Emerging Therapies for R/R Follicular Lymphoma

Ian Flinn, MD, PhD: Andy, let’s turn the discussion to new agents that are being developed in follicular lymphoma. We’re going to talk at length about CAR [chimeric antigen receptor] T cells in a few minutes. Aside from CAR T cells, what are some of the other exciting things that you’ve seen? There were a couple of publications on bispecific antibodies at this year’s ASH [American Society of Hematology Annual Meeting]. What’s your take on that data, and how likely is it that these agents are going to be used?

Andrew M. Evens, DO, MSc, FACP: The data for bispecific antibodies are extremely encouraging. As you said, what does bispecific mean? It’s a fully humanized CD20xCD3 bispecific antibody, so it is attaching to the CD20 B-cell lymphoma and then attracts T cells to hopefully engage against the lymphoma. You mentioned ASH. I don’t think I’ve ever seen so much about this topic at ASH. There was 1 session that presented on 4 different bispecifics, back to back to back to back. Four different products, and they were all similarly efficacious. Rutgers Cancer Institute of New Jersey has helped lead the Regeneron Pharmaceuticals, Inc product. Dr Rajat Bannerji has been a part of that.

There are 2 others I’ll highlight. One product is mosunetuzumab, the Roche product. You might recognize that. That was presented in CAR T failure at ASH 2019. The UPenn [University of Pennsylvania] group led that and Dr Stephen Schuster.

In follicular lymphoma, these are incredibly active. Looking across all 4 of the drugs, we’re looking at an overall response rate from 70% to 100% in some of the studies in follicular lymphoma, with a fairly decent CR [complete response] rate—some rates over 50%.

Another compound is epcoritamab. What’s unique about this drug is it can be given subcutaneously. That can be of some potential benefit. Someone might ask, “What about CRS [cytokine-release syndrome], neurotoxicity, etc?” It is seen with these bispecifics, but as someone who’s probably put 10-plus patients on at least the Regeneron product, the rates of occurrence are markedly less. And this is mostly, if not completely, an outpatient treatment.

Ian Flinn, MD, PhD: I’m glad you brought that up about: the outpatient therapy. Loretta, it’s 1 thing to do something at The University of Texas MD Anderson Cancer Center. But to treat in community oncology offices around the country, how low does the AE [adverse event] profile need to get for a community physician to feel safe treating patients with the drug in their offices? It’s not a big deal for us to have a little CRS. We can easily handle it. But I’m not sure that’s true in some of these other offices.

Loretta J. Nastoupil, MD: The critical thing is how you’re going to handle that toxicity. If you need to administer something like tocilizumab, it’s probably a deal breaker for most community and even academic centers. If it’s infusion-related symptoms such as fever and chills, these can be monitored and managed with something like Tylenol or Benadryl. That’s a much different scenario from a patient who needs to be in an inpatient unit monitored, potentially needing things like tocilizumab or even ICU [intensive care unit] care.

Those subtle differences are hard to tease out when you’re looking at the rates of grades 1 to 3 CRS. More important, we need to know what strategies were employed to really manage some of these toxicities. Any strategy that can be employed that will reduce the rates of grade 2 or higher CRS is critical, such as more aggressive premeds with dexamethasone, these ramp-ups, or these debulking strategies. All those need to be explored and need to be very effective before you can roll this out to larger centers.

Ian Flinn, MD, PhD: Yeah, that’s true as well. I was impressed with some of the data in terms of looking at the neurotoxicity. For instance, when reading the details for mosunetuzumab and X-number of patients with neurological toxicity, insomnia was considered a neurotoxicity. So we’re probably overestimating some of that from what we would really think of as neurotoxicity.

Were there other agents that we haven’t talked about that are in the pipeline and are coming? Krish, is there anything that you think is really exciting that’s going to make its way through the developmental pathway in the next few years to treat patients with follicular lymphoma?

Krish Patel, MD: Yeah. There are a number of immunotherapy approaches that look pretty exciting. Regarding what we’ve been involved with that seem exciting to watch for are the use of anti-CD47 agents, so-called macrophage checkpoint inhibitors. They certainly seem to be well tolerated and have some meaningful activity in a broader array of lymphomas, including follicular lymphoma. In particular, other cellular therapies like natural killer cell-based therapies look exciting. These are another potent platform to use. Immunotherapy approaches, at least from the early data that have been published for small studies, seem to have a very distinct toxicity profile from T-cell–based immunotherapies.

Ian Flinn, MD, PhD: Caron, what about BCL2 inhibitors? You think of a disease that was set up for a BCL2 inhibitor to work well in, but so far we haven’t seen a lot of data on using venetoclax, at least as a single agent, and sometimes even with the combination of bendamustine and rituximab. It doesn’t really add much to that. Do you think that’s true as a class? Or is there anything else that’s in development for antiapoptotic approaches?

Caron A. Jacobson, MD, MMSc: I think you’re right. The single-agent data look as though it leads to meaningful responses in about 20% of patients. But those patients who do respond actually have quite durable responses, and some of those responses last 2 or more years. This gets to the point that Loretta made earlier, which is that we really are lacking biomarkers to understand who’s going to respond to which therapy. I would hate to throw away a whole class of drugs for a group of patients who could get an average 2 or more years’ remission duration from them. There’s more to understand for drugs like venetoclax in this disease, in terms of patient selection, but it doesn’t seem to be a blockbuster drug as we would have expected. The biomarker is not the 14;18 translocation.

Ian Flinn, MD, PhD: Yeah, I was sort of taken aback. I didn’t predict that was going to happen with that drug in that disease.

Transcript Edited for Clarity