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Follicular Lymphoma: Considering All Novel Agents

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: Friday, Oct 27, 2017



Transcript: 

Bruce Cheson, MD: We’ve been talking about the same drugs, over and over again, and the same classes of drugs. There are quite a number of other novel agents out there, some of which seem to have promise in follicular lymphoma. Some have less promise than we would like them to, despite their mechanisms of action. I think it teaches us a lesson that not all B-cell lymphomas should be considered the same. Let’s look at ibrutinib, for example. Ibrutinib and follicular lymphoma.

Anas Younes, MD: Ibrutinib, the B-cell receptor–targeting agent, is targeting BTK [Bruton's tyrosine kinase]. It’s approved by the FDA for 4 different indications: CLL, Waldenström’s macroglobulinemia, marginal zone lymphomas, and mantle cell lymphoma.

Bruce Cheson, MD: And GVH.

Anas Younes, MD: And GVH, right. For follicular lymphoma, the response rate measured by PR plus CR is not very good—depending on the study, 18% to 24%—and for some odd reason, rituximab-refractory patients didn’t do well either. But if you look at the waterfall plot in the PFS, it’s actually not bad. This means the PFS is almost about a year, despite the low response rate.

So, it didn’t generate a lot of excitement, but there seemed to be some benefit from it. The question is, how do you position this in this landscape? I think it’s going to be mainly in combination strategies. There are trials looking at single-agent ibrutinib in patients with follicular lymphoma, who are PET-positive at the end of induction therapy, to see if you can convert PET-positive to PET-negative and whether or not this will improve PFS. It’s a single arm. It’s just exploratory. Whether this will become a space for the drug to be developed, I don’t know. But I think it’s going to be a combination drug. I don’t think it’s going to be a single-agent drug.

Bruce Cheson, MD: The response rate of the DAWN study was 20.8%, and that was the registration trial. It was considered a negative study. So, I think I agree with you. And we’re doing a combination of that plus venetoclax at our institution now. What about venetoclax? It’s the same kind of situation.

Nathan Fowler, MD: Yes, you would think that a drug targeting BCL2, which is the hallmark mutation of this disease, would have very high responses in follicular lymphoma. It’s funny how in lymphoma, we get so used to responses of 80% or 90% that anything less than 50% we don’t pay as much attention to. But the drug does have activity in low-grade lymphomas.

Bruce Cheson, MD: But it’s not in CLL, it’s not in mantle cell lymphoma.

Nathan Fowler, MD: It has not really been the homerun that we thought it might be. There are, as you mentioned, several combination studies looking at venetoclax plus ibrutinib, venetoclax plus lenalidomide, and, I think, venetoclax plus rituximab in low-grade lymphomas. But I think that drug as a single agent will probably not have a major impact like we’ve seen with some of the other drugs in low-grade lymphoma.

Bruce Cheson, MD: What about other pathways? SYK/JAK, SYK plus JAK?

Anas Younes, MD: I think the ones that come to mind, that are making a lot of news and attraction, are the immune therapies, checkpoint inhibitors and CAR T cells. Unfortunately, there’s not much exciting news coming from follicular lymphomas. There’s some activity for checkpoint inhibitors. There could be a combination. We did a trial in the frontline setting with R-bendamustine, combining it with atezolizumab followed by maintenance atezolizumab plus rituximab. So, we’ll see. There are a lot of studies looking at minimal residual disease and surveying tumor DNA. But as a single agent, it doesn’t stand out as well in, let’s say, Hodgkin’s lymphoma, which has approved at least the PD-1–targeted agents.

With CAR T cells, I think they’re falling behind. There’s not much of publicly reported data about their activity, mainly because people think it’s not an unmet medical need, the toxicity seen with the CAR T cells. But I think at one point, they will come into the picture for maybe a fourth relapse or fifth relapse, where the outcome is poor. But there are not much data about CAR T cells in follicular lymphoma at the present time.

Bruce Cheson, MD: I’ve had a couple of patients who had failed everything and had bulky disease. I couldn’t think of another drug, and we sent them for CAR T-cell therapy. And the 2 who I’ve sent off are in CR 5 or 6 years later. It was rather striking.

Anas Younes, MD: Right.

Bruce Cheson, MD: And there are studies now looking at it in follicular lymphoma. There are those patients out there. As we’ve all talked about, they’re in the minority, but they are certainly an unmet need.

Anas Younes, MD: Right.

Bruce Cheson, MD: Are there any other drugs out there that are catching your fancy?

Nathan Fowler, MD: There are other targeted drugs that look very attractive. We saw data at this recent meeting in Lugano [International Conference on Malignant Lymphoma] with an EZH2 inhibitor, a drug called tazemetostat, which is pretty neat. We know that EZH2 is mutated in about 15% to 20% of patients with follicular lymphoma. Actually, patients with EZH2 mutations at diagnosis tend to do a little better than patients with a wild-type EZH2. But it looks like targeting EZH2 with a drug like tazemetostat can lead to significant responses. In fact, in the study that was presented by Franck Morschhauser in Lugano, he showed that 92% of patients who had an EZH2 mutation and received tazemetostat with relapsed follicular lymphoma responded to therapy.

Bruce Cheson, MD: It had 18 patients. That’s a small number.

Nathan Fowler, MD: But still, even with the small number, if you were to argue that the response rate dropped to 50% with longer follow-up, it still suggests that using a drug that targeted a known mutation in that cancer led to higher responses. We did have a larger cohort of patients who were wild-type EZH2, and it was clear that they didn’t see that same response rate—patients who did not have the mutation. So, unfortunately, it’s only in a minority of patients that we see this target.

Bruce Cheson, MD: And it’s in follicular lymphoma, not in large cell lymphoma.

Nathan Fowler, MD: It’s in follicular lymphoma. But it’s a proof of principle, I think, that if you have a mutation that’s potentially targetable and you have a drug that works, you can see a response in a significant number of patients.

Bruce Cheson, MD: But we don’t have long-term follow-up to see how long those responses last.

Nathan Fowler, MD: You’re absolutely right, yes.

Bruce Cheson, MD: That’s the problem with a lot of these drugs that we’re testing, like the checkpoint inhibitors. The follow-up is relatively short, even in Hodgkin’s lymphoma.

Transcript Edited for Clarity 
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Transcript: 

Bruce Cheson, MD: We’ve been talking about the same drugs, over and over again, and the same classes of drugs. There are quite a number of other novel agents out there, some of which seem to have promise in follicular lymphoma. Some have less promise than we would like them to, despite their mechanisms of action. I think it teaches us a lesson that not all B-cell lymphomas should be considered the same. Let’s look at ibrutinib, for example. Ibrutinib and follicular lymphoma.

Anas Younes, MD: Ibrutinib, the B-cell receptor–targeting agent, is targeting BTK [Bruton's tyrosine kinase]. It’s approved by the FDA for 4 different indications: CLL, Waldenström’s macroglobulinemia, marginal zone lymphomas, and mantle cell lymphoma.

Bruce Cheson, MD: And GVH.

Anas Younes, MD: And GVH, right. For follicular lymphoma, the response rate measured by PR plus CR is not very good—depending on the study, 18% to 24%—and for some odd reason, rituximab-refractory patients didn’t do well either. But if you look at the waterfall plot in the PFS, it’s actually not bad. This means the PFS is almost about a year, despite the low response rate.

So, it didn’t generate a lot of excitement, but there seemed to be some benefit from it. The question is, how do you position this in this landscape? I think it’s going to be mainly in combination strategies. There are trials looking at single-agent ibrutinib in patients with follicular lymphoma, who are PET-positive at the end of induction therapy, to see if you can convert PET-positive to PET-negative and whether or not this will improve PFS. It’s a single arm. It’s just exploratory. Whether this will become a space for the drug to be developed, I don’t know. But I think it’s going to be a combination drug. I don’t think it’s going to be a single-agent drug.

Bruce Cheson, MD: The response rate of the DAWN study was 20.8%, and that was the registration trial. It was considered a negative study. So, I think I agree with you. And we’re doing a combination of that plus venetoclax at our institution now. What about venetoclax? It’s the same kind of situation.

Nathan Fowler, MD: Yes, you would think that a drug targeting BCL2, which is the hallmark mutation of this disease, would have very high responses in follicular lymphoma. It’s funny how in lymphoma, we get so used to responses of 80% or 90% that anything less than 50% we don’t pay as much attention to. But the drug does have activity in low-grade lymphomas.

Bruce Cheson, MD: But it’s not in CLL, it’s not in mantle cell lymphoma.

Nathan Fowler, MD: It has not really been the homerun that we thought it might be. There are, as you mentioned, several combination studies looking at venetoclax plus ibrutinib, venetoclax plus lenalidomide, and, I think, venetoclax plus rituximab in low-grade lymphomas. But I think that drug as a single agent will probably not have a major impact like we’ve seen with some of the other drugs in low-grade lymphoma.

Bruce Cheson, MD: What about other pathways? SYK/JAK, SYK plus JAK?

Anas Younes, MD: I think the ones that come to mind, that are making a lot of news and attraction, are the immune therapies, checkpoint inhibitors and CAR T cells. Unfortunately, there’s not much exciting news coming from follicular lymphomas. There’s some activity for checkpoint inhibitors. There could be a combination. We did a trial in the frontline setting with R-bendamustine, combining it with atezolizumab followed by maintenance atezolizumab plus rituximab. So, we’ll see. There are a lot of studies looking at minimal residual disease and surveying tumor DNA. But as a single agent, it doesn’t stand out as well in, let’s say, Hodgkin’s lymphoma, which has approved at least the PD-1–targeted agents.

With CAR T cells, I think they’re falling behind. There’s not much of publicly reported data about their activity, mainly because people think it’s not an unmet medical need, the toxicity seen with the CAR T cells. But I think at one point, they will come into the picture for maybe a fourth relapse or fifth relapse, where the outcome is poor. But there are not much data about CAR T cells in follicular lymphoma at the present time.

Bruce Cheson, MD: I’ve had a couple of patients who had failed everything and had bulky disease. I couldn’t think of another drug, and we sent them for CAR T-cell therapy. And the 2 who I’ve sent off are in CR 5 or 6 years later. It was rather striking.

Anas Younes, MD: Right.

Bruce Cheson, MD: And there are studies now looking at it in follicular lymphoma. There are those patients out there. As we’ve all talked about, they’re in the minority, but they are certainly an unmet need.

Anas Younes, MD: Right.

Bruce Cheson, MD: Are there any other drugs out there that are catching your fancy?

Nathan Fowler, MD: There are other targeted drugs that look very attractive. We saw data at this recent meeting in Lugano [International Conference on Malignant Lymphoma] with an EZH2 inhibitor, a drug called tazemetostat, which is pretty neat. We know that EZH2 is mutated in about 15% to 20% of patients with follicular lymphoma. Actually, patients with EZH2 mutations at diagnosis tend to do a little better than patients with a wild-type EZH2. But it looks like targeting EZH2 with a drug like tazemetostat can lead to significant responses. In fact, in the study that was presented by Franck Morschhauser in Lugano, he showed that 92% of patients who had an EZH2 mutation and received tazemetostat with relapsed follicular lymphoma responded to therapy.

Bruce Cheson, MD: It had 18 patients. That’s a small number.

Nathan Fowler, MD: But still, even with the small number, if you were to argue that the response rate dropped to 50% with longer follow-up, it still suggests that using a drug that targeted a known mutation in that cancer led to higher responses. We did have a larger cohort of patients who were wild-type EZH2, and it was clear that they didn’t see that same response rate—patients who did not have the mutation. So, unfortunately, it’s only in a minority of patients that we see this target.

Bruce Cheson, MD: And it’s in follicular lymphoma, not in large cell lymphoma.

Nathan Fowler, MD: It’s in follicular lymphoma. But it’s a proof of principle, I think, that if you have a mutation that’s potentially targetable and you have a drug that works, you can see a response in a significant number of patients.

Bruce Cheson, MD: But we don’t have long-term follow-up to see how long those responses last.

Nathan Fowler, MD: You’re absolutely right, yes.

Bruce Cheson, MD: That’s the problem with a lot of these drugs that we’re testing, like the checkpoint inhibitors. The follow-up is relatively short, even in Hodgkin’s lymphoma.

Transcript Edited for Clarity 
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