Improving Outcomes in Relapsed/Refractory Diffuse Large B-Cell Lymphoma - Episode 9

Safety and Efficacy of Oral Agents in R/R DLBCL

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John P. Leonard, MD: I want to move to another drug that is undergoing regulatory review for relapsed and refractory diffuse large B-cell lymphoma and that is selinexor. This is an agent that has a somewhat different mechanism of action and is already approved in some myeloma subsets so the audience may be familiar with it. Nathan, tell us why selinexor might be a reasonable agent for this patient population and the data supporting its potential use.

Nathan H. Fowler, MD:This is a new class of drugs and it's not anything that we have for large cell lymphoma or any other cancers. It's called a SINE [selective inhibitor of nuclear export] and it targets certain proteins that are exported out of the nucleus that gives cells a pro-survival advantage. It is not necessarily specific to large cell lymphoma, but it targets the mechanism that large cell lymphoma probably uses to keep itself alive and potentially resistant.

The drug is oral. It's a single agent. It's associated with some unique effects– a lot of which are GI and we've seen now some fairly decent size phase 2 trials targeting patients that have large cell lymphoma. In this trial [phase 2b SADAL trial] looked at a fairly difficult population. Most of these patients had at least 2 prior lines of therapy, some patients were failing transplant, and some patients were double-hit patients. In that study, they saw almost 30% overall response rate with a complete remission rate of around 10%. If you think about CAR T-cell data and others, it's not quite as good. It's a single drug so it’s fairly easy to give. It is effective in a subset of patients that have pretty difficult-to-treat large cell lymphoma, including patients that have double-hit lymphoma.

One thing I really thought was interesting with the drug is that in the responders, we saw pretty good long-term responses. In fact, if you look at patients that have PR or better, the duration of response is over 2 years. There is a select group of patients that do achieve durable benefit with the drug.

John P. Leonard, MD: I want to ask Matt and then Kami your experiences with the drug if you've used it, and/or your take on reading the literature about it from the standpoint of efficacy as well as the safety profile. So Matt, your thoughts.

Matthew Lunning, DO: I have not used the drug in lymphoma. We do have it available in myeloma, as you pointed out, and use it in a clinical and a research setting. My read of the initial paper that was published is it went on an adventure of dose-escalation, dose-finding, and schedule-finding driven mostly by GI toxicity, as was pointed out. How could you get enough drug in the subjects that allow them to respond and want to stay on it? Over time, if it takes a while, where's the enthusiasm for continued use?

If this drug is going to continue to be used, it may have to be with other drugs, if it can be playing in the sandbox together. We have these other novel agents, like tafasitamab and some other oral lenalidomides, where you're seeing longevity in this population. We also should be studying patients are who are responding, even if it’s a small piece of the pie, so we can know who it's worth potentially having those toxicities. Those toxicities can be manageable over time, per the paper. We really need to identify those patients.

John P. Leonard, MD:Kami, your thoughts and experience?

Kami Maddocks, MD: I've had experience with the drug in a few different ways. We were involved in the phase 1 study, and as mentioned, there was this toxicity, weight loss, and fatigue, and those seem to be problematic. However, once they were able to address these effects by looking at appetite stimulants and scheduled antiemetics, we have a phase 2 study in combination with ibrutinib and it seems to be much better tolerated with the use of these agents now that it's recognized that there are side effects.

It's an oral therapy that can be given to high risk patients so it does provide an option for those patients. When you look at the overall responses, I think that Matt and Nathan are right, that it's probably best used in combination with another therapy to get the best bang for your buck.

John P. Leonard, MD:We participated in some trials and now that the dose level is better settled as you cited, it does seem to be better tolerated. It's going to be important for people—when they have access to it and are considering using it—to really think about the toxicity in the context of the dose they're using rather than the up-and-down doses that were studied.

We have also had a study looking at it in combination with RICE [rituximab, ifosfamide, carboplatin, etoposide] chemotherapy in relapsed large cell lymphoma. Interestingly, it may be tolerable and can be given with chemotherapy, with support from a randomized trial, and that’s what you're seeing with your ibrutinib study.

Nathan, as you look at this, if you have this available as a single agent and you had a patient with large cell lymphoma, where do you see this used relative to CAR T-cells, tafasitamab, and other kind of standard chemotherapy drugs? The nice thing about it is it's an oral regimen that is relatively easy from the perspective of administration for patients to take. Who do you think would be the patient getting single agent, assuming you have access to it and had a patient population?

Nathan H. Fowler, MD:When I think about patients that are failing CAR T, and that's going to be at least half, maybe more of those patients, I don't have good options for those patients. Generally, I'm thinking about clinical trials. We talked about a Revlimid-containing regimen, but we’re still grasping those patients. We often do things like radiation to limited sites, but they don't have a lot of great options that could give them a durable remission.

What I really liked about this is that in those patients who responded, they've got over 2-year PFS. So that suggests that it's an active drug. I don't think this is going to replace auto [autologous stem cell transplantation] or CAR T. In patients that are failing those kind of approaches, we don't have a lot and we can do Revlimid and Revlimid plus a CD19. Post-CAR T-cell failure patients or patients that would not qualify, and are not near a center are the obvious population.

John P. Leonard, MD:Kami and Matt, your thoughts, anything different?

Kami Maddocks, MD: I agree with that.

Matthew Lunning, DO: Yeah, I agree.

Transcript Edited for Clarity