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Immunotherapeutic Agents Against Follicular Lymphoma

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: Wednesday, Feb 13, 2019



Transcript: 

Ian W. Flinn, MD, PhD: Let’s talk about other new approaches. We’ve got a lot of new agents out there. There are combinations of looking at checkpoint inhibitors with antibodies, with obinutuzumab and lenalidomide. Let’s start there. Nathan, you’ve done a lot of work obviously with the R2. And I think you also have data with obinutuzumab. How about with atezolizumab, using 3 agents?

Nathan H. Fowler, MD: It’s a very interesting concept. With atezolizumab, which is a checkpoint inhibitor, we had hoped, or I guess the hypothesis is that you can further augment the immune response. Again, you give it with lenalidomide, which is an immune modulator and an antibody, we could create this kind of perfect storm that attacks the follicular lymphoma. There were studies combining checkpoint inhibitors with lenalidomide in myeloma that unfortunately showed excess mortality. And so I think that for that triplet, at least in lymphoma, we’ve been very cautious proceeding with atezolizumab or any of the other checkpoint inhibitors combined with lenalidomide because of the worry of excess immune flare or excess toxicity, infections, etc.

There was an abstract by Gilles Salles at this meeting where they combined atezo with obinutuzumab and lenalidomide. I looked at this yesterday. I was looking very carefully. Not a lot of –itises. So they didn’t report any pneumonitis or hepatitis or colitis. Now, there was adverse-event rate, which was I think around 70% or 80% grade 3 or higher, but it didn’t appear that those were immune mediated. So maybe it’s something we could look at further, but at least in the myeloma setting, there were unexpected toxicities which halted that triplet.

Nathan H. Fowler, MD: So combining lenalidomide with other antibodies also looks as if it could be a very interesting concept. We now have data with lenalidomide and obinutuzumab. My colleague Loretta Nastoupil presented that data, and at this ASH, Franck Morschhauser is presenting lenalidomide-obinutuzumab in frontline follicular lymphoma, 100 patients, and it looks quite interesting. We also have seen lenalidomide combined with anti-CD19 agents, both in follicular and in large cell lymphoma, presented by Gilles Salles, which also looks really intriguing, especially again in these kind of hard-to-treat patients. So I do think there are other combinations we can look at with lenalidomide. I’m waiting a little bit for the checkpoint inhibitors, but monoclonal antibodies I think are wide open.

Ian W. Flinn, MD, PhD: For other monoclonal antibodies, polatuzumab vedotin, antibody drug conjugates, it’s fairly advanced in development. Scott, what do you think of this data?

Scott Huntington, MD, MPH, MSc: Yeah, I think the data are most mature in refractory large cell lymphoma, and I think they’re encouraging when combined with bendamustine-rituximab. It seems to be safe. It seems to improve overall response rate and certainly durability or PFS [progression-free survival]. I think it’s likely to move up with follicular, in terms of combination therapy as well. There are some trials that are exciting, combining that with, say, venetoclax or obinutuzumab. So I think pola will likely find its way to follicular lymphoma as well.

Ian W. Flinn, MD, PhD: Yeah, I guess for some of the initial studies with higher doses and more prolonged use, there are issues with neuropathy. But in the subsequent dose, reducing and limiting how many cycles you give, that seems like the adverse-event profile is a lot better. Are you using CAR [chimeric antigen receptors] T cells? You have trials with CAR T cells available?

Ajay Gopal, MD, FACP: We have trials. We’re obviously excited about this modality. The approvals are in aggressive B-cell lymphomas, but the data, very early anecdotal data, suggest that the response rates might be even higher in indolent histologies. I suspect this will be something else in our armamentarium over the years. This will come and be available. I think we’ll need to be sure that we’re doing it in the right patients. Their risk is considerably higher than anything we’ve talked about so far, except for maybe allotransplant. So we want to make sure that this is applied in the proper patient population, keeping in mind that 80% will have a normal life span. But certainly there are some very exciting early data.

Ian W. Flinn, MD, PhD: You brought up a really important point, and it gets all back to sequencing that we’ve discussed. When do you pull the trigger on something that may have awesome results but could come with substantial toxicity? I guess the thing I worry most about is the neurotoxicity. The cytokine release you can easily manage. Nathan, I wanted to ask you 1 more thing. I think your colleague Loretta Nastoupil also has data with pembro and rituximab, a checkpoint inhibitor without lenalidomide.

Nathan H. Fowler, MD: The data look good. This was in relapsed patients, and we saw a response rate around 80%. The CR [complete response] rate was, I want to say, around 50%. It’s hard to know. The problem with the studies in which you’re using rituximab as a partner is that it’s hard to know the contribution of rituximab versus pembrolizumab. That response rate is a bit higher than we would expect with single-agent rituximab, and the CR rate was higher. But it will kind of require other studies to truly understand the contribution of pembrolizumab. Unfortunately, pembrolizumab as a single agent, and this was presented at ASCO [American Society of Clinical Oncologists Annual Meeting], had a 9% response rate in follicular. So as a single agent, checkpoint inhibitors have been a bit underwhelming in the low-grade lymphomas. Maybe combining with rituximab, again augmenting ADCC [antibody-dependent cellular cytotoxicity] could be the way to move forward. But I think it requires larger trials.

Ian W. Flinn, MD, PhD: I thought there was some. I mean, I read through the data and I thought that was interesting, but I also worried a little bit about the adverse events, right? There were some checkpoint inhibitor problems.

Nathan H. Fowler, MD: We have seen a couple of cases of pneumonitis and inflammation that we would not expect to see with rituximab as a single agent. So there clearly, I think, was some additional toxicity adding a checkpoint.

Ian W. Flinn, MD, PhD: And clearly a person in need, the right patient, might be willing to take that adverse event, but it’s not for everybody.

Ajay Gopal, MD, FACP: We’re actually doing a confirmatory trial at our center with Rituxan-pembrolizumab to see if we can, in rituximab-refractory patients, see what data we get. And we’re also looking, as a window study with single-agent pembrolizumab in the frontline setting for high-risk follicular, with the idea that they have a replete immune system. And you actually might see the ceiling of the response rate but very selected patients for that.

Scott Huntington, MD, MPH, MSc: I think there are some interesting data on intratumoral injections as well combined with checkpoint inhibitors in a select population. Intratumoral radiation and checkpoint may lead to some durable responses—from the Stanford University group and the Cedar Sinai group. It’s an exciting time. There are certainly lots of things that we combine. I think the trials need to be well developed and rational. I think we’re moving the field forward, certainly.


Transcript Edited for Clarity
 

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Transcript: 

Ian W. Flinn, MD, PhD: Let’s talk about other new approaches. We’ve got a lot of new agents out there. There are combinations of looking at checkpoint inhibitors with antibodies, with obinutuzumab and lenalidomide. Let’s start there. Nathan, you’ve done a lot of work obviously with the R2. And I think you also have data with obinutuzumab. How about with atezolizumab, using 3 agents?

Nathan H. Fowler, MD: It’s a very interesting concept. With atezolizumab, which is a checkpoint inhibitor, we had hoped, or I guess the hypothesis is that you can further augment the immune response. Again, you give it with lenalidomide, which is an immune modulator and an antibody, we could create this kind of perfect storm that attacks the follicular lymphoma. There were studies combining checkpoint inhibitors with lenalidomide in myeloma that unfortunately showed excess mortality. And so I think that for that triplet, at least in lymphoma, we’ve been very cautious proceeding with atezolizumab or any of the other checkpoint inhibitors combined with lenalidomide because of the worry of excess immune flare or excess toxicity, infections, etc.

There was an abstract by Gilles Salles at this meeting where they combined atezo with obinutuzumab and lenalidomide. I looked at this yesterday. I was looking very carefully. Not a lot of –itises. So they didn’t report any pneumonitis or hepatitis or colitis. Now, there was adverse-event rate, which was I think around 70% or 80% grade 3 or higher, but it didn’t appear that those were immune mediated. So maybe it’s something we could look at further, but at least in the myeloma setting, there were unexpected toxicities which halted that triplet.

Nathan H. Fowler, MD: So combining lenalidomide with other antibodies also looks as if it could be a very interesting concept. We now have data with lenalidomide and obinutuzumab. My colleague Loretta Nastoupil presented that data, and at this ASH, Franck Morschhauser is presenting lenalidomide-obinutuzumab in frontline follicular lymphoma, 100 patients, and it looks quite interesting. We also have seen lenalidomide combined with anti-CD19 agents, both in follicular and in large cell lymphoma, presented by Gilles Salles, which also looks really intriguing, especially again in these kind of hard-to-treat patients. So I do think there are other combinations we can look at with lenalidomide. I’m waiting a little bit for the checkpoint inhibitors, but monoclonal antibodies I think are wide open.

Ian W. Flinn, MD, PhD: For other monoclonal antibodies, polatuzumab vedotin, antibody drug conjugates, it’s fairly advanced in development. Scott, what do you think of this data?

Scott Huntington, MD, MPH, MSc: Yeah, I think the data are most mature in refractory large cell lymphoma, and I think they’re encouraging when combined with bendamustine-rituximab. It seems to be safe. It seems to improve overall response rate and certainly durability or PFS [progression-free survival]. I think it’s likely to move up with follicular, in terms of combination therapy as well. There are some trials that are exciting, combining that with, say, venetoclax or obinutuzumab. So I think pola will likely find its way to follicular lymphoma as well.

Ian W. Flinn, MD, PhD: Yeah, I guess for some of the initial studies with higher doses and more prolonged use, there are issues with neuropathy. But in the subsequent dose, reducing and limiting how many cycles you give, that seems like the adverse-event profile is a lot better. Are you using CAR [chimeric antigen receptors] T cells? You have trials with CAR T cells available?

Ajay Gopal, MD, FACP: We have trials. We’re obviously excited about this modality. The approvals are in aggressive B-cell lymphomas, but the data, very early anecdotal data, suggest that the response rates might be even higher in indolent histologies. I suspect this will be something else in our armamentarium over the years. This will come and be available. I think we’ll need to be sure that we’re doing it in the right patients. Their risk is considerably higher than anything we’ve talked about so far, except for maybe allotransplant. So we want to make sure that this is applied in the proper patient population, keeping in mind that 80% will have a normal life span. But certainly there are some very exciting early data.

Ian W. Flinn, MD, PhD: You brought up a really important point, and it gets all back to sequencing that we’ve discussed. When do you pull the trigger on something that may have awesome results but could come with substantial toxicity? I guess the thing I worry most about is the neurotoxicity. The cytokine release you can easily manage. Nathan, I wanted to ask you 1 more thing. I think your colleague Loretta Nastoupil also has data with pembro and rituximab, a checkpoint inhibitor without lenalidomide.

Nathan H. Fowler, MD: The data look good. This was in relapsed patients, and we saw a response rate around 80%. The CR [complete response] rate was, I want to say, around 50%. It’s hard to know. The problem with the studies in which you’re using rituximab as a partner is that it’s hard to know the contribution of rituximab versus pembrolizumab. That response rate is a bit higher than we would expect with single-agent rituximab, and the CR rate was higher. But it will kind of require other studies to truly understand the contribution of pembrolizumab. Unfortunately, pembrolizumab as a single agent, and this was presented at ASCO [American Society of Clinical Oncologists Annual Meeting], had a 9% response rate in follicular. So as a single agent, checkpoint inhibitors have been a bit underwhelming in the low-grade lymphomas. Maybe combining with rituximab, again augmenting ADCC [antibody-dependent cellular cytotoxicity] could be the way to move forward. But I think it requires larger trials.

Ian W. Flinn, MD, PhD: I thought there was some. I mean, I read through the data and I thought that was interesting, but I also worried a little bit about the adverse events, right? There were some checkpoint inhibitor problems.

Nathan H. Fowler, MD: We have seen a couple of cases of pneumonitis and inflammation that we would not expect to see with rituximab as a single agent. So there clearly, I think, was some additional toxicity adding a checkpoint.

Ian W. Flinn, MD, PhD: And clearly a person in need, the right patient, might be willing to take that adverse event, but it’s not for everybody.

Ajay Gopal, MD, FACP: We’re actually doing a confirmatory trial at our center with Rituxan-pembrolizumab to see if we can, in rituximab-refractory patients, see what data we get. And we’re also looking, as a window study with single-agent pembrolizumab in the frontline setting for high-risk follicular, with the idea that they have a replete immune system. And you actually might see the ceiling of the response rate but very selected patients for that.

Scott Huntington, MD, MPH, MSc: I think there are some interesting data on intratumoral injections as well combined with checkpoint inhibitors in a select population. Intratumoral radiation and checkpoint may lead to some durable responses—from the Stanford University group and the Cedar Sinai group. It’s an exciting time. There are certainly lots of things that we combine. I think the trials need to be well developed and rational. I think we’re moving the field forward, certainly.


Transcript Edited for Clarity
 
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