R/R DLBCL: Novel Therapies in the Pipeline

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Ian W. Flinn, MD, PhD: We’re going to switch gears and talk about new therapies that are in the pipeline but not yet FDA approved. To me, 1 of the most exciting classes of agents are these bispecific antibodies, Loretta. There are multiple options making their way through the development process. Epcoritamab was recently published on, and others as well. Are you working with these agents? What’s your take?

Loretta J. Nastoupil, MD: At ASH [American Society of Hematology Annual Meeting] this year, particularly, there was a lot of excitement surrounding these bispecific antibodies that are targeting tumor antigens, specifically CD20, and then engaging the T cells with CD3 binding. As you mentioned, a number of these were presented. They are being studied in third-line space for large B-cell lymphoma in addition to some other B-cell lymphoma subtypes.

The efficacy looks quite promising with these as single agents. There have been attempts to try to mitigate some of the cytokine-release syndrome [CRS], which appears to be a class effect. In my experience, it’s not the same cytokine-release syndrome we see with CAR [chimeric antigen receptor] T-cell therapy. This is earlier in onset but shorter in duration, and it usually doesn’t progress to severe situations. It is usually grade 1 or 2. It looks a lot more like an infusion reaction, and for that we’ve had many years of experience with rituximab-based approaches. Epcoritamab is a subcutaneous administration, and you have this blunted absorption that leads to less potential cytokine-release syndrome.

There have been strategies with glofitamab, such as debulking patients with obinutuzumab a week before introducing the agent. All of them have looked at a ramp-up dosing schedule where you start with a very low dose at day 1, dose a little higher at day 8, and then finally give the full dose by day 15. With that strategy we’ve seen that you can mitigate some of the CRS. That will lend itself to outpatient administration because most of these studies thus far required admission and monitoring for the first 24 to 72 hours. To me, that is a nonstarter if we’re trying to get this out of the academic centers and into the community setting. I think we can accomplish this with some of these strategies.

The other potential limitation is this ramp-up. For these aggressive-behaving large B-cell lymphoma patients, sometimes you can’t get them to full dose before they progress. So I think these are very promising. We’re still learning how to administer them, but I think they’re going to have a foothold in the treatment of B-cell lymphomas.

Ian W. Flinn, MD, PhD: Amit, do you think this is going to replace CAR T-cell therapy, or be a challenger against CAR T?

Amitkumar Mehta, MD: This will definitely challenge CAR T. As Loretta mentioned, most of the studies are single-agent trials. We are not seeing combinations yet. We are not seeing a combination with chemotherapy yet. We have seen that they’re all rapidly escalating in the frontline setting in combination with CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and they are randomizing them head-to-head with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. There’s a lot of excitement. In the next 5 years, I hope that we will have a regimen that can beat R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] in the frontline setting. Definitely, this will compete with CAR T. As Loretta mentioned, this will surely be a game changer for community physicians. 

One other aspect that I want to mention is that as we have more and more CAR T patients, post–CAR T relapses are very common. Especially at academic centers, we are seeing post–CAR T relapses become an emerging area, in regard to unmet needs. In 2019 at ASH, we had a plenary session where we reviewed data on mosunetuzumab. This drug showed great responses in those patients who progressed after CAR T. So it’s going to challenge using CAR T, but at the same time, for those patients who are progressing through CAR T, this will be a great option.

Ian W. Flinn, MD, PhD: Yeah. I confess that it wasn’t obvious to me that a bispecific antibody was going to work well after CAR T, but I was impressed and happy to see those data that you mentioned. 

John, let’s get your take on this. Even if the results weren’t quite as good as they could be with a CAR T-cell therapy, if you were able to apply it to many more people, the ultimate number of patients you’re helping is going to be greater. But there are obstacles to doing this in the community. Are you participating in these trials, or do you foresee being able to administer it in your clinic or your partners’ clinics?

John M. Burke, MD: That’s a great question, and I have several comments. Looking at the data, do they really approximate what you get with CAR T-cell therapy? Many of these are dose-escalation phase 1 studies. From what was initially reported at ASH, they would report some of the higher-dose levels of these products now. The overall response rate is in the ballpark of two-thirds for most of these, and the CR [complete response] rates are in the ballpark of 30% to 50%. They’re treating 10 to 15 patients at these target full doses with those kinds of numbers. If those data are confirmed with more patients treated and with longer follow-up, this could potentially not be a threat to CAR-T but could be another alternative to CAR-T, especially for the folks who might be more frail, might have a harder time traveling from a community practice to a tertiary center to receive CAR T-cell therapy.

As was mentioned before, it’s not always necessarily a direct threat. Amit talked about combination studies with chemotherapy. This might be more of a threat to rituximab, if it gets moved earlier in the course of disease in large B-cell lymphoma. And CAR T-cell therapy is still there. I don’t think CAR T-cell therapy is going away. I don’t think this is going to replace CAR T-cell therapy. Certainly, you can imagine these being used in different settings, and the same with CAR T. You can imagine both of the therapies being used earlier.

Can community doctors do this? I think the answer is yes, probably. I have a Mosun [mosunetuzumab] trial available, although I have been restricted in my ability to treat large B-cell lymphoma patients. Earlier, the Mosun trials required hospitalization for large B-cell lymphoma because of concerns about CNS [central nervous system] toxicity, driving restrictions and things like that. But as was mentioned, there’s a lot of work going on in terms of trying to mitigate some of the CRS and some of the neurotoxicity with the ramp-up dosing. There is even talk about steroid use and other things that might be able to mitigate that risk and allow these treatments to be delivered in the outpatient setting. Even if it does require a hospitalization or 2 for a couple of days, it’s not to the extent of what has to be done with axi-cel [axicabtagene ciloleucel]. I do foresee that this will be deliverable by community practitioners and will have an impact on patients.

Transcript Edited for Clarity

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