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Follicular Lymphoma: Results from Phase II GALLIUM Study

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Joshua Brody, MD, Icahn School of Medicine at Mount Sanai; Nathan H. Fowler, MD, University of Texas MD Anderson Cancer Center; John P. Leonard, MD, New York Presbyterian/Weill Cornell Medical Center; Matthew Lunning, DO, University of Nebraska Medical Center; Sonali M. Smith, MD, University of Chicago
Published: Friday, Jul 27, 2018



Transcript: 

Ian W. Flinn, MD, PhD: There’s more than one anti-CD20. We’ve recently seen the publication of the GALLIUM data with obinutuzumab in combination with chemotherapy. What do you think, John? What do you do?

John P. Leonard, MD: Just briefly, to summarize the GALLIUM study. Obinutuzumab, as the audience knows, is a newer anti-CD20 antibody. It’s engineered to have better antibody-dependent cellular cytotoxicity and also have better direct killing. It’s approved in CLL, which we’re not going to focus on today, but has been studied in other lymphomas. The GOYA study looked at it in large cell lymphoma, where it seemed to not be better than rituximab.

On the other hand, the GALLIUM study, which has been published in the New England Journal of Medicine, by Robert Marcus, suggests that it was a randomized trial looking at over 1000 patients randomized to rituximab chemotherapy or obinutuzumab chemotherapy, and the chemotherapy could have been a couple of different choices. Then all patients got 2 years of maintenance, so if they were on the rituximab chemotherapy, they got rituximab maintenance for 2 years. If they were on the obinutuzumab chemotherapy, they got an obinutuzumab maintenance for 2 years.

There are a couple of different aspects about the study that I think are interesting, before we get into the data. The first is that, if you’re going to use that regimen and follow the data, you have to decide up front, are you going to use maintenance. I’m sure we’ll get to maintenance in a few minutes, but I don’t necessarily always commit to maintenance. I certainly don’t always decide that at the very beginning.

The second aspect of things is that, and there was a recent editorial on this, hopefully this will be one of the last kind of brute force follicular lymphoma studies where we just combine everybody with advanced-stage disease into a huge trial. Hopefully, we can get to better biomarkers and other times, but time will tell on that regard.

The net of this is that there was a little bit better efficacy with the obinutuzumab-containing regimen. PFS was better, but the difference was under 5% difference between the arms at 3 years. The overall survival was the same, surprisingly, in follicular lymphoma. The toxicity was a little bit more, as far as infections with obinutuzumab. So, I think it’s a fine option for people to use, particularly if you’re pretty much decided on maintenance. But I don’t think it’s a major advance, and I would say that clearly without overall survival, without definitively better quality of life, it’s a modest incremental improvement. Honestly, for many patients, it’s not been a big push for me to move away from rituximab to switch to obinutuzumab in this situation, although we can talk about others later in the course of the disease.

Ian W. Flinn, MD, PhD: Nathan, what about at MD Anderson? Are you using a lot of obinutuzumab?

Nathan H. Fowler, MD: We are using it, and we have several clinical trials combining obinutuzumab with some novel agents like lenalidomide. As far as the standard of care, I have to agree with John. It’s hard to know; it’s kind of like rituximab. This is the same argument when rituximab first came out. As long as you get it, does it matter where you get it? So, in other words, if you lead with a rituximab-plus-chemotherapy regimen, and you relapse, and you then get obinutuzumab, is it the same as getting in the frontline and then getting in the second line? When we see these studies that, again, have a prolongation of progression-free survival and there’s no difference in overall survival, and it’s not clear that if you crossed over you would have the same result, it’s hard to argue against the switch if there’s a more toxic regimen. So, I think—I don’t know if I answered my own question—but I’ve yet to use a whole lot of it. I might use it maybe in a higher-risk patient who has a high risk of early progression, because, again, there is a—albeit it moderate—progression-free survival benefit in the experimental arm.

Ian W. Flinn, MD, PhD: There was some interesting data presented at ASCO this year about that same trial looking at MRD testing, looking at PET scanning. Sonali, did you see the data? Any thoughts on it? Do you do MRD testing in your patients? Do you think it adds to PET scanning, if you do PET scanning?

Sonali M. Smith, MD: Yes, those are really good questions. I think knowing that we have a disease that’s really a chronic and long-term disease, it would be fantastic to have some type of biomarkers, including MRD or PET negativity, to be used to figure out who has early progression or not. What is interesting about the MRD data and the PET data for the GALLIUM trial is that obinutuzumab in all of the arms had a greater degree of MRD negativity than the rituximab arm. But when bendamustine was the chemotherapy that it was combined to, the difference was essentially minimal. To me, it seems that it’s the bendamustine that is doing a larger share of the work there to get it to MRD negativity. That’s sort of less compelling, since I do use a lot of bendamustine up front, that it may not matter whether you use the rituximab or the obinutuzumab when it comes to achieving the deepest response possible. I’m not convinced that its necessarily going to be true.

Your question about whether I do MRD testing, there is no standard of care for MRD testing. People have looked at PCR. Now with some next-generation sequencing, and I know there are others at the table who have a lot of familiarity with this, maybe that will change. But we don’t have a good MRD marker. PET scan is helpful. I think there’s some really nice work from Judith Trotman and others that has shown that a negative PET scan at the end of therapy is associated with a small improvement in overall survival in this group of patients. So, perhaps that is where we need to go.

Matthew Lunning, DO: What would be interesting, though, based upon the paper, is you all worry about that 20% who we can’t predict, who’re going to be the early progressors, and where’s he going to come out in the GALLIUM trial; but also using MRD negativity and PET negativity as a surrogate for saying, “Maybe there’s a certain percentage that we don’t need to give maintenance to from that.” If they’re MRD negative and PET negative, maybe we don’t need to give them obinutuzumab maintenance. Maybe we don’t need to give them rituximab maintenance. This trial and this analysis may be a split point where we can ask that question. I know there are other important questions to ask but think about the people who we can take away therapies from.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: There’s more than one anti-CD20. We’ve recently seen the publication of the GALLIUM data with obinutuzumab in combination with chemotherapy. What do you think, John? What do you do?

John P. Leonard, MD: Just briefly, to summarize the GALLIUM study. Obinutuzumab, as the audience knows, is a newer anti-CD20 antibody. It’s engineered to have better antibody-dependent cellular cytotoxicity and also have better direct killing. It’s approved in CLL, which we’re not going to focus on today, but has been studied in other lymphomas. The GOYA study looked at it in large cell lymphoma, where it seemed to not be better than rituximab.

On the other hand, the GALLIUM study, which has been published in the New England Journal of Medicine, by Robert Marcus, suggests that it was a randomized trial looking at over 1000 patients randomized to rituximab chemotherapy or obinutuzumab chemotherapy, and the chemotherapy could have been a couple of different choices. Then all patients got 2 years of maintenance, so if they were on the rituximab chemotherapy, they got rituximab maintenance for 2 years. If they were on the obinutuzumab chemotherapy, they got an obinutuzumab maintenance for 2 years.

There are a couple of different aspects about the study that I think are interesting, before we get into the data. The first is that, if you’re going to use that regimen and follow the data, you have to decide up front, are you going to use maintenance. I’m sure we’ll get to maintenance in a few minutes, but I don’t necessarily always commit to maintenance. I certainly don’t always decide that at the very beginning.

The second aspect of things is that, and there was a recent editorial on this, hopefully this will be one of the last kind of brute force follicular lymphoma studies where we just combine everybody with advanced-stage disease into a huge trial. Hopefully, we can get to better biomarkers and other times, but time will tell on that regard.

The net of this is that there was a little bit better efficacy with the obinutuzumab-containing regimen. PFS was better, but the difference was under 5% difference between the arms at 3 years. The overall survival was the same, surprisingly, in follicular lymphoma. The toxicity was a little bit more, as far as infections with obinutuzumab. So, I think it’s a fine option for people to use, particularly if you’re pretty much decided on maintenance. But I don’t think it’s a major advance, and I would say that clearly without overall survival, without definitively better quality of life, it’s a modest incremental improvement. Honestly, for many patients, it’s not been a big push for me to move away from rituximab to switch to obinutuzumab in this situation, although we can talk about others later in the course of the disease.

Ian W. Flinn, MD, PhD: Nathan, what about at MD Anderson? Are you using a lot of obinutuzumab?

Nathan H. Fowler, MD: We are using it, and we have several clinical trials combining obinutuzumab with some novel agents like lenalidomide. As far as the standard of care, I have to agree with John. It’s hard to know; it’s kind of like rituximab. This is the same argument when rituximab first came out. As long as you get it, does it matter where you get it? So, in other words, if you lead with a rituximab-plus-chemotherapy regimen, and you relapse, and you then get obinutuzumab, is it the same as getting in the frontline and then getting in the second line? When we see these studies that, again, have a prolongation of progression-free survival and there’s no difference in overall survival, and it’s not clear that if you crossed over you would have the same result, it’s hard to argue against the switch if there’s a more toxic regimen. So, I think—I don’t know if I answered my own question—but I’ve yet to use a whole lot of it. I might use it maybe in a higher-risk patient who has a high risk of early progression, because, again, there is a—albeit it moderate—progression-free survival benefit in the experimental arm.

Ian W. Flinn, MD, PhD: There was some interesting data presented at ASCO this year about that same trial looking at MRD testing, looking at PET scanning. Sonali, did you see the data? Any thoughts on it? Do you do MRD testing in your patients? Do you think it adds to PET scanning, if you do PET scanning?

Sonali M. Smith, MD: Yes, those are really good questions. I think knowing that we have a disease that’s really a chronic and long-term disease, it would be fantastic to have some type of biomarkers, including MRD or PET negativity, to be used to figure out who has early progression or not. What is interesting about the MRD data and the PET data for the GALLIUM trial is that obinutuzumab in all of the arms had a greater degree of MRD negativity than the rituximab arm. But when bendamustine was the chemotherapy that it was combined to, the difference was essentially minimal. To me, it seems that it’s the bendamustine that is doing a larger share of the work there to get it to MRD negativity. That’s sort of less compelling, since I do use a lot of bendamustine up front, that it may not matter whether you use the rituximab or the obinutuzumab when it comes to achieving the deepest response possible. I’m not convinced that its necessarily going to be true.

Your question about whether I do MRD testing, there is no standard of care for MRD testing. People have looked at PCR. Now with some next-generation sequencing, and I know there are others at the table who have a lot of familiarity with this, maybe that will change. But we don’t have a good MRD marker. PET scan is helpful. I think there’s some really nice work from Judith Trotman and others that has shown that a negative PET scan at the end of therapy is associated with a small improvement in overall survival in this group of patients. So, perhaps that is where we need to go.

Matthew Lunning, DO: What would be interesting, though, based upon the paper, is you all worry about that 20% who we can’t predict, who’re going to be the early progressors, and where’s he going to come out in the GALLIUM trial; but also using MRD negativity and PET negativity as a surrogate for saying, “Maybe there’s a certain percentage that we don’t need to give maintenance to from that.” If they’re MRD negative and PET negative, maybe we don’t need to give them obinutuzumab maintenance. Maybe we don’t need to give them rituximab maintenance. This trial and this analysis may be a split point where we can ask that question. I know there are other important questions to ask but think about the people who we can take away therapies from.

Transcript Edited for Clarity 
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