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FL: The Impact of Data from Clinical Trials

Panelists:Bruce Cheson, MD, Georgetown Lombardi Comprehensive Cancer Center; Nathan Fowler, MD, The University of Texas MD Anderson Cancer Center; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Oct 26, 2017



Transcript: 

Bruce Cheson, MD: We’ve all seen multiple presentations of some large studies in follicular lymphoma that may or may not be moving the field forward, such as the GALLIUM study. What was the GALLIUM study and what did we learn from it?

Nathan Fowler, MD: The GALLIUM study was a study that was actually just presented within the last year. An update was presented at our recent Lugano [International Conference on Malignant Lymphoma] meeting, looking at upfront or untreated patients with follicular lymphoma and randomizing them—a pretty simple design, 1-to-1—to get rituximab plus chemotherapy versus obinutuzumab plus chemotherapy. And the chemotherapy arms could be bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisolone], or CDP [cisplatin]. A pretty simple design, basically switching out the monoclonal antibody between the 2 arms.

Bruce Cheson, MD: What did we learn from that study?

Anas Younes, MD: We learned that you can use obinutuzumab with some of these regimens safely. It may add value in terms of PFS. At the time when the data were presented, there was no difference in overall survival. We also learned that when you combine obinutuzumab with bendamustine and give it as maintenance, there are increased toxicities beyond what we’ve seen with rituximab. So, again, there will be some individual patients who may benefit from this combination. For others, it may not be their best option. There will be, I think, choices to use obinutuzumab plus CDP. It wouldn’t be wrong. Obinutuzumab plus R [rituximab]-CHOP wouldn’t be wrong. I would not use obinutuzumab plus bendamustine. I would use rituximab with bendamustine.

Bruce Cheson, MD: I still haven’t really gotten my hands around that observation, because in the GADOLIN trial, which I presented at ASH a couple of years ago, was bendamustine versus bendamustine/obinutuzumab in rituximab-refractory patients, with a survival benefit in the combination arm and no increase in toxicity. So, we have multiple studies showing no increase in toxicity from bendamustine and CD20s, including obinutuzumab. I just don’t know what to make of the GALLIUM study.

Anas Younes, MD: In a way, the data do not fit. But also remember that when you treat patients in the relapsed setting, people tend to tolerate toxicities more than in the frontline setting. They may be underreported, I think.

Bruce Cheson, MD: But there were more deaths, too.

Anas Younes, MD: That’s right, in the frontline. But in the relapsed setting, people tend to underreport toxicities, probably because they expect it. They can live with it. In the frontline, I think people tend to watch these patients very carefully and tend to report the toxicity more carefully. But I agree with you. In the relapsed setting, it was not alarming. But now, with what we know from the frontline setting, I think we have to look back again and see whether or not maintenance with obinutuzumab after bendamustine would be a reasonable option for every patient. I think for some patients it will be, but you at least need to watch these patients carefully and make decisions on whether you want to continue with obinutuzumab or do something else.

Nathan Fowler, MD: It looked like most of the excess deaths that we saw with obinutuzumab plus bendamustine occurred late—interestingly, as Anas mentioned—in the maintenance arm. And one thing they had done in this study, in several patients, was monitor their T-cell levels after they received bendamustine. We saw that many patients who received bendamustine, and I think we’ve all known about this, have a prolonged immunosuppression that continued after they finished treatment into the maintenance arm.
So, it’s unclear. One other thing is that the excess deaths were seen both with rituximab and with obinutuzumab during the maintenance following bendamustine. What I find, as you mentioned, is that in other studies—including the BRIGHT study, including the StiL study—is that even in the patients who were not monitored, we didn’t see a signal with regards to mortality, excess mortality, in the bendamustine arm.

In the GALLIUM trial, there were more elderly patients who were on the bendamustine arms. They’re not significant, but there were slightly more patients who were in their 70s and 80s in those arms. Maybe that caused excess deaths. In addition, you can hypothesize that if you knew your patients were going to get bendamustine, they were probably patients who were less healthy. They went on to those arms compared to R-CHOP. So, there may have been some patient selection in the process. But I don’t think you can argue with the T-cell numbers, really. There was definitely immunosuppression that lasted after you stopped bendamustine. What I take out of that study is that with patients who I’m going to give bendamustine plus obinutuzumab or Rituxan [rituximab] to, you have to follow them closely. You have to give them prophylaxis.

Anas Younes, MD: What’s your practice, Bruce? Let me ask you, what do you do with these data? How do you use it in your practice?

Bruce Cheson, MD: Well we have been using either BR [bendamustine and rituximab] or R-squared [rituximab and lenalidomide] upfront. And for those patients who didn’t get those up front, we’re doing the GADOLIN regimen, BO [bendamustine and obinutuzumab], in the relapsed setting. Of course, we try and put all the patients on clinical trials without chemotherapy, but that’s our paradigm.

Anas Younes, MD: Once obinutuzumab is expected to get approved for frontline, how would you use it?

Bruce Cheson, MD: I don’t plan on using it. Not because of this, but because of the GALLIUM results. Yes, they met their endpoint for PFS, but there was no survival benefit, and the toxicity, no matter what you looked at, was greater with obinutuzumab. So, it just, to me, doesn’t seem like enough information to change my paradigm yet. And you?

Anas Younes, MD: As I said, I think it’s a discussion point. It’s not approved yet, so I haven’t used it outside of clinical trials, but we’ll have to learn from the long-term follow-up.

Bruce Cheson, MD: And you?

Nathan Fowler, MD: I think that I probably will use it in the front line with bendamustine or CHOP based upon the PFS curves. I agree, with overall survival, there’s no difference yet, and that’s going to take a longer time. But still, I think that we have to, at least most of us, agree that it’s a randomized study and it met its primary endpoint. Not that that should always be the trigger, but the primary endpoint of PFS should lead, if you follow these curves out, to a 3-year prolongation in PFS in the obinutuzumab arm. That’s hard for me to argue with.

Bruce Cheson, MD: Let me throw this at you. Since most of the troublesome adverse effects occurred during maintenance, would you use maintenance?

Nathan Fowler, MD: I would not. I think that—again, this is speculating, as it’s not FDA approved yet—if I was going to use it in combination, I probably would not use maintenance.

Anas Younes, MD: Again, I have not been a big fan of maintenance to start with, but just because the toxicities occur during maintenance doesn’t mean that maintenance is responsible for it. Because we may have just delayed side effects from induction.

Bruce Cheson, MD: The MAGNIFY and the AUGMENT trials. One of our favorite regimens?

Nathan Fowler, MD: What Bruce is talking about is that there are 2 studies, potential registration studies, for lenalidomide/rituximab, or R-squared, in relapsed follicular lymphoma. The first is the MAGNIFY trial, where everybody’s getting R-squared. Then, basically, the study is looking at maintenance, either with rituximab or with R-squared.

The AUGMENT study is a phase III study where—this is, again, all relapsed follicular lymphoma—half the patients are getting R-squared and half the patients are getting rituximab as a single agent. With the AUGMENT study, we may see some data here within the next 6 to 12 months, depending on how the study is accruing, etc. The MAGNIFY study, I think, is still quite a way out from reading. We saw some preliminary data at the national meetings this year from the MAGNIFY trial, but those were really just the results from the induction arm. They basically looked at patients and looked at the overall response. They also looked at patients who were double refractory—that means refractory to an alkylator as well as rituximab—as well as patients in this group that we’ve been talking about; these patients who progress within 2 years. And it looked like R2-squared in both of those groups had a response rate over 60%.

I have a little bit of a problem, because these are, again, interim results from an ongoing phase III trial. It’s hard to know how that’s going to translate with regards to PFS when you put patients on a different maintenance. It’s a subset analysis of a study. It’s not a part of the primary endpoint. So I’d take that as evidence that the regimen probably does work in the group of patients who are relapsed, but I would not change practice based upon it. These are the results from the MAGNIFY trial. With the AUGMENT study, there’s nothing published yet.

Transcript Edited for Clarity 

 
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Transcript: 

Bruce Cheson, MD: We’ve all seen multiple presentations of some large studies in follicular lymphoma that may or may not be moving the field forward, such as the GALLIUM study. What was the GALLIUM study and what did we learn from it?

Nathan Fowler, MD: The GALLIUM study was a study that was actually just presented within the last year. An update was presented at our recent Lugano [International Conference on Malignant Lymphoma] meeting, looking at upfront or untreated patients with follicular lymphoma and randomizing them—a pretty simple design, 1-to-1—to get rituximab plus chemotherapy versus obinutuzumab plus chemotherapy. And the chemotherapy arms could be bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisolone], or CDP [cisplatin]. A pretty simple design, basically switching out the monoclonal antibody between the 2 arms.

Bruce Cheson, MD: What did we learn from that study?

Anas Younes, MD: We learned that you can use obinutuzumab with some of these regimens safely. It may add value in terms of PFS. At the time when the data were presented, there was no difference in overall survival. We also learned that when you combine obinutuzumab with bendamustine and give it as maintenance, there are increased toxicities beyond what we’ve seen with rituximab. So, again, there will be some individual patients who may benefit from this combination. For others, it may not be their best option. There will be, I think, choices to use obinutuzumab plus CDP. It wouldn’t be wrong. Obinutuzumab plus R [rituximab]-CHOP wouldn’t be wrong. I would not use obinutuzumab plus bendamustine. I would use rituximab with bendamustine.

Bruce Cheson, MD: I still haven’t really gotten my hands around that observation, because in the GADOLIN trial, which I presented at ASH a couple of years ago, was bendamustine versus bendamustine/obinutuzumab in rituximab-refractory patients, with a survival benefit in the combination arm and no increase in toxicity. So, we have multiple studies showing no increase in toxicity from bendamustine and CD20s, including obinutuzumab. I just don’t know what to make of the GALLIUM study.

Anas Younes, MD: In a way, the data do not fit. But also remember that when you treat patients in the relapsed setting, people tend to tolerate toxicities more than in the frontline setting. They may be underreported, I think.

Bruce Cheson, MD: But there were more deaths, too.

Anas Younes, MD: That’s right, in the frontline. But in the relapsed setting, people tend to underreport toxicities, probably because they expect it. They can live with it. In the frontline, I think people tend to watch these patients very carefully and tend to report the toxicity more carefully. But I agree with you. In the relapsed setting, it was not alarming. But now, with what we know from the frontline setting, I think we have to look back again and see whether or not maintenance with obinutuzumab after bendamustine would be a reasonable option for every patient. I think for some patients it will be, but you at least need to watch these patients carefully and make decisions on whether you want to continue with obinutuzumab or do something else.

Nathan Fowler, MD: It looked like most of the excess deaths that we saw with obinutuzumab plus bendamustine occurred late—interestingly, as Anas mentioned—in the maintenance arm. And one thing they had done in this study, in several patients, was monitor their T-cell levels after they received bendamustine. We saw that many patients who received bendamustine, and I think we’ve all known about this, have a prolonged immunosuppression that continued after they finished treatment into the maintenance arm.
So, it’s unclear. One other thing is that the excess deaths were seen both with rituximab and with obinutuzumab during the maintenance following bendamustine. What I find, as you mentioned, is that in other studies—including the BRIGHT study, including the StiL study—is that even in the patients who were not monitored, we didn’t see a signal with regards to mortality, excess mortality, in the bendamustine arm.

In the GALLIUM trial, there were more elderly patients who were on the bendamustine arms. They’re not significant, but there were slightly more patients who were in their 70s and 80s in those arms. Maybe that caused excess deaths. In addition, you can hypothesize that if you knew your patients were going to get bendamustine, they were probably patients who were less healthy. They went on to those arms compared to R-CHOP. So, there may have been some patient selection in the process. But I don’t think you can argue with the T-cell numbers, really. There was definitely immunosuppression that lasted after you stopped bendamustine. What I take out of that study is that with patients who I’m going to give bendamustine plus obinutuzumab or Rituxan [rituximab] to, you have to follow them closely. You have to give them prophylaxis.

Anas Younes, MD: What’s your practice, Bruce? Let me ask you, what do you do with these data? How do you use it in your practice?

Bruce Cheson, MD: Well we have been using either BR [bendamustine and rituximab] or R-squared [rituximab and lenalidomide] upfront. And for those patients who didn’t get those up front, we’re doing the GADOLIN regimen, BO [bendamustine and obinutuzumab], in the relapsed setting. Of course, we try and put all the patients on clinical trials without chemotherapy, but that’s our paradigm.

Anas Younes, MD: Once obinutuzumab is expected to get approved for frontline, how would you use it?

Bruce Cheson, MD: I don’t plan on using it. Not because of this, but because of the GALLIUM results. Yes, they met their endpoint for PFS, but there was no survival benefit, and the toxicity, no matter what you looked at, was greater with obinutuzumab. So, it just, to me, doesn’t seem like enough information to change my paradigm yet. And you?

Anas Younes, MD: As I said, I think it’s a discussion point. It’s not approved yet, so I haven’t used it outside of clinical trials, but we’ll have to learn from the long-term follow-up.

Bruce Cheson, MD: And you?

Nathan Fowler, MD: I think that I probably will use it in the front line with bendamustine or CHOP based upon the PFS curves. I agree, with overall survival, there’s no difference yet, and that’s going to take a longer time. But still, I think that we have to, at least most of us, agree that it’s a randomized study and it met its primary endpoint. Not that that should always be the trigger, but the primary endpoint of PFS should lead, if you follow these curves out, to a 3-year prolongation in PFS in the obinutuzumab arm. That’s hard for me to argue with.

Bruce Cheson, MD: Let me throw this at you. Since most of the troublesome adverse effects occurred during maintenance, would you use maintenance?

Nathan Fowler, MD: I would not. I think that—again, this is speculating, as it’s not FDA approved yet—if I was going to use it in combination, I probably would not use maintenance.

Anas Younes, MD: Again, I have not been a big fan of maintenance to start with, but just because the toxicities occur during maintenance doesn’t mean that maintenance is responsible for it. Because we may have just delayed side effects from induction.

Bruce Cheson, MD: The MAGNIFY and the AUGMENT trials. One of our favorite regimens?

Nathan Fowler, MD: What Bruce is talking about is that there are 2 studies, potential registration studies, for lenalidomide/rituximab, or R-squared, in relapsed follicular lymphoma. The first is the MAGNIFY trial, where everybody’s getting R-squared. Then, basically, the study is looking at maintenance, either with rituximab or with R-squared.

The AUGMENT study is a phase III study where—this is, again, all relapsed follicular lymphoma—half the patients are getting R-squared and half the patients are getting rituximab as a single agent. With the AUGMENT study, we may see some data here within the next 6 to 12 months, depending on how the study is accruing, etc. The MAGNIFY study, I think, is still quite a way out from reading. We saw some preliminary data at the national meetings this year from the MAGNIFY trial, but those were really just the results from the induction arm. They basically looked at patients and looked at the overall response. They also looked at patients who were double refractory—that means refractory to an alkylator as well as rituximab—as well as patients in this group that we’ve been talking about; these patients who progress within 2 years. And it looked like R2-squared in both of those groups had a response rate over 60%.

I have a little bit of a problem, because these are, again, interim results from an ongoing phase III trial. It’s hard to know how that’s going to translate with regards to PFS when you put patients on a different maintenance. It’s a subset analysis of a study. It’s not a part of the primary endpoint. So I’d take that as evidence that the regimen probably does work in the group of patients who are relapsed, but I would not change practice based upon it. These are the results from the MAGNIFY trial. With the AUGMENT study, there’s nothing published yet.

Transcript Edited for Clarity 

 
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