Emerging Data in Diffuse Large B-Cell Lymphoma

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John Leonard, MD: I'd like to move to new agents that- even beyond this has been a full program and we've had lots to talk about and lots of new things that we didn't have even a year or two ago in some cases. But there are two big categories that have been presented at ASH and at ASCO more recently and I want to ask Cyrus and David, first about new CAR T cell therapies and what you're most excited about. Then I'll ask Loretta and Greg about the bispecific antibodies and where they're going. These are two huge areas that seem to me to be fairly high impact in the future. Cyrus and then David, what's your take of the new CAR T cell constructs and the themes that come out of that?

Cyrus Khan, MD: I think tow of the main themes in ASH as well as ASCO are what to do if patients either fail the current generation of CAR T or how to improve upon them. I think one of the- this is out of a sort of Chinese group that the anti-CD20 and CD3 CAR T construct have been used in patients who have relapsed after anti-CD19 CAR T and those patients have responded. I think that's pretty exciting. Something to look forward to, even if patients don't really respond or relapse after anti-CD19 based CAR T cell therapy. I think the second theme has been off the shelf CAR T or allogenic CAR T. I think that would create an ease with which we can move forward with instead of waiting for the manufacturing in a spot, we can quickly move on to this kind of therapy. I think third, which wasn't really a theme in these conferences has been homegrown CAR T. So we know the Miltenyi Biotec machine, which we actually have one here about to start constructing CAR T within the centers so that you don't have to wait for the manufacturing and quickly get patients on to them. I think that's pretty exciting technology too and also cost reduction that would come with it as far a CAR T cell therapies are concerned.

John Leonard, MD: David, your thoughts on this area? Are these going to be used after standard CAR T or are they going to replace standard CAR T? It seems to me like randomized studies comparing them may be challenging so they might come in afterwards more but what's your take on that? That seems to me to be a niche challenging area but on that's certainly exciting based on the early data.

David Rizzieri, MD: Maybe it's a field that's going to be a victim of it's early success. The durability in responding patients is so encouraging. But I view these next generation CAR T's as slowly replacing the current therapies we have, from an ease of access such as Cyrus mentioned, the off the shelf product. We'll lose about somewhere between 25% to a third of patients from the time you want to put them on CAR T, do you get the product backed ex cetera. You would remove that loss of patients who are in need. Then I have to believe in the bi-specificity. When you think about the resistance mechanisms to CAR T, which we're just starting to try to understand, if you resistance to targeting one antigen, will you also be resistant to the other or not? I think there's a lot of interest in these multi-specific CAR T products that I think have great potential to replace the current generation.

John Leonard, MD: The other area that we're seeing a lot in is the bispecific antibodies and Loretta, what is your take on those? I think we have probably almost as many as those as we have CAR T's, at least in clinical trials. To me they seem to be pretty good and easier to use that people could use in their practice ultimately or at least locally as opposed to a cell therapy center. What's your take on them?

Loretta Nastoupil, MD: I think that's really the goal is, can you have broader application of a bispecific antibody and can they actually challenge the CAR T's? What we've seen between ASH and ASCO, at least for some of the studies, is larger sample size, longer follow up, and I continue to be impressed with the durability of the CRs that also appear to be getting larger portion of CRs as they get to higher doses during the dose escalation study. I am quite optimistic. The ease off use I would caution a little bit about, just based off our experience in some of the studies. They're really trying to figure out how to eliminate this CRS. It generally occurs during the first cycle and, in my experience, is very different from CAR T CRS and in some ways is more akin to infusion reaction in terms of how you might manage it. That being said, if you have to hospitalize a patient to monitor or if you have those that are Grade 2 or higher, that require intervention, that's going to make it harder to apply, at least in a traditional community setting or in a setting that's not used to administering things like tocilizumab. They're employing strategies such as subcutaneous administration, ramping up the dose, we saw data with Glofitamab where they sort of bind up some of the CD20 cites with Obinutuzumab a week before they start the ramp up with Glofitamab, and then the SubQ data with epcoritamab. They also use pretty hefty premeds, so again experience that I've learned is you have to be mindful and then back off on the steroid once they get beyond that time window of risk for CRS. There's going to be a steep learning curve but I do think these will probably be easier than the CAR Ts and you'll likely have a larger group of patients that will see them at some point.

John Leonard, MD: Greg, what's your sense of the bispecifics and I know there are some trials looking at them early in the course of the disease even combinations with R-CHOP type treatment?

Greg Nowakowski, MD: That's exactly right and I think you nailed it by saying that there are combinations moving up front. In a sense it's been easier to combine with other modalities than CAR T cells. I think that's a huge opportunity for moving the bar by specifics because you can audit as early on as with CHOP. You can do it almost across any line of therapy and there are other pre-clinical studies building very nice rational why some of those agents should be combined with bispecific antibodies, for example with Imits or novel cell modes and other drugs moving in this area. I actually see a great future for bispecific therapy. I think we will learn to deal with the toxicities much better and this flexibility and ability of those types to be combined with other agents really propel it, I think, to the future even more. Although the data are early, the response rates are comparable with CAR T cells, their durability is still unknown so have to wait for that. but you can actually extend this durability and efficacy by adding something on the top of those bispecific as well if needed.

John Leonard, MD: Well before we wrap up, I'd like to just go around to each of you and get your- some of your final thoughts about either what you're most excited about for the future amongst the things we've talked about or something we didn't get a chance to mention that you think people should keep an eye out for. I'm going to ask you first Dr. Khan, for your take on what's getting you really excited amongst other things?

Cyrus Khan, MD: I think just increasing the cure rate really with whatever we have available to us and moving the easier treatments more up front. Truly one of my passions is CNS lymphoma in both primary and secondary's. I'm really hoping that a lot of these newer therapies will find space in both prevention as well as treatment off those patients as well.

John Leonard, MD: OK, Dr. Nastoupil?

Loretta Nastoupil, MD: I agree. I think the other that, now that we have some novel therapies in that third line or later space, it looked very promising carving out these high-risk population that are anthracycline candidates for instance in front line. I think now provides us an opportunity to study drugs or even Lonca by specific antibodies. I agree, I think this will only help us cure a larger portion of the pie and then for those relapses now we're going to have likely CAR T in the second line space. So again, this is all just good news for patients.

John Leonard, MD: Dr. Nowakowski?

Greg Nowakowski, MD: As we see the CAR T cells expanding and based on the press release, maybe even moving to the second line. What I still think is a bigger unmet need is for post-CAR T cell relapse and we know that about half of those will be profoundly cytopenic and they're not candidates for traditional clinical trials if you use traditional inclusion criteria. I think one of the unmet needs and potentials for development is here. We need to come to the consensus how to develop agents in this space. I think their inclusion criteria to the studies for those patients need to be very, very different than other. Here, the drugs which cause relatively little myelosuppression like bispecifics for example, could be really getting a lot of traction.

John Leonard, MD: All right and last but not least, Dr. Rizzieri, your thoughts?

David Rizzieri, MD: While I share my colleagues views, I would maybe just add one thing that we haven't really talked about but maybe we should more is where are these patients being treated right? In 20,000 patients per year, they're not being treated at our centers. Most of them are treated in the community as I think Loretta brought up earlier. So are these therapies able to be done safely in the community and if not, do we need to change how we monitor and provide these therapies, whether it's us finding new ways to collaborate with our colleagues or certain outreach programs for therapy in the home. Because, as you know the patients don't want to be traveling to our major medical centers for all these new things. I think we have to do more in that regard to see that they can be safely delivered in their community and at their home. Also, as we look at the outcomes from many of these studies, some of the ASH abstracts I was struck at how non-diverse the patients were who were accrued to studies. It's a problem that we and others have been looking at for a long time. We're obviously in an age where we need to do better. So that's another area that we should spend more time thinking about and addressing, in our leadership roles, as we develop clinical trials.

John Leonard, MD: All really important points and I've really also enjoyed your perspectives on these important and challenging topics. I want to thank you all for joining us today and sharing your insights. I want to also thank our viewing audience, we hope you found this ONCLive Peer Exchange Discussion to be useful and informative.

TRANSCRIPT EDITED FOR CLARITY