What is the Role of Bispecifics in Relapsed/Refractory DLBCL?

Transcript:
Matthew A. Lunning, DO, FACP: I want to understand the sequencing discussion now with the bispecifics entering the landscape. It’s the new piece that entered the chess board recently. Dr Flinn, where is that going to be placed or utilized in your relapsed/refractory large cell lymphoma patients?

Ian W. Flinn, MD, PhD: I don’t think we have any evidence to date that giving bispecific antibody in the relapsed large cell population is a curative therapy. That would be great, and we can hope for that in the future, but we don’t have data on that today. I still think we’re using that as just another part of our armamentarium about other many different salvage therapy options out there. That said, it’s got some attractiveness in it that the first approved is CD20 versus a CD19-targeted, and the next ones through are probably CD20-targeted agents, so you don’t get any issues with antigen loss by using another CD19 therapy.

The downside I think about the bispecific antibodies is that initially we had thought these were off-the-shelf CAR [chimeric antigen receptor] T-cell type of probe that we maybe allow the bang form as a CAR T-cell would with a little bit easier use. To date, the CD20, the bispecific antibodies all require hospitalization. This is going to cut into the community use of this until we get this figured out, and I think it will be figured out. We now do CAR-T cells as an outpatient. I’m pretty sure we’re going to be giving bispecific antibodies as an outpatient, but now it’s largely confined to the centers, the same centers that are the high tertiary care facilities that can do these other therapies are doing the bispecifics.

Matthew A. Lunning, DO, FACP: With axi-cel [axicabtagene ciloleucel; Yescarta] in the second line, and liso-cel [lisocabtagene maraleucel; Breyanzi] in the second line, lonca T [loncastuximab tesirine], TAFA/LEN [tafasitamab plus lenalidomide (Revlimid)], and bispecifics, and those are what you’re scrambling around in your practice, on which one you think the patient should get next. But does it take any of those off the table?

Ian W. Flinn, MD, PhD: I think that it depends on are we going to CAR T or are we after CAR T? I love the bispecifics and the mechanism of action. I think it’s probably exciting both to the patients and the physicians treating for these patients, but which is the best therapy is hard to say in terms of which of those therapies you just mentioned is. If we’re duly talking about palliative therapy, I don’t know that we know which one’s the best.

Matthew A. Lunning, DO, FACP: Dr Wang, what are your thoughts on patients who are CAR T-cell ineligible? So we have those CAR T-cell after, does it change at all if they’re CAR T-cell ineligible in your mind, second, third, fourth line, and beyond large cell lymphoma, with what you have to offer, whether or not it’s lonca T, TAFA/LEN, or epcoritamab [Epkinly] now?

Yucai Wang, MD, PhD: Yes. Post-CAR T treatment is still challenging. With the available approved therapy, the outcomes look varied in several different retrospective series and Pola-BR [polatuzumab vedotin (Polivy), bendamustine (Treanda), and rituximab (Rituxan)] appears to be a good option. TAFA/LEN has been tried in that setting; certainly not as good as online data because you’re using it at a different setting. People thought checkpoint inhibitors react to some of the CAR-T cells, but that didn’t pan out real good in retrospective studies. I guess you just reach out to the therapy that’s available, and you think you have a reasonable safety profile for the patient. Now with the bispecifics, for anybody entering our practice, that’ll probably be used more, maybe even before you try to do the Pola-BR or TAFA/LEN for those folks again.

Matthew A. Lunning, DO, FACP: Very good. Dr Westin, we started the conversation or gone down the road with speaking to bispecifics, namely those that are engaging CD3 and CD20 likely going to come. We know that the CD3, CD19 lives in a different disease right now. Can you walk through epcoritamab and the EPCORE trial [NCT04628494] that led to its recent approval and just a class in general in where you think their toxicity profile and efficacy. Walk us through that landscape.

Jason Westin, MD, MS, FACP: Yes, I’d be happy to. I think CD19/CD3 bispecifics will come to large cell. We’re seeing some emerging data from some of the newer CD19/CD3s, but I agree with you that as of today, blinatumomab [Blincyto] is not a large cell lymphoma drug. Epcoritamab, is an impressive new drug, which I’m happy to see it be approved for patients that have relapsed large cell lymphoma, and the trial data showed it’s very active in a difficult to treat patient population, both in patients who had not had CAR as well as had previous CAR. The overall response rates, CR [complete response] rates, and durability of response were impressive. Which, getting a good response is always wonderful to see, but if it doesn’t last, it’s not as impressive. In the epcoritamab studies, patients who get a CR tend to keep that CR; they tend to have a durable benefit. One thing about epcoritamab, which is different from some of the other bispecifics, is that it is a continuous therapy. Once you start this therapy, you continue until progression, which sometimes feels like you’re still actively fighting the disease. In a setting where patients have a refractory disease continuing indefinite therapy, there’s no precedent to do that. I think that’s something that we’ll have to look at, a fixed-duration therapy, something that may be explored in the future. That’s not what the current epcoritamab label is. It’s an indefinite therapy, treat to progression, but the side effects of these drugs are not trivial. Dr Flinn mentioned that this may not be something that will take over the world in community settings because of the need to admit patients for the first full dose. It’s recommended, but I think many people, at least early on, will probably do that for the first full dose of the step-up dosing for epcoritamab. I am a little concerned that community physicians are going to want to learn about how to grade CRS; Do you have tocilizumab on standby, and wake up at 3 in the morning for a management algorithm that you don’t do on a regular basis? It’s certainly possible that people may be referred to CAR T-cell centers to start the epcoritamab and then go back to their referring physician, but I think that will be a challenge as a field to work out.

Matthew A. Lunning, DO, FACP: Is the SubQ [subcutaneous] administration of epcoritamab a positive or a negative in your mind?

Jason Westin, MD, MS, FACP: It cuts both ways. I think that’s a good way to think of it, is that the dependence of SubQ being an advantage or disadvantage depends upon your practice setting. Where I practice at MD Anderson, I’m not going to do subcutaneous injections in my clinic. The patients are still going to go to an infusion area and take up a seat, and they won’t be there for as long as they would be for an IV infusion, but it still requires a dedicated slot for the patient to get that. In a setting where somebody may be set up to do subcutaneous injections in their clinic, maybe that would be a differentiating factor. I think that will take time to figure out which practices feel more comfortable using SubQ in their clinic.

Matthew A. Lunning, DO, FACP: Do you think that we’re on par? One of the interesting things is about toxicity management with this class, and it was as in institutional guidance, how are we going to walk through, we have the CAR T-cell CRS [cytokine release syndrome], the ICANS [immune effector cell-associated neurotoxicity syndrome] management, do you think it will be easier or harder to adopt, or we’ll figure it out?

Jason Westin, MD, MS, FACP: Having already had years of experience with CAR-T cells will help a lot for how to manage bispecifics. Some of the low-grade CRS, or what we call CRS for bispecifics, if we didn’t have CAR-T cells we might call it a Rituxan reaction. We may not call this some unique toxicity. Many of these patients can be managed as an outpatient with Tylenol or with steroids, with observation, and may not require an admission for low-grade CRS. Having that experience, especially in centers that have done a lot of CAR T-cells, will help a lot for the management. We don’t know that this is going to be a one-size-fits-all management approach. Maybe we’ll need to tailor things to bispecifics as we get more hands-on experience outside of a clinical trial.

Matthew A. Lunning, DO, FACP: Dr Flinn, you see mostly lymphoma patients, have you had this discussion with your colleagues back at your institution around bispecifics coming and toxicity management plans and how you’re going to admit them, when you’re going to admit them?

Ian W. Flinn, MD, PhD: We haven’t advanced the discussion that far in terms of that topic. We’ve been using mosunetuzumab [Lunsumio], which has a very different phenotype and toxicity profile, and my partners in my practice are comfortable giving mosun [mosunetuzumab] as an outpatient for patients without any difficulty. It is going to be a discussion, for instance giving EPCORE, on how they’re going to do that. I think many, as Dr Westin was talking about, are not going to be willing to do this or not have the facilities to do that right. They don’t normally admit people for chemotherapy that’s outside of what their practice patterns are, so they don’t have a facility for which they can do it. I think in the beginning they might be referring in, but hopefully we’ll get beyond that and get people more comfortable with this so that they can administer it in their local practice.

Transcript edited for clarity.