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Combination Therapies in CLL

Panelists: William G. Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center; Steven Coutre, MD, Stanford University Medical Center; Matthew S. Davids, MD, MMSc, Dana-Farber Cancer Institute; Nicole Lamanna, MD, Columbia University Medical Center; Shuo Ma, MD, PhD, Robert H. Lurie Comprehensive Cancer Center
Published: Monday, Feb 12, 2018



Transcript: 

William G. Wierda, MD, PhD: Matt, there were several abstracts at this meeting looking at combinations. So, that’s the next obvious question. We’d like to be able to treat patients and give them a treatment-free interval. Maybe you can comment on where the field is going and what’s the strategy for a combination therapy.

Matthew S. Davids, MD, MMSc: So, this is becoming a complicated area. We had a session yesterday with a number of these and it’s a bit of an alphabet soup. I think some of the key agents to consider are ibrutinib, venetoclax, and obinutuzumab, and you’re seeing all different versions of combinations of these. Some studies, like the one that was presented from your center, were looking at the doublet of ibrutinib with venetoclax without a CD20 antibody. The group at Ohio State University Comprehensive Cancer Center presented 3-drug data with ibrutinib, venetoclax, and obinutuzumab. We’ve seen some data now from the UK Group and Pete Hillman looking at their CLARITY study with ibrutinib and venetoclax. And there’s different durations of therapy based on various factors. So, I think that the jury is still out as to which approach is best.

These are all early, mainly phase II studies. I can say that they all look very promising. We’re really seeing some dramatic rates of MRD negativity. Another one to mention is the venetoclax/obinutuzumab study, the phase Ib study that Ian Flinn presented here, which showed a 63% rate of bone marrow MRD negativity in a frontline CLL population. I think that’s very impressive without the need for chemoimmunotherapy.

So, I think as we move forward, it’s going to be a challenge to figure out which of these regimens to take into the phase III setting. There have been efforts now to expand the FLAIR study in the UK to include venetoclax-containing arms. The German CLL13 study, as was mentioned before, has now been also compared to chemoimmunotherapy. Eventually, we’ll have some answers, but right now we just have a lot of very promising phase II data. It’s challenging because right now in the United States, we don’t have access to combinations of these agents so we can’t really do this off-label. I don’t think most insurers would pay for both novel agents at the same time. So, I think these data are going to need to be maturing more before we see them in practice.

William G. Wierda, MD, PhD: And what will you be looking for in terms of that strategy? How will we show that that’s an advance with the combinations?

Matthew S. Davids, MD, MMSc: I think particularly having a time-limited therapy with novel agents will be a major advance compared to having to continue patients on ibrutinib monotherapy, for example. But again, I think it depends on the patient population. So, going back to what Steve was saying, if I have an 82-year-old who wants to have good disease control, I think ibrutinib monotherapy may be a great option. But if I have a 62-year-old who wants to live another 30 years, that might be a patient I want to focus on a time-limited combination approach, get them into an MRD-negative state, and then hopefully give them a long treatment-free interval before they may need treatment again.

Steven Coutre, MD: And all of those trials that were presented, you’re right, it was an alphabet soup. All were very impressive. Whether it’s upfront or relapsed, the median age was in the 60s. These are the folks who we have to really focus on, especially with the combinations, especially with time-limited therapy. And to Bill’s point, you know the ones really getting to undetectable disease because that’s going to at least translate into prolonged benefit, I think.

So, I think the German trial, which is multiarmed, that might be a registration trial in the upfront setting. The next planned US Intergroup trial for the younger patients—the follow-up of the FCR, which is IRR—is planned to be ibrutinib/obinutuzumab versus ibrutinib/obinutuzumab/venetoclax, a year of venetoclax, 18 months of ibrutinib, and then stop. I think it’s going to be exciting. I think a year from now at ASH, we’ll get some more good data.

Matthew S. Davids, MD, MMSc: And of course, just as we start to work all of this out with the first-generation agents, we have all these exciting second-generation agents. Whether acalabrutinib and ublituximab and umbralisib will make a difference in these types of combination regimens is going to keep us in business in clinical trials for a long time.

William G. Wierda, MD, PhD: The thing that I would add with regard to your comment and the age, I think it’s very important for us to develop regimens that are appropriate and effective and tolerated in the most common population of patients we have. Just with our ibrutinib/venetoclax experience, it appears that that combination is equally well tolerated in patients who are over 70, for example, compared to younger than 70, and it’s active. So, I think, from my own perspective, that we’re moving into this era where we can talk about MRD-negative remissions in 75-year-olds.

Steven Coutre, MD: Yes, and stopping therapy because of that, which is a big advantage.

Shuo Ma, MD, PhD: And then your frontline population by 12 months, 100% MRD elimination.

William G. Wierda, MD, PhD: But it was an early report and there were very limited numbers that had gotten all the way out. So, it’s an ongoing trial. Patients can get up to 2 years of therapy. So, we’ll see where there’s more work to do.

Transcript Edited for Clarity 

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Transcript: 

William G. Wierda, MD, PhD: Matt, there were several abstracts at this meeting looking at combinations. So, that’s the next obvious question. We’d like to be able to treat patients and give them a treatment-free interval. Maybe you can comment on where the field is going and what’s the strategy for a combination therapy.

Matthew S. Davids, MD, MMSc: So, this is becoming a complicated area. We had a session yesterday with a number of these and it’s a bit of an alphabet soup. I think some of the key agents to consider are ibrutinib, venetoclax, and obinutuzumab, and you’re seeing all different versions of combinations of these. Some studies, like the one that was presented from your center, were looking at the doublet of ibrutinib with venetoclax without a CD20 antibody. The group at Ohio State University Comprehensive Cancer Center presented 3-drug data with ibrutinib, venetoclax, and obinutuzumab. We’ve seen some data now from the UK Group and Pete Hillman looking at their CLARITY study with ibrutinib and venetoclax. And there’s different durations of therapy based on various factors. So, I think that the jury is still out as to which approach is best.

These are all early, mainly phase II studies. I can say that they all look very promising. We’re really seeing some dramatic rates of MRD negativity. Another one to mention is the venetoclax/obinutuzumab study, the phase Ib study that Ian Flinn presented here, which showed a 63% rate of bone marrow MRD negativity in a frontline CLL population. I think that’s very impressive without the need for chemoimmunotherapy.

So, I think as we move forward, it’s going to be a challenge to figure out which of these regimens to take into the phase III setting. There have been efforts now to expand the FLAIR study in the UK to include venetoclax-containing arms. The German CLL13 study, as was mentioned before, has now been also compared to chemoimmunotherapy. Eventually, we’ll have some answers, but right now we just have a lot of very promising phase II data. It’s challenging because right now in the United States, we don’t have access to combinations of these agents so we can’t really do this off-label. I don’t think most insurers would pay for both novel agents at the same time. So, I think these data are going to need to be maturing more before we see them in practice.

William G. Wierda, MD, PhD: And what will you be looking for in terms of that strategy? How will we show that that’s an advance with the combinations?

Matthew S. Davids, MD, MMSc: I think particularly having a time-limited therapy with novel agents will be a major advance compared to having to continue patients on ibrutinib monotherapy, for example. But again, I think it depends on the patient population. So, going back to what Steve was saying, if I have an 82-year-old who wants to have good disease control, I think ibrutinib monotherapy may be a great option. But if I have a 62-year-old who wants to live another 30 years, that might be a patient I want to focus on a time-limited combination approach, get them into an MRD-negative state, and then hopefully give them a long treatment-free interval before they may need treatment again.

Steven Coutre, MD: And all of those trials that were presented, you’re right, it was an alphabet soup. All were very impressive. Whether it’s upfront or relapsed, the median age was in the 60s. These are the folks who we have to really focus on, especially with the combinations, especially with time-limited therapy. And to Bill’s point, you know the ones really getting to undetectable disease because that’s going to at least translate into prolonged benefit, I think.

So, I think the German trial, which is multiarmed, that might be a registration trial in the upfront setting. The next planned US Intergroup trial for the younger patients—the follow-up of the FCR, which is IRR—is planned to be ibrutinib/obinutuzumab versus ibrutinib/obinutuzumab/venetoclax, a year of venetoclax, 18 months of ibrutinib, and then stop. I think it’s going to be exciting. I think a year from now at ASH, we’ll get some more good data.

Matthew S. Davids, MD, MMSc: And of course, just as we start to work all of this out with the first-generation agents, we have all these exciting second-generation agents. Whether acalabrutinib and ublituximab and umbralisib will make a difference in these types of combination regimens is going to keep us in business in clinical trials for a long time.

William G. Wierda, MD, PhD: The thing that I would add with regard to your comment and the age, I think it’s very important for us to develop regimens that are appropriate and effective and tolerated in the most common population of patients we have. Just with our ibrutinib/venetoclax experience, it appears that that combination is equally well tolerated in patients who are over 70, for example, compared to younger than 70, and it’s active. So, I think, from my own perspective, that we’re moving into this era where we can talk about MRD-negative remissions in 75-year-olds.

Steven Coutre, MD: Yes, and stopping therapy because of that, which is a big advantage.

Shuo Ma, MD, PhD: And then your frontline population by 12 months, 100% MRD elimination.

William G. Wierda, MD, PhD: But it was an early report and there were very limited numbers that had gotten all the way out. So, it’s an ongoing trial. Patients can get up to 2 years of therapy. So, we’ll see where there’s more work to do.

Transcript Edited for Clarity 
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