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Emerging Therapies and Combinations

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Feb 21, 2019



Transcript: 

Ian W. Flinn, MD, PhD: Scott, let’s talk about a slightly different topic, a little bit away from  immunotherapy, but venetoclax, right? I guess I would have thought if ever there was a disease that was going to respond to venetoclax where BCL2 is important, it would be follicular lymphoma.

Scott Huntington, MD, MPH, MSc: Yes.

Ian W. Flinn, MD, PhD: But the results so far as single-agent have not been as impressive as I think many of us had hoped. Now we’re seeing studies, the CONTRALTO data are being presented combining venetoclax with rituximab or venetoclax with bendamustine/rituximab. And what do you think?

Scott Huntington, MD, MPH, MSc: I think that’s been a surprise for all of us where this is a BCL2-driven malignancy. These are highly potent BCL2 inhibitors, and we’re not seeing great responses, even at much higher doses than we see say for CLL [chronic lymphocytic leukemia]. The data presented here with bendamustine and rituximab with venetoclax or venetoclax/rituximab I think are difficult to interpret. We need some randomized data. Certainly more cytopenias combining venetoclax with bendamustine/rituximab, and I think we need some more basic science research of trying to tease out who’s the right partner with venetoclax in follicular lymphoma, is it chemotherapy, is it other novel agents? But there’s certainly some more work to be done there.

Ian W. Flinn, MD, PhD: It was a confusing study. There were all these different arms and you could select rituximab, a lead-in phase. But then there was a portion where it was a randomization, and it really didn’t look to me like the venetoclax added anything to overaIl survival, which was really disappointing. I really thought this was going to be a backbone. The rituximab part, there was no randomization, but maybe with a combination of that, it could be a backbone.

Scott Huntington, MD, MPH, MSc: Yes. I think the takeaway point from the authors was that you could have similar efficacy of BR [bendamustine/rituximab] to VEN [venetoclax] combination, but the number of cycles that the patients got because of toxicities was lower, and so the efficacy was. I would take, if efficacy is going to be the same, I would take the lower adverse effect profile. So I think that combination—bendamustine/rituximab/venetoclax—is unlikely to move forward as a major treatment.

Ian W. Flinn, MD, PhD: As one of the authors, I feel like you’re always faced with trying to find something that’s positive. But I think we’re still going to have to do more work with venetoclax. I feel like there’s got to be a place for venetoclax in the treatment of follicular lymphoma at some point.

Nathan H. Fowler, MD: My sense, there may be other family members of BCL2 that are more relevant. As you know, venetoclax is very specific. We, as a field, kind of hypothesized why we have not seen the responses. My gut is either, again, as I mentioned earlier in the program that there are other mutations that occur as this follicular lymphoma evolves. And, although BCL2 is the hallmark mutation, by the time patients develop overt disease, there are other drivers that may be more relevant. So, even if you shut down BCL2, the cell is somewhat on autopilot, so you take out the driver, but the car keeps moving. That or again, it’s a target that it’s not hitting. But I agree, it’s a little atypical that the hallmark mutation, if you knock that out, it does not appear to be, as a single-agent, all that effective.

Ajay K. Gopal, MD, FACP: Yes, I take it as really kind of humbling and reminding us why we do clinical trials, why we need translational science. But we ultimately need to do the clinical trial.

Ian W. Flinn, MD, PhD: You’re right, it is humbling. How about bispecifics? We spent a lot of time talking about other immunotherapeutics, but there are several bispecifics that are making their way through that.

Scott Huntington, MD, MPH, MSc: So certainly anti-CD3, bringing T cells, anti-CD20 is a drug that’s being studied in multiple settings. I think there is a signal of activity in follicular lymphoma, and I think we do see more toxicity in that compared to rituximab, certainly, some CRS [cytokine release syndrome]. There is some hepatotoxicity reported. So I think it’s also finding those patients that are early relapsers where we need to add these novel therapies and moving that in an upfront setting where patients will do quite well, 80% with standard therapy. It’s a tough sell. The administration of the bispecifics is also tricky. Some are infusion, some are weekly. I think there is some movement perhaps to subQ [subcutaneous] that could help. I think there is certainly more work but some exciting preliminary data.

Ian W. Flinn, MD, PhD: I think the hope was that this would be an off-the-shelf CAR [chimeric antigen receptor] T cell and maybe it could be at some point with the next generations of these molecules to get that powerful impact. But now combining it with the checkpoint inhibitors. We were talking about the checkpoint inhibitors combined with rituximab, with some adverse events. I’m sure there is going to be more with this. And, again, the patient selection is key.

Scott Huntington, MD, MPH, MSc: It’s key, sure.

Ian W. Flinn, MD, PhD: There’s another really exciting therapy that we haven’t talked about so far, that’s blocking this 47 axis. There is a recent publication in the New England Journal of Medicine about this. We’ve been using it and part of that experience, I’m biased, but I think it’s fantastic. Can you explain the biology here, Ajay, and your thoughts about it?

Ajay K. Gopal, MD, FACP: Basically, I think the simple way to think about it is as a macrophage checkpoint inhibitor. We know that there’s an immunosuppressive environment within the tumor microenvironment, and many of these macrophages are switched off by targeting CD47. This is similar to targeting PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1] in the T-cell synapse. So it’s really a macrophage checkpoint inhibitor, and the recent data in diffuse large B-cell are most exciting in combination with rituximab. These first-generation drugs are very exciting. There are a number of compounds out there. There is some cross-reactivity with red blood cells, as I understand, and there’s some hemolytic anemia. I’m really excited as we further tweak this approach to find something that’s really going to be widely applicable. But you can imagine us fine-tuning each element of the immune system to eradicate the malignancy.

Ian W. Flinn, MD, PhD: It is exciting. I think that none of these companies should rest on their laurels because there’s many people coming up behind it. Another group looking at blocking the ligand rather than the receptor, sort of like the PD-L1, PD-1, there’s a same sort of approach that you can do with the CD47 axis. So, yes, it seems pretty exciting. We’ll see how that plays out.


Transcript Edited for Clarity
 

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Transcript: 

Ian W. Flinn, MD, PhD: Scott, let’s talk about a slightly different topic, a little bit away from  immunotherapy, but venetoclax, right? I guess I would have thought if ever there was a disease that was going to respond to venetoclax where BCL2 is important, it would be follicular lymphoma.

Scott Huntington, MD, MPH, MSc: Yes.

Ian W. Flinn, MD, PhD: But the results so far as single-agent have not been as impressive as I think many of us had hoped. Now we’re seeing studies, the CONTRALTO data are being presented combining venetoclax with rituximab or venetoclax with bendamustine/rituximab. And what do you think?

Scott Huntington, MD, MPH, MSc: I think that’s been a surprise for all of us where this is a BCL2-driven malignancy. These are highly potent BCL2 inhibitors, and we’re not seeing great responses, even at much higher doses than we see say for CLL [chronic lymphocytic leukemia]. The data presented here with bendamustine and rituximab with venetoclax or venetoclax/rituximab I think are difficult to interpret. We need some randomized data. Certainly more cytopenias combining venetoclax with bendamustine/rituximab, and I think we need some more basic science research of trying to tease out who’s the right partner with venetoclax in follicular lymphoma, is it chemotherapy, is it other novel agents? But there’s certainly some more work to be done there.

Ian W. Flinn, MD, PhD: It was a confusing study. There were all these different arms and you could select rituximab, a lead-in phase. But then there was a portion where it was a randomization, and it really didn’t look to me like the venetoclax added anything to overaIl survival, which was really disappointing. I really thought this was going to be a backbone. The rituximab part, there was no randomization, but maybe with a combination of that, it could be a backbone.

Scott Huntington, MD, MPH, MSc: Yes. I think the takeaway point from the authors was that you could have similar efficacy of BR [bendamustine/rituximab] to VEN [venetoclax] combination, but the number of cycles that the patients got because of toxicities was lower, and so the efficacy was. I would take, if efficacy is going to be the same, I would take the lower adverse effect profile. So I think that combination—bendamustine/rituximab/venetoclax—is unlikely to move forward as a major treatment.

Ian W. Flinn, MD, PhD: As one of the authors, I feel like you’re always faced with trying to find something that’s positive. But I think we’re still going to have to do more work with venetoclax. I feel like there’s got to be a place for venetoclax in the treatment of follicular lymphoma at some point.

Nathan H. Fowler, MD: My sense, there may be other family members of BCL2 that are more relevant. As you know, venetoclax is very specific. We, as a field, kind of hypothesized why we have not seen the responses. My gut is either, again, as I mentioned earlier in the program that there are other mutations that occur as this follicular lymphoma evolves. And, although BCL2 is the hallmark mutation, by the time patients develop overt disease, there are other drivers that may be more relevant. So, even if you shut down BCL2, the cell is somewhat on autopilot, so you take out the driver, but the car keeps moving. That or again, it’s a target that it’s not hitting. But I agree, it’s a little atypical that the hallmark mutation, if you knock that out, it does not appear to be, as a single-agent, all that effective.

Ajay K. Gopal, MD, FACP: Yes, I take it as really kind of humbling and reminding us why we do clinical trials, why we need translational science. But we ultimately need to do the clinical trial.

Ian W. Flinn, MD, PhD: You’re right, it is humbling. How about bispecifics? We spent a lot of time talking about other immunotherapeutics, but there are several bispecifics that are making their way through that.

Scott Huntington, MD, MPH, MSc: So certainly anti-CD3, bringing T cells, anti-CD20 is a drug that’s being studied in multiple settings. I think there is a signal of activity in follicular lymphoma, and I think we do see more toxicity in that compared to rituximab, certainly, some CRS [cytokine release syndrome]. There is some hepatotoxicity reported. So I think it’s also finding those patients that are early relapsers where we need to add these novel therapies and moving that in an upfront setting where patients will do quite well, 80% with standard therapy. It’s a tough sell. The administration of the bispecifics is also tricky. Some are infusion, some are weekly. I think there is some movement perhaps to subQ [subcutaneous] that could help. I think there is certainly more work but some exciting preliminary data.

Ian W. Flinn, MD, PhD: I think the hope was that this would be an off-the-shelf CAR [chimeric antigen receptor] T cell and maybe it could be at some point with the next generations of these molecules to get that powerful impact. But now combining it with the checkpoint inhibitors. We were talking about the checkpoint inhibitors combined with rituximab, with some adverse events. I’m sure there is going to be more with this. And, again, the patient selection is key.

Scott Huntington, MD, MPH, MSc: It’s key, sure.

Ian W. Flinn, MD, PhD: There’s another really exciting therapy that we haven’t talked about so far, that’s blocking this 47 axis. There is a recent publication in the New England Journal of Medicine about this. We’ve been using it and part of that experience, I’m biased, but I think it’s fantastic. Can you explain the biology here, Ajay, and your thoughts about it?

Ajay K. Gopal, MD, FACP: Basically, I think the simple way to think about it is as a macrophage checkpoint inhibitor. We know that there’s an immunosuppressive environment within the tumor microenvironment, and many of these macrophages are switched off by targeting CD47. This is similar to targeting PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1] in the T-cell synapse. So it’s really a macrophage checkpoint inhibitor, and the recent data in diffuse large B-cell are most exciting in combination with rituximab. These first-generation drugs are very exciting. There are a number of compounds out there. There is some cross-reactivity with red blood cells, as I understand, and there’s some hemolytic anemia. I’m really excited as we further tweak this approach to find something that’s really going to be widely applicable. But you can imagine us fine-tuning each element of the immune system to eradicate the malignancy.

Ian W. Flinn, MD, PhD: It is exciting. I think that none of these companies should rest on their laurels because there’s many people coming up behind it. Another group looking at blocking the ligand rather than the receptor, sort of like the PD-L1, PD-1, there’s a same sort of approach that you can do with the CD47 axis. So, yes, it seems pretty exciting. We’ll see how that plays out.


Transcript Edited for Clarity
 
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