Emerging Agents in the Management of R/R DLBCL



Andre Goy, MD, MS: Nathan, what else is coming in the pipeline? We obviously have the cytotoxic, the immunotherapy, we have the targeted therapy, and a little bit of radiation. We don’t use a lot of radiation in large cell lymphoma, but we should talk about this in a second. What else do you see coming?

Nathan H. Fowler, MD: It’s good news that there are a lot of new targeted drugs hitting different types of targets that are being developed. A lot of these are bispecific antibodies. There are a couple of these bispecific T-cell engagers that are in late-stage development. There’s a plenary session at ASH [the American Society of Hematology 2019 annual meeting] looking at responses with bispecific in CAR [chimeric antigen receptor] T-cell failures. It’s a small study, but the data look pretty good for the CAR T-cell failures.

Andre Goy, MD, MS: …CRs [complete responses], right?

Nathan H. Fowler, MD: Yes. For me, probably one of the most exciting of the targeted drugs are these bispecific antibodies that potentially could do similar things that we see with CAR T-cells really, only they’re using your own CAR T-cells, drawing them to the tumor, and hopefully inducing this T-cell response. There are also some conjugated antibodies against other targets. I’ve seen some recent looks at things with, again, CD47, CD79b. So, there are some other interesting conjugated antibodies.

Andre Goy, MD, MS: The “don’t eat me” antibody targets.

Nathan H. Fowler, MD: Yes.

Grzegorz S. Nowakowski, MD: I think this is a time where we actually see huge development coming in this area of multiple compounds. The challenge of this will be how we study them and how we move them forward. Here is where the new regulator pathways using real-world data could actually help us to develop those combinations faster than we typically would. Sometimes it’s difficult to understand the contribution of agents in the combination of novel agents. But if you have some real-world data about the single-agent activity, you can actually use it to supplement and have some idea if your combination really is helpful. Also with all the molecular diversity of the patients, I know some of those novel agents are limited to certain populations of patients, with a specific set of molecular markers, such as for example, MYD88. Comparing the outcome of patients with a MYD88 mutation treated with any therapy versus the targeted agent is very promising.

There was actually a very interesting session on the innovation of clinical trials at the 2019 ASH annual meeting where we had folks from the FDA and also statisticians who were talking a lot about how we develop those new studies, and what’s the threshold of evidence now that we need to move it. But I think we are coming to an understanding that we won’t be able to do randomized studies for all those agents. There is a huge unmet medical need, and what we need to do is to work in a novel way to be able to move those drugs very quickly to the clinic.

Andre Goy, MD, MS: Absolutely. First of all, we lose a lot of drugs by doing randomized studies because of the issues we discussed earlier, but we cannot do a conventional trial the same way. We lose the trees in the forest all the time, and we need to be able to do a small trial based on molecular rationale that’s measurable looking hopefully at metabolic response—not necessarily just clinical—and to try to be able to make an early decision. This is a real challenge because patients do well, better, with lymphoma, and large cell lymphoma particularly. But it’s still a lymphoma that is increasing, and mortality by lymphoma has increased in spite of all the high-dose therapy and transplant.

If you look at the lymphoma incidence, it has increased 500% in folks who are 80-years-old and over who are still in very good shape in Florida and exercising. So, we need to make sure that we have options.

Transcript Edited for Clarity

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