BTK Inhibition in B-Cell Lymphomas - Episode 7

Selecting Between Targeted Therapies in B-Cell Lymphomas

June 21, 2019

Harry P. Erba, MD, PhD:OK. Now this may be a little bit more of a difficult question. We have a number of targeted therapies that have been approved in different disease states in the lymphomas—BCL2 inhibition, PI3 kinase inhibition, BTK [Bruton tyrosine kinase] inhibition. How do you decide? How do you choose which ones to use and where?

Anthony R. Mato, MD, MSCE:That’s a great question that everybody is talking about at this ASCO [American Society of Clinical Oncology] meeting. One of the most difficult things we have to face is that the control arms for most of the randomized trials that have been completed are almost clinically insignificant at this time. You know, chlorambucil’s a drug that’s been around since the mid-’50s. This is a comparator in the ibrutinib study, for example, for single-agent anti-CD20 antibodies in the case of idelalisib or ibrutinib. So it becomes very difficult to look at these trials and say anything about how these drugs compare to each other in a head-to-head fashion, prospectively.

This is 1 area where I really think the cooperative groups have an opportunity to contribute sequencing knowledge, because I’m not expecting industry to be able to complete those types of studies. They’re risky. It’s very difficult to get access to drugs that are not yet approved, especially to do head-to-head comparisons. So sequencing is one of the biggest questions in CLL [chronic lymphocytic leukemia] and lymphoma right now. We do have some prospective data.

For example, there is a trial specifically looking at the use of venetoclax in BTK and PI3K inhibitor failures. These are heavily pretreated patients. Venetoclax was a monotherapy, and we saw a 65% response rate and a 24-month PFS [progression-free survival] for the BTK failures, for example. So it’s kind of slowly coming out, but this is one of those areas where the registries, where the real-world studies can take 1000 or 2000 patients treated with targeted agents, look and see what was done, and look and see what happens next. Unfortunately, clinical trials censor patients. When they progress or they come off for whatever reason, we never know what they get next. So, I think that needs to change from our prospective trials.

Harry P. Erba, MD, PhD:I agree. And I’m glad you mentioned cooperative groups because I chair the SWOG Leukemia Committee. I clearly believe in that mechanism. Right now, the cooperative groups are looking at combinations of targeted therapies in CLL. Do you want to say more about those studies, or I’ll say more about those studies?

Anthony R. Mato, MD, MSCE:I’ll say more about them. They’re very early on right now, and the cooperative groups have kind of divided between elderly versus younger patients with age 65 being the cutoff. The comparisons are essentially that the control arm is ibrutinib plus obinutuzumab as a continuous therapy, and the comparator arm is the triplet regimen of ibrutinib, venetoclax, and obinutuzumab. I think they’re interesting questions, although, to me, I think that there are other questions that I would hope those trials could have also answered. But I think at least it’ll give us an answer of whether 1 continuous therapy is better than a combination at a fixed duration.

Harry P. Erba, MD, PhD:Right, and I think that’s important, that we can look at the cooperative group system of fixed duration and use MRD [minimal residual disease] in that situation to help make that decision.

Anthony R. Mato, MD, MSCE:Yes. So the ECOG [Eastern Cooperative Oncology Group] trial I do not believe has an MRD endpoint, but the CALGB [Cancer and Leukemia Group B]/SWOG trial, or the Alliance trial, does have an MRD endpoint.

Harry P. Erba, MD, PhD:WithSWOG, just to fill out the playing field, we are going to have a high-risk CLL protocol with early intervention for asymptomatic patients versus observation. It’s been attempted before, as you know, in the cooperative groups with fludarabine and Rituxan. The studies failed to accrue.

Anthony R. Mato, MD, MSCE:I actually enrolled a patient into that trial. Probably 1 of the very few number of patients.

Harry P. Erba, MD, PhD:Well, we’re hoping that with these oral therapies that are quite effective that maybe we’ll get more of these high-risk patients on.

Anthony R. Mato, MD, MSCE:I think it’s an interesting question, although I’m still not convinced that we’re not adversely altering biology such that later they have more trouble than it’s worth, in terms of getting the disease under control. And you know, personally, I’m questioning whether that rationale makes sense. I’m sure it’s another topic we’ll talk about, but these drugs are not without toxicity.

Harry P. Erba, MD, PhD:Exactly. It’s interesting that you said that because if you go way back to the French study that looked at chlorambucil versus observation, that was one of their observations. The patients who did progress after chlorambucil had worse outcomes than patients who clearly, as you might expect, progressed after observation, where they were more easily treated.

Anthony R. Mato, MD, MSCE:Yes. And we know that these cells can escape these drugs. When patients warrant therapy, and when they do escape, they’re difficult to treat. So there’s no reason, in my mind, to think that may not be the case for high-risk CLLs, whatever the inclusion is going to be. We’ll find out.

Harry P. Erba, MD, PhD:Exactly.

Anthony R. Mato, MD, MSCE:Thirty years from now we’ll find out.

Harry P. Erba, MD, PhD:Yes, that is the trouble. We’ll need to do it on a clinical trial though. I agree with being careful about that.

Transcript edited for clarity.