inhibitor like midostaurin? We need to try to do that. The role of transplant: should we be giving it after transplant? Yes, I think we should in the context of clinical trial, certainly. Should we be performing transplants on everybody with an FLT3 ITD mutation? The results from the RATIFY trial support doing that, even though that wasn’t a specific question that was going to be answered. It’s still unclear whether you should transplant a FLT3 TKD patient or not, but I would at least consider it. I think we have some new standards to look at, ie, giving the midostaurin the way it was given in the RATIFY trial to the people who would have been eligible for that trial. But we have, as all good research does, more questions now than we did before midostaurin was approved. That’s a good thing.

There are many other agents in this class of FLT3 inhibitors that are being developed. One of the first ones was a drug called lestaurtinib, which was subject to a randomized phase III trial in relapsed patients. Standard chemotherapy for relapsed patients was either high-dose Ara-C or mitoxantrone/etoposide/cytarabine alone or with lestaurtinib. It was a negative trial. It didn’t impact complete remission or survival, but many of the patients were shown by Dr. Levis not to have adequate levels of the drug in their blood to inhibit the enzyme. That was a reason that it didn’t work out. Lestaurtinib has also been tried in an upfront setting by Dr. Burnett of the MRC (Medical Research Council) of the UK (United Kingdom). We’ll have to see what those results show.

Other drugs that have been tested, or are being tested, that are FLT3 inhibitors include a drug called quizartinib, which is a specific inhibitor. It is not protein-bound and does not hit the tyrosine kinase domain. In fact, some of the patients who have been on it, and responded, ended up relapsing with a TKD mutation. It’s a more specific drug. Right now, the key piece of clinical research with that drug is a phase III trial in relapsed/refractory patients, which is randomizing such patients to either that drug or to a standard that includes “dealer’s choice” chemotherapy with some popular relapsed regimens. Another drug, which is also a specific nonprotein-bound FLT3 inhibitor, happens to also hit the tyrosine kinase domain mutation, distinguishing it from the aforementioned quizartinib. It is called gilteritinib, and gilteritinib is also being subjected to a phase III trial in relapsed/refractory patients as a single agent versus “dealer’s choice” chemotherapy. This includes both TKD and ITD patients.

Another drug is called crenolanib, which also is a drug that inhibits both the ITD and the FLT3 TKD-mutant patients. That’s being combined with chemotherapy now in a phase II trial and may be subject to a phase III trial with or without chemotherapy down the road. There are a lot of drugs that are in play. To me, the main scientific question is whether or not specific inhibitors will be “better” compared to a nonspecific inhibitor like midostaurin. One more drug worth noting is sorafenib, which is a multi-kinase inhibitor that does inhibit FLT3 and is approved in renal cancer and in hepatocellular carcinoma. That’s out there, and you can write a prescription for it, and if the insurance company will pay for it, you can give it to your patient. That’s a nonspecific inhibitor that has some side effects, but also has been associated with some remissions in advanced patients.

Hervé Dombret, MD: Currently, the companies and the investigators like me, we are trying to develop ways to treat patients with AML by targeting something that occurs in AML developments. This something could be a mutation like FLT3, and there are other gene mutations. There are other targeting agents that target a specific mutation. The most developed and the most exciting at the present time are IDH-mutated-protein inhibitors. These agents are very effective in early trials to target patients with IDH1 or IDH2 gene mutation, and this is certainly a very promising field—very close to what has been done with FLT3 with respect to FLT3 inhibitors.

But there are other ways leukemic drugs work. They target not just a mutation, but target the pathway as well, for instance. What is really important, and exciting currently, is to target apoptotic pathways, because leukemic cells frequently have anti-apoptotic signals. There are a lot of new drugs and molecules like this that are currently being developed to try to target proteins like BRCA2, for instance, or MDM2. This is another field that is very exciting. Finally, with respect to what we have done in ALL, immunotherapeutic approaches are really, really important. Antibodies, bispecific inhibitors, and CAR-T cells against AML could be very, very important in the near future.

Transcript Edited for Clarity
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Transcript:

Richard M. Stone, MD:
I have a lot of experience with midostaurin because I participated in the initial single-agent trial in relapsed/refractory patients. I participated in the trial in which we combined the drug with chemotherapy, and I obviously participated in the RATIFY trial, which was a randomized trial.

I think it should be a new standard of care for those patients who fit the approved indication: those who are between ages 18 and 60, maybe older, who are getting chemotherapy and who have a FLT3 mutation. There are plenty of other issues that need to be explored. Can we improve upon the results with chemotherapy plus a FLT3 inhibitor like midostaurin? We need to try to do that. The role of transplant: should we be giving it after transplant? Yes, I think we should in the context of clinical trial, certainly. Should we be performing transplants on everybody with an FLT3 ITD mutation? The results from the RATIFY trial support doing that, even though that wasn’t a specific question that was going to be answered. It’s still unclear whether you should transplant a FLT3 TKD patient or not, but I would at least consider it. I think we have some new standards to look at, ie, giving the midostaurin the way it was given in the RATIFY trial to the people who would have been eligible for that trial. But we have, as all good research does, more questions now than we did before midostaurin was approved. That’s a good thing.

There are many other agents in this class of FLT3 inhibitors that are being developed. One of the first ones was a drug called lestaurtinib, which was subject to a randomized phase III trial in relapsed patients. Standard chemotherapy for relapsed patients was either high-dose Ara-C or mitoxantrone/etoposide/cytarabine alone or with lestaurtinib. It was a negative trial. It didn’t impact complete remission or survival, but many of the patients were shown by Dr. Levis not to have adequate levels of the drug in their blood to inhibit the enzyme. That was a reason that it didn’t work out. Lestaurtinib has also been tried in an upfront setting by Dr. Burnett of the MRC (Medical Research Council) of the UK (United Kingdom). We’ll have to see what those results show.

Other drugs that have been tested, or are being tested, that are FLT3 inhibitors include a drug called quizartinib, which is a specific inhibitor. It is not protein-bound and does not hit the tyrosine kinase domain. In fact, some of the patients who have been on it, and responded, ended up relapsing with a TKD mutation. It’s a more specific drug. Right now, the key piece of clinical research with that drug is a phase III trial in relapsed/refractory patients, which is randomizing such patients to either that drug or to a standard that includes “dealer’s choice” chemotherapy with some popular relapsed regimens. Another drug, which is also a specific nonprotein-bound FLT3 inhibitor, happens to also hit the tyrosine kinase domain mutation, distinguishing it from the aforementioned quizartinib. It is called gilteritinib, and gilteritinib is also being subjected to a phase III trial in relapsed/refractory patients as a single agent versus “dealer’s choice” chemotherapy. This includes both TKD and ITD patients.

Another drug is called crenolanib, which also is a drug that inhibits both the ITD and the FLT3 TKD-mutant patients. That’s being combined with chemotherapy now in a phase II trial and may be subject to a phase III trial with or without chemotherapy down the road. There are a lot of drugs that are in play. To me, the main scientific question is whether or not specific inhibitors will be “better” compared to a nonspecific inhibitor like midostaurin. One more drug worth noting is sorafenib, which is a multi-kinase inhibitor that does inhibit FLT3 and is approved in renal cancer and in hepatocellular carcinoma. That’s out there, and you can write a prescription for it, and if the insurance company will pay for it, you can give it to your patient. That’s a nonspecific inhibitor that has some side effects, but also has been associated with some remissions in advanced patients.

Hervé Dombret, MD: Currently, the companies and the investigators like me, we are trying to develop ways to treat patients with AML by targeting something that occurs in AML developments. This something could be a mutation like FLT3, and there are other gene mutations. There are other targeting agents that target a specific mutation. The most developed and the most exciting at the present time are IDH-mutated-protein inhibitors. These agents are very effective in early trials to target patients with IDH1 or IDH2 gene mutation, and this is certainly a very promising field—very close to what has been done with FLT3 with respect to FLT3 inhibitors.

But there are other ways leukemic drugs work. They target not just a mutation, but target the pathway as well, for instance. What is really important, and exciting currently, is to target apoptotic pathways, because leukemic cells frequently have anti-apoptotic signals. There are a lot of new drugs and molecules like this that are currently being developed to try to target proteins like BRCA2, for instance, or MDM2. This is another field that is very exciting. Finally, with respect to what we have done in ALL, immunotherapeutic approaches are really, really important. Antibodies, bispecific inhibitors, and CAR-T cells against AML could be very, very important in the near future.

Transcript Edited for Clarity
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