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Frontline Venetoclax Combination Therapy for AML

Insights From: Naval G. Daver, MD, MD Anderson Cancer Center; Anthony Mato, MD, MSCE, Memorial Sloan Kettering Center
Published: Monday, Jun 24, 2019



Transcript:

Naval G. Daver, MD
: This trial M14-358 combined a BCL2 inhibitor, venetoclax, with azacitidine or decitabine. It’s very important to know the historical perspective of how we got to the study.

We’ve used low intensity therapies in patients usually about 65 years old, more commonly in patients above 70, who we know will have a very high early mortality—early mortality is defined as 8-week mortality—with intensive therapy such as 3+7 [cytarabine/daunorubicin] or other Ara-C[cytarabine]/anthracycline combinations. And actually one of the large papers published for The University of Texas MD Anderson Cancer Center almost 10 years ago showed up to 25%, 30% early mortality in patients above 65 getting such induction therapies, even in the very large academic center with expertise.

This has led to efforts to develop lower intensity treatments like azacitidine/decitabine, which have now been approved for about 10 to 12 years in the United States. They show response rates about 20%, 25%, with a median overall survival of 7 to 10 months, and at 3 years the number of people who have survival is about 15% to 20%. So this is a historical perspective, this is what we were doing for these elderly patients not fit for induction for the last decade.

Then we had a drug called venetoclax, which as a single agent showed limited efficacy in the relapsed/refractory setting. But when combined in the frontline with azacitidine and decitabine has shown dramatic response rates. The overall CR/CRi [complete response/complete response with incomplete hematologic recovery] rate now is about 70% to 72%. So not double, actually 3 times higher than we would get with azacitidine/decitabine alone. The median overall survival is 18 months, which is double of what we got with azacitidine or decitabine in large phase III studies, and the 3-year survival at this time looks at about 45% to 50%. So again, almost 2 to 3 times higher than what we expected with azacitidine/decitabine alone.

So for the first time now in AML [acute myeloid leukemia] therapy we have really a good chance in elderly patients who would not benefit from high-dose chemotherapy that they can get a lower intensity regimen and have almost a 50/50 chance of getting long-term survival, at least 3 years and beyond, which is the follow-up we have available. So this is probably the most important change in older AML therapy that has occurred ever. And so this is a major study and has led to a phase III study that will hopefully read out by the end of this year to show if we confirm these results that were seen in the phase II that I just discussed.

The other study, M14-387, that we’re doing in combination with venetoclax in the frontline elderly AML patients is a combination of low-dose cytarabine with venetoclax. This is a study that has enrolled extensively outside the United States, because low-dose cytarabine is frequently used in Europe and Australia. The PI [principal investigator] of the study is Dr Andrew Wei ,MBBS, PhD, who is a good colleague of ours and works on a lot of collaborations. With this combination we see that the overall response rate is a little bit lower than with the azacitidine or decitabine combinations. But in general, you know historically with low-dose cytarabine the response rates are about 10% to 14%, and with this combination we’re seeing about 55% to 60%. So again, 3 to 4 times higher response, and the median overall survival is about 12 to 13 months, which is again double of what you would get with low-dose cytarabine. Especially in people who have had prior hypomethylating agent treatment, like azacitidine/ decitabine for MDS [myelodysplastic syndrome], who then convert to AML, we feel that the efficacy of the low-dose cytarabine and venetoclax is better than doing azacitidine/venetoclax since these people are already resistant to the azacitidine. And in that subset even at MD Anderson and other large US institutions, this has led to a resurgence of the use of low-dose cytarabine-based combos, and may be a good option for those kind of patients.

The third study, G039902, looking at combination venetoclax is a novel combination. We have done the studies with azacitidine, decitabine, with low-dose cytarabine. Now we’re coming venetoclax with a drug called idasanutlin, which is an MDM2 inhibitor. There was a huge amount of preclinical data published in Cancer Cell about a year ago that was done at MD Anderson, Michael Andreeff ,MD, PhD, with Marina Konopleva,MD, PhD, that led to the development of the study. So it’s very nice where we actually have a very powerful preclinical rationale, and now we’re seeing clinical efficacy rather than just putting 2 drugs together and then trying to figure the rationale, which is often what we do.

In this study we had two arms. One arm was a combination of venetoclax with idasanutlin, the MDM2 inhibitor. The other was venetoclax in combination with cobimetinib, which is a MEK kinase inhibitor. This was a phase Ib dose escalation. And then expansion would be in the arm that we felt was efficacious.

We did not see very high efficacy in the venetoclax/cobimetinib arm. The overall response rate in these relapsed/refractory elderly patients was about 25% to 30%, which is a little bit higher than what you get with single-agent venetoclax, but not a great blockbuster. So we have actually stopped enrolling to that arm.

The arm where we are seeing efficacy is the combination of idasanutlin and venetoclax. Now again, to put this in perspective, unlike the other 2 venetoclax studies, which are in the frontline setting where we see the 55%, 70% CR/CRi, this is a relapse population, and this is an elderly relapse. So we actually are kind of picking the worst of worst, older patients who are difficult to treat already, and in the relapsed setting. Historically you would expect a response rate of 20% to 30% if you used chemotherapy such as fludarabine, cytarabine; or if you use another hypomethylating agent or other antibody treatments such as gemtuzumab.

So we are seeing a CR/CRi rate of about 45% at the effective dose combination level, and this study is now being expanded into a large study that will hopefully be reviewed for registration if we continue to maintain more than 40% CR/CRi, or 30%, 35% CR/CRh [complete response with partial hematologic recovery].

In addition, this study is also going to be moved into the front line because the thought process is if azacitidine/venetoclax is good and can give you 70%, 75% response with 17, 18 months’ survival, which is nice, but not enough; we would like to get to 24-, 28-month median and 3 year survivals of 80%. By adding idasanutlin, of course with dose modifications, interactions, etcetera, we would hopefully be able to further improve the outcome. So there is a frontline study of azacitidine/venetoclax with idasanutlin that we’ll be starting in the near future.

Transcript Edited for Clarity
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Transcript:

Naval G. Daver, MD
: This trial M14-358 combined a BCL2 inhibitor, venetoclax, with azacitidine or decitabine. It’s very important to know the historical perspective of how we got to the study.

We’ve used low intensity therapies in patients usually about 65 years old, more commonly in patients above 70, who we know will have a very high early mortality—early mortality is defined as 8-week mortality—with intensive therapy such as 3+7 [cytarabine/daunorubicin] or other Ara-C[cytarabine]/anthracycline combinations. And actually one of the large papers published for The University of Texas MD Anderson Cancer Center almost 10 years ago showed up to 25%, 30% early mortality in patients above 65 getting such induction therapies, even in the very large academic center with expertise.

This has led to efforts to develop lower intensity treatments like azacitidine/decitabine, which have now been approved for about 10 to 12 years in the United States. They show response rates about 20%, 25%, with a median overall survival of 7 to 10 months, and at 3 years the number of people who have survival is about 15% to 20%. So this is a historical perspective, this is what we were doing for these elderly patients not fit for induction for the last decade.

Then we had a drug called venetoclax, which as a single agent showed limited efficacy in the relapsed/refractory setting. But when combined in the frontline with azacitidine and decitabine has shown dramatic response rates. The overall CR/CRi [complete response/complete response with incomplete hematologic recovery] rate now is about 70% to 72%. So not double, actually 3 times higher than we would get with azacitidine/decitabine alone. The median overall survival is 18 months, which is double of what we got with azacitidine or decitabine in large phase III studies, and the 3-year survival at this time looks at about 45% to 50%. So again, almost 2 to 3 times higher than what we expected with azacitidine/decitabine alone.

So for the first time now in AML [acute myeloid leukemia] therapy we have really a good chance in elderly patients who would not benefit from high-dose chemotherapy that they can get a lower intensity regimen and have almost a 50/50 chance of getting long-term survival, at least 3 years and beyond, which is the follow-up we have available. So this is probably the most important change in older AML therapy that has occurred ever. And so this is a major study and has led to a phase III study that will hopefully read out by the end of this year to show if we confirm these results that were seen in the phase II that I just discussed.

The other study, M14-387, that we’re doing in combination with venetoclax in the frontline elderly AML patients is a combination of low-dose cytarabine with venetoclax. This is a study that has enrolled extensively outside the United States, because low-dose cytarabine is frequently used in Europe and Australia. The PI [principal investigator] of the study is Dr Andrew Wei ,MBBS, PhD, who is a good colleague of ours and works on a lot of collaborations. With this combination we see that the overall response rate is a little bit lower than with the azacitidine or decitabine combinations. But in general, you know historically with low-dose cytarabine the response rates are about 10% to 14%, and with this combination we’re seeing about 55% to 60%. So again, 3 to 4 times higher response, and the median overall survival is about 12 to 13 months, which is again double of what you would get with low-dose cytarabine. Especially in people who have had prior hypomethylating agent treatment, like azacitidine/ decitabine for MDS [myelodysplastic syndrome], who then convert to AML, we feel that the efficacy of the low-dose cytarabine and venetoclax is better than doing azacitidine/venetoclax since these people are already resistant to the azacitidine. And in that subset even at MD Anderson and other large US institutions, this has led to a resurgence of the use of low-dose cytarabine-based combos, and may be a good option for those kind of patients.

The third study, G039902, looking at combination venetoclax is a novel combination. We have done the studies with azacitidine, decitabine, with low-dose cytarabine. Now we’re coming venetoclax with a drug called idasanutlin, which is an MDM2 inhibitor. There was a huge amount of preclinical data published in Cancer Cell about a year ago that was done at MD Anderson, Michael Andreeff ,MD, PhD, with Marina Konopleva,MD, PhD, that led to the development of the study. So it’s very nice where we actually have a very powerful preclinical rationale, and now we’re seeing clinical efficacy rather than just putting 2 drugs together and then trying to figure the rationale, which is often what we do.

In this study we had two arms. One arm was a combination of venetoclax with idasanutlin, the MDM2 inhibitor. The other was venetoclax in combination with cobimetinib, which is a MEK kinase inhibitor. This was a phase Ib dose escalation. And then expansion would be in the arm that we felt was efficacious.

We did not see very high efficacy in the venetoclax/cobimetinib arm. The overall response rate in these relapsed/refractory elderly patients was about 25% to 30%, which is a little bit higher than what you get with single-agent venetoclax, but not a great blockbuster. So we have actually stopped enrolling to that arm.

The arm where we are seeing efficacy is the combination of idasanutlin and venetoclax. Now again, to put this in perspective, unlike the other 2 venetoclax studies, which are in the frontline setting where we see the 55%, 70% CR/CRi, this is a relapse population, and this is an elderly relapse. So we actually are kind of picking the worst of worst, older patients who are difficult to treat already, and in the relapsed setting. Historically you would expect a response rate of 20% to 30% if you used chemotherapy such as fludarabine, cytarabine; or if you use another hypomethylating agent or other antibody treatments such as gemtuzumab.

So we are seeing a CR/CRi rate of about 45% at the effective dose combination level, and this study is now being expanded into a large study that will hopefully be reviewed for registration if we continue to maintain more than 40% CR/CRi, or 30%, 35% CR/CRh [complete response with partial hematologic recovery].

In addition, this study is also going to be moved into the front line because the thought process is if azacitidine/venetoclax is good and can give you 70%, 75% response with 17, 18 months’ survival, which is nice, but not enough; we would like to get to 24-, 28-month median and 3 year survivals of 80%. By adding idasanutlin, of course with dose modifications, interactions, etcetera, we would hopefully be able to further improve the outcome. So there is a frontline study of azacitidine/venetoclax with idasanutlin that we’ll be starting in the near future.

Transcript Edited for Clarity
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