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Follicular Lymphoma: Challenges in Moving Forward

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: Wednesday, Oct 25, 2017



Transcript: 

Nathan Fowler, MD: I think one of the issues, and we’ve had problems with this for quite a long time with follicular lymphoma, is that moving novel agents into the frontline is potentially dangerous. What you don’t want to do is take a drug with unknown side effect profile in that setting and expose it to a group of patients who may be cured with standard therapy.

Bruce Cheson, MD: You used the C-word.

Nathan Fowler, MD: I do think there is a percentage of patients—unfortunately today, it’s still a minority of patients—who are probably cured with frontline chemoimmunotherapy in follicular lymphoma.

Bruce Cheson, MD: Do you agree?

Anas Younes, MD: There are some long-term survivors, that’s for sure. They may be cured, it’s possible, unless we do this, as you mentioned before, circulating tumor DNA testing. It’s hard to tell. But there are some long-term survivors. Back to your questions, I see your concern. But we cannot extrapolate from idelalisib into the copanlisib, because it’s given on a weekly basis where you have a peak and then the drug clears. There is not a continuous level of the drug in the blood forever. So, we have to keep an open mind with this drug. It may be different in terms of safety. But, yes, the trials in the up-front setting have to be monitored very carefully to make sure that this will not happen to a patient who otherwise would be destined to live for a long time.

I think the only way we can improve the cure rate for follicular lymphoma is to improve on the treatment outcomes of the front line. The reason why we watch and wait, or that delayed treatment makes no difference, is because what we have is a lousy treatment. Otherwise, it would have made a difference, right? So, unless you improve on the regimen, I think it will not be able to make an impact on patients’ cure rate.

Nathan Fowler, MD: I totally agree, and all of us have worked on frontline regimens using novel agents in follicular lymphoma. And truly, I think the way we are going to cure these patients is some combination of novel therapies. But I think, at least in my own world, that until we have long-term follow-up on drugs like this, I’m still a little hesitant to move them into the frontline.

Bruce Cheson, MD: But we’ve done that. You and I have both moved R-squared [lenalidomide and rituximab] into the frontline. There wasn’t a lot of data—there was our CALGB [Cancer and Leukemia Group B] data at the time—but we both did it, and the results were spectacular. So, let’s create the scenario here.

Based on the data that you and Peter Martin from our group have published, the response rates with R-squared up front are in the range of 95%, with CRs around 80% plus or minus 5%. If the RELEVANCE trial, which was R-squared versus R-chemotherapy, favors R-squared with those kinds of data—which is unlikely because phase II data are never the same in phase III, but even if they’re close— where can we go from there?

Nathan Fowler, MD: With that, going back to cure, although the response rates are very, very high with that regimen, as you mentioned, we still see a percentage of patients who relapse in multiple phase II trials. We’ve seen that now with longer follow-up that both Peter and I have presented at the last Lugano [International Conference on Malignant Lymphoma] meeting. We still probably see, if you’re looking at about 4 or 5 years, that 30% of patients are still relapsing, 30% or 40%.

Bruce Cheson, MD: Beyond the magical 2-year mark.

Nathan Fowler, MD: Yes, they’re late relapsers. I’m hopeful with the data that will be coming out from the RELEVANT study that we’re going to see a group of patients who are doing are better than R-chemotherapy. But I think that it’s not curative in everyone yet. And so, I think we’re going to have to focus on increasing the percentage of patients who truly get long-term remission or potentially cure. It goes back to what Anas mentioned earlier: Newer techniques serving very low levels of tumor in patients, whether that’s circulating tumor DNA or assays looking at very low levels of progenitor cells, are how we’re going to move the field forward. So, I agree. The old standard design of looking at a drug in combination or as a single agent using overall response rate, and maybe even PFS, will probably be coming to an end. We’re going to have to develop newer biomarkers to truly assess which patients are cured and which patients have no more detectable DNA.

Bruce Cheson, MD: A couple of years ago, we all went to these NCI working group committees. Nathan and I were follicular group, Anas was probably in Hodgkin’s. The follicular group came up with a study design where patients with early relapse were going to be randomized to O [obinutuzumab]-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone]; O-umbralisib, or TGR-1202; or O-lenalidomide. And so, they’re focusing on these early relapsed patients and doing a bunch of molecular testing. Do you think that’s the correct approach?

Anas Younes, MD: It’s a good approach. It’s not a wrong approach. You have to work with what you have, and at that time, that’s what we had. That’s we knew. I think there are multiple ways to approach it, and this is one of them: looking at different regimens to see which one is the winner. I forgot the design, whether it was multiarm in the same trial. These are separate causes.

Bruce Cheson, MD: Yes, multiarm and separate causes, but they were focusing on patients with early relapse.

Anas Younes, MD: That’s a good question. Is this going to hold? I don’t know. You’ve seen the data, and now they’re coming in for R-squared in patients who had early relapse. They’re not doing as poorly as we thought. The same thing with idelalisib. Even though we know patients who had early progression with a single-agent oral PI3 kinase inhibitor, they’re not doing as bad as we thought. Based on what we knew at that time, everybody freaked out that if you progress within 2 years, your survival is impacted. Whether these data are going to hold as we introduce more agents, I don’t know.

Bruce Cheson, MD: My concern is that we’re focusing all the national resources on relapsed patients, and not on where I think we should.

Anas Younes, MD: Yes, but they readout faster, right? If you want to test new agents, to see what your potential is before you move them up front, the readout is faster for relapsed patients. So, it wouldn’t be wrong to test these agents in relapsed setting, but that should not be the end point. The end point is that you should move them up front. I agree with you.

Transcript Edited for Clarity 
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Transcript: 

Nathan Fowler, MD: I think one of the issues, and we’ve had problems with this for quite a long time with follicular lymphoma, is that moving novel agents into the frontline is potentially dangerous. What you don’t want to do is take a drug with unknown side effect profile in that setting and expose it to a group of patients who may be cured with standard therapy.

Bruce Cheson, MD: You used the C-word.

Nathan Fowler, MD: I do think there is a percentage of patients—unfortunately today, it’s still a minority of patients—who are probably cured with frontline chemoimmunotherapy in follicular lymphoma.

Bruce Cheson, MD: Do you agree?

Anas Younes, MD: There are some long-term survivors, that’s for sure. They may be cured, it’s possible, unless we do this, as you mentioned before, circulating tumor DNA testing. It’s hard to tell. But there are some long-term survivors. Back to your questions, I see your concern. But we cannot extrapolate from idelalisib into the copanlisib, because it’s given on a weekly basis where you have a peak and then the drug clears. There is not a continuous level of the drug in the blood forever. So, we have to keep an open mind with this drug. It may be different in terms of safety. But, yes, the trials in the up-front setting have to be monitored very carefully to make sure that this will not happen to a patient who otherwise would be destined to live for a long time.

I think the only way we can improve the cure rate for follicular lymphoma is to improve on the treatment outcomes of the front line. The reason why we watch and wait, or that delayed treatment makes no difference, is because what we have is a lousy treatment. Otherwise, it would have made a difference, right? So, unless you improve on the regimen, I think it will not be able to make an impact on patients’ cure rate.

Nathan Fowler, MD: I totally agree, and all of us have worked on frontline regimens using novel agents in follicular lymphoma. And truly, I think the way we are going to cure these patients is some combination of novel therapies. But I think, at least in my own world, that until we have long-term follow-up on drugs like this, I’m still a little hesitant to move them into the frontline.

Bruce Cheson, MD: But we’ve done that. You and I have both moved R-squared [lenalidomide and rituximab] into the frontline. There wasn’t a lot of data—there was our CALGB [Cancer and Leukemia Group B] data at the time—but we both did it, and the results were spectacular. So, let’s create the scenario here.

Based on the data that you and Peter Martin from our group have published, the response rates with R-squared up front are in the range of 95%, with CRs around 80% plus or minus 5%. If the RELEVANCE trial, which was R-squared versus R-chemotherapy, favors R-squared with those kinds of data—which is unlikely because phase II data are never the same in phase III, but even if they’re close— where can we go from there?

Nathan Fowler, MD: With that, going back to cure, although the response rates are very, very high with that regimen, as you mentioned, we still see a percentage of patients who relapse in multiple phase II trials. We’ve seen that now with longer follow-up that both Peter and I have presented at the last Lugano [International Conference on Malignant Lymphoma] meeting. We still probably see, if you’re looking at about 4 or 5 years, that 30% of patients are still relapsing, 30% or 40%.

Bruce Cheson, MD: Beyond the magical 2-year mark.

Nathan Fowler, MD: Yes, they’re late relapsers. I’m hopeful with the data that will be coming out from the RELEVANT study that we’re going to see a group of patients who are doing are better than R-chemotherapy. But I think that it’s not curative in everyone yet. And so, I think we’re going to have to focus on increasing the percentage of patients who truly get long-term remission or potentially cure. It goes back to what Anas mentioned earlier: Newer techniques serving very low levels of tumor in patients, whether that’s circulating tumor DNA or assays looking at very low levels of progenitor cells, are how we’re going to move the field forward. So, I agree. The old standard design of looking at a drug in combination or as a single agent using overall response rate, and maybe even PFS, will probably be coming to an end. We’re going to have to develop newer biomarkers to truly assess which patients are cured and which patients have no more detectable DNA.

Bruce Cheson, MD: A couple of years ago, we all went to these NCI working group committees. Nathan and I were follicular group, Anas was probably in Hodgkin’s. The follicular group came up with a study design where patients with early relapse were going to be randomized to O [obinutuzumab]-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone]; O-umbralisib, or TGR-1202; or O-lenalidomide. And so, they’re focusing on these early relapsed patients and doing a bunch of molecular testing. Do you think that’s the correct approach?

Anas Younes, MD: It’s a good approach. It’s not a wrong approach. You have to work with what you have, and at that time, that’s what we had. That’s we knew. I think there are multiple ways to approach it, and this is one of them: looking at different regimens to see which one is the winner. I forgot the design, whether it was multiarm in the same trial. These are separate causes.

Bruce Cheson, MD: Yes, multiarm and separate causes, but they were focusing on patients with early relapse.

Anas Younes, MD: That’s a good question. Is this going to hold? I don’t know. You’ve seen the data, and now they’re coming in for R-squared in patients who had early relapse. They’re not doing as poorly as we thought. The same thing with idelalisib. Even though we know patients who had early progression with a single-agent oral PI3 kinase inhibitor, they’re not doing as bad as we thought. Based on what we knew at that time, everybody freaked out that if you progress within 2 years, your survival is impacted. Whether these data are going to hold as we introduce more agents, I don’t know.

Bruce Cheson, MD: My concern is that we’re focusing all the national resources on relapsed patients, and not on where I think we should.

Anas Younes, MD: Yes, but they readout faster, right? If you want to test new agents, to see what your potential is before you move them up front, the readout is faster for relapsed patients. So, it wouldn’t be wrong to test these agents in relapsed setting, but that should not be the end point. The end point is that you should move them up front. I agree with you.

Transcript Edited for Clarity 
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