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Glasdegib for AML

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, Perelman School of Medicine; Eunice Wang, MD, Roswell Park Cancer Institute
Published: Monday, Jan 21, 2019



Transcript:

Harry Erba, MD, PhD:
On the same day that venetoclax was approved, glasdegib was approved in the same population—older, unfit, previously untreated AML [acute myeloid leukemia]—but here in combination with low-dose ara-C [cytarabine]. Now, glasdegib, as you know, is a hedgehog inhibitor, an oral early bioavailable drug. And on its own has virtually no activity. It’s very similar to venetoclax on its own as a single agent. But, in a randomized phase II study, the combination of glasdegib with low-dose ara-C resulted in higher response rates and better survival than for patients who just got low-dose ara-C. And that led to the approval.

I have a concern about it. It was not a blinded study. So, imagine if you’re the clinician taking care of a patient and you know they’re getting low-dose ara-C and you’re at The University of Texas MD Anderson Cancer Center, or Memorial Sloan Kettering Cancer Center, and all of these institutions that have other drugs, would you be more willing or quicker to pull them off study, if they’re on ara-C, to do something else? And that’s my concern about a study that was not blinded. So we’re hopeful that when we do the randomized trials that are blinded with placebo, that maybe we’ll get a better understanding of the true benefit of glasdegib. So, with my very leading comments, glasdegib, venetoclax. They’re in the same patient population. Which do we use now, Raajit?

Raajit K. Rampal, MD, PhD: Again, it’s a difficult question. We suddenly are faced with all of these agents and they all have activity to various degrees, but for whom and in what order? Those are the 2 big questions. I think that we certainly don’t want to get into comparing response rates across trials, which these are not arms of 1 trial, but there is, relatively speaking, it seems a higher rate of response with the venetoclax combinations. That being said, we can’t stand on that as sufficient evidence to pick one or the other. I think it really comes down to, in part, toxicity profile, because some of the toxicities of the hedgehog inhibitors are well known and affect quality of life. And certainly that is one of the things that we are talking about in terms of venetoclax, having potentially some quality of life benefits in terms of allowing people to be transfusion dependent.

Harry Erba, MD, PhD: Expound on that, because I don’t think a lot of people have experience with this hedgehog inhibitor. What are the toxicities?

Raajit K. Rampal, MD, PhD: The major things are loss of appetite and hair loss, and those can be quite profound. So, if we’re giving a drug like that where we are going to incur those adverse effects, what are we doing to the quality of life for the patient? And that has to be a principle concern of ours in patients who potentially have a limited life span when we start initiating treatment.

Mark J. Levis, MD, PhD: We participated in both trials. The AZA [azacitidine]/venetoclax or decitabine/venetoclax, or low DAC [decitabine]/venetoclax was sort of eye-opening. Everybody heard about this, and patients were being flung at this trial. We didn’t have the same experience with the glasdegib. That said, I’m glad we have glasdegib to look at a completely different mechanism of action. We don’t know what to do with it yet. It’s a fun, new toy maybe. Yes, the hair loss, those things I think are quite important, but could you fold this in? Now we’ve got something new to experiment with. I don’t think we know what to do with it now and I don’t think it’s going to be used like the AZA.

Alexander Perl, MD: But I think what’s exciting is we have it. So now we can figure that out.

Mark J. Levis, MD, PhD: Yes, exactly.

Alexander Perl, MD: That’s what’s different. Now that you have more lures in your tackle box, you can figure out in which pond does one work and in which pond should you try something different, and in which combinations will this be best. Are we going to use low-dose ara-C now in the United States based on this approval? I doubt it. But are we going to use this drug in combinations to figure out how best to use it to improve outcomes in AML? I expect it.

Naval G. Daver, MD: Yes, I think it’s amazing. Four or 5 years ago, we wouldn’t be discussing low-dose ara-C at all in the United States. So now we have the argument of which low-dose ara-C, which is great. I mean this is a good thing, right? And today I agree with all of you. If I had a patient or a recommendation, the HMA [hypomethylating agent], VEN [venetoclax], low-dose ara-C when in the same population is giving us very exciting responses, survival. It’s hard to use low-dose ara-C, the glasdegib, in that population.
But we actually, at MD Anderson, we didn’t ever use low-dose ara-C, but we’re using low-dose ara-C/VEN in 1 specific group—and I think that’s an important point—the HMA failure group. Because most of the data with HMA/VEN, except I think City of Hope has a little bit different, but most experiences are if you’ve received HMA for 4 cycles, 6 cycles for MDS [myelodysplastic syndromes], for CMML [chronic myelomonocytic leukemia], for AML, and then you’re failing, adding venetoclax is giving you marginal to no benefit. In fact, we started excluding those people from our trials of HMA/VEN. But, with low-dose ara-C/VEN, you do get good response rates, 55%, 58%. The survival is still not great. It’s about 8 to 10 months, but that could be a group to build on. You could have low-dose ara-C/VEN. Maybe could there be a role to add something like a hedgehog? And in that situation, I think....

Mark J. Levis, MD, PhD: You have to applaud the regulatory agencies, whatever is getting them to make these approvals. Once the drug is approved, then the research really explodes.

Raajit K. Rampal, MD, PhD: I think an important point along those is that a biological signal might emerge, right? As we have more experience. As an example, we’ve seen that patients with IDH [isocitrate dehydrogenase] mutations seem to have a pretty high response rate to the venetoclax combinations. We have to see if that holds up as we get more data. But will we begin to see patterns that emerge to particular cytogenetic groups or molecular groups who have an enhanced response to one of these regimens? We’ll get an answer to that eventually.

Transcript edited for clarity.

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Transcript:

Harry Erba, MD, PhD:
On the same day that venetoclax was approved, glasdegib was approved in the same population—older, unfit, previously untreated AML [acute myeloid leukemia]—but here in combination with low-dose ara-C [cytarabine]. Now, glasdegib, as you know, is a hedgehog inhibitor, an oral early bioavailable drug. And on its own has virtually no activity. It’s very similar to venetoclax on its own as a single agent. But, in a randomized phase II study, the combination of glasdegib with low-dose ara-C resulted in higher response rates and better survival than for patients who just got low-dose ara-C. And that led to the approval.

I have a concern about it. It was not a blinded study. So, imagine if you’re the clinician taking care of a patient and you know they’re getting low-dose ara-C and you’re at The University of Texas MD Anderson Cancer Center, or Memorial Sloan Kettering Cancer Center, and all of these institutions that have other drugs, would you be more willing or quicker to pull them off study, if they’re on ara-C, to do something else? And that’s my concern about a study that was not blinded. So we’re hopeful that when we do the randomized trials that are blinded with placebo, that maybe we’ll get a better understanding of the true benefit of glasdegib. So, with my very leading comments, glasdegib, venetoclax. They’re in the same patient population. Which do we use now, Raajit?

Raajit K. Rampal, MD, PhD: Again, it’s a difficult question. We suddenly are faced with all of these agents and they all have activity to various degrees, but for whom and in what order? Those are the 2 big questions. I think that we certainly don’t want to get into comparing response rates across trials, which these are not arms of 1 trial, but there is, relatively speaking, it seems a higher rate of response with the venetoclax combinations. That being said, we can’t stand on that as sufficient evidence to pick one or the other. I think it really comes down to, in part, toxicity profile, because some of the toxicities of the hedgehog inhibitors are well known and affect quality of life. And certainly that is one of the things that we are talking about in terms of venetoclax, having potentially some quality of life benefits in terms of allowing people to be transfusion dependent.

Harry Erba, MD, PhD: Expound on that, because I don’t think a lot of people have experience with this hedgehog inhibitor. What are the toxicities?

Raajit K. Rampal, MD, PhD: The major things are loss of appetite and hair loss, and those can be quite profound. So, if we’re giving a drug like that where we are going to incur those adverse effects, what are we doing to the quality of life for the patient? And that has to be a principle concern of ours in patients who potentially have a limited life span when we start initiating treatment.

Mark J. Levis, MD, PhD: We participated in both trials. The AZA [azacitidine]/venetoclax or decitabine/venetoclax, or low DAC [decitabine]/venetoclax was sort of eye-opening. Everybody heard about this, and patients were being flung at this trial. We didn’t have the same experience with the glasdegib. That said, I’m glad we have glasdegib to look at a completely different mechanism of action. We don’t know what to do with it yet. It’s a fun, new toy maybe. Yes, the hair loss, those things I think are quite important, but could you fold this in? Now we’ve got something new to experiment with. I don’t think we know what to do with it now and I don’t think it’s going to be used like the AZA.

Alexander Perl, MD: But I think what’s exciting is we have it. So now we can figure that out.

Mark J. Levis, MD, PhD: Yes, exactly.

Alexander Perl, MD: That’s what’s different. Now that you have more lures in your tackle box, you can figure out in which pond does one work and in which pond should you try something different, and in which combinations will this be best. Are we going to use low-dose ara-C now in the United States based on this approval? I doubt it. But are we going to use this drug in combinations to figure out how best to use it to improve outcomes in AML? I expect it.

Naval G. Daver, MD: Yes, I think it’s amazing. Four or 5 years ago, we wouldn’t be discussing low-dose ara-C at all in the United States. So now we have the argument of which low-dose ara-C, which is great. I mean this is a good thing, right? And today I agree with all of you. If I had a patient or a recommendation, the HMA [hypomethylating agent], VEN [venetoclax], low-dose ara-C when in the same population is giving us very exciting responses, survival. It’s hard to use low-dose ara-C, the glasdegib, in that population.
But we actually, at MD Anderson, we didn’t ever use low-dose ara-C, but we’re using low-dose ara-C/VEN in 1 specific group—and I think that’s an important point—the HMA failure group. Because most of the data with HMA/VEN, except I think City of Hope has a little bit different, but most experiences are if you’ve received HMA for 4 cycles, 6 cycles for MDS [myelodysplastic syndromes], for CMML [chronic myelomonocytic leukemia], for AML, and then you’re failing, adding venetoclax is giving you marginal to no benefit. In fact, we started excluding those people from our trials of HMA/VEN. But, with low-dose ara-C/VEN, you do get good response rates, 55%, 58%. The survival is still not great. It’s about 8 to 10 months, but that could be a group to build on. You could have low-dose ara-C/VEN. Maybe could there be a role to add something like a hedgehog? And in that situation, I think....

Mark J. Levis, MD, PhD: You have to applaud the regulatory agencies, whatever is getting them to make these approvals. Once the drug is approved, then the research really explodes.

Raajit K. Rampal, MD, PhD: I think an important point along those is that a biological signal might emerge, right? As we have more experience. As an example, we’ve seen that patients with IDH [isocitrate dehydrogenase] mutations seem to have a pretty high response rate to the venetoclax combinations. We have to see if that holds up as we get more data. But will we begin to see patterns that emerge to particular cytogenetic groups or molecular groups who have an enhanced response to one of these regimens? We’ll get an answer to that eventually.

Transcript edited for clarity.
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