Yi Lin:

Hello, I’m Yi Lin from Mayo Clinic and I am here with Dr Suzanne Trudel from Princess Margaret, Dr Fred Locke from Moffitt, and Dr. Krina Patel from MD Anderson. And we are here for day three of iwCAR-T, where we covered a lot of grounds in two major heme malignancies where we have both FDA approved CAR-T and lots of investigations. So, first I’m going to hand it over to Dr Locke, please give us some highlights of all the topics that we’re discussing lymphoma.

Frederick Locke:

Yeah, so it’s been a great iwCAR-T meeting, and it was really exciting today to have the lymphoma session where David Maloney and I chaired the session and we had lots of great talks. We talked about the pivotal trial data or more specifically the randomized controlled trials in third-line setting for large B-cell lymphomas, [inaudible] second-line setting, randomized Phase III trials, and really exciting data. The results show that CAR-T in the second-line setting can improve outcomes, event-free survival’s better for patients who get CAR-T in the second line, it’s better than the existing standard of care, which was chemotherapy followed by transplant. We also heard about follicular lymphoma and maybe could we even potentially be curing follicular lymphoma? We talked quite a bit about why CAR-T doesn’t work for all patients in lymphoma. We talked about mantle cell lymphoma results.It was really a stimulating discussion.

Yi Lin:

Excellent. Lots of practice-changing….

Frederick Locke:

Yeah, that’s exciting.

Yi Lin:

….Discussions and yeah, more data to come. So in the myeloma session, we also started off with ide-cel and cilta-cel that are both FDA approved and that the studies where they’re moving on to earlier lines, we saw some clinical prognostic factors that may be associated with response with these CAR-Ts and for the first time we heard some real-world data from Moffitt and will be data coming at ASCO as well from a number of institutions in the use of ide-cel in standard of care practice. So that is very interesting, particularly considering we haven’t had as much good fortunes in standard of care practice in terms of slot access as we’ve had in lymphoma. So some discussion about how to try to select patients for those. But so related to that, we heard perhaps some opportunities for our next generation CAR-T investigation that might help overcome some of the challenges that we’re seeing in CAR-T. And in particular with Dr Patel, would you like to give us some highlights in a discussion about allogeneic CAR-T in myeloma space?

Krina Patel:

Yeah, so I think as you alluded to, not only slot envy that we have of lymphoma, as Nina had said, we have this plateau envy. So how can we improve that? And I think that’s a whole another segment that hopefully next year will have a lot more translational data to talk about. But in terms of slots, not only the patients who can’t get a slot right now, but we have, if you look at the intention to treat, there are patients who can’t make cells, who can’t get to an auto CAR-T. And so having an off the shelf ALLO product makes sense. Different than the bispecifics, which I’ll know we’ll talk about too, it’s still a one and done. So that’s the advantage that you get that one and done, but it’s still off-the-shelf. So the ALLO-715 trial that Sham Mailankody presented shows a great response rate, 71%. So, small number of patients still, but they were able to give cells within, I think five days for some patients and really didn’t see ICANS or any neurotoxicity and definitely not graft-versus-host, which people worry about with allo. So we’re waiting for the PFS at the higher dose levels and looking at their different lymphodepletion. Because again, I think compared to auto CAR-Ts, allos, they’re more likely to get rejected. And so the lymphodepletion question is still there, which then comes to the trial that I presented with UCARTCS1. So here you have a different antigen, CS1 that’s expressed on lots of myeloma, but unfortunately is also expressed on other T-cells, B-cells. And so lymphodepletion there, we learned that maybe we didn’t have to have as high of a lymphodepletion because those cells in the two patients that did expand and had a great response, unfortunately they expanded really fast and caused HLH and other toxicities that the patients unfortunately succumb to. So now we’re redoing the trial at a lower lymphodepletion and hoping that the expansion happens a little bit over time, and those cells may be persistent and give us a better PFS, but we’ll hopefully have more data in the next year.

Yi Lin:

Very interesting. And, allo CAR-T certainly been looked upon as one opportunity to have something more readily available to our patients, still a lot of science to be investigated behind that. And bispecific is another opportunity for something that is more readily off-the-shelf. And in myeloma, we’re fortunate to have data not only in BCMA, but other targets as well. So Dr Trudel would you like to give us a summary of what was discussed?

Suzanne Trudel:

Yeah, it’s very exciting. We first talked about teclistamab, which is on my understanding is that it’s going through review with the FDA and hopefully will be approved sometime this year. And they’ll give the patients another opportunity for BCMA targeted therapy in addition to the ADCs and the CAR-T and off-the-shelf product. And that certainly the results are still not fully mature, but certainly response rates are high. And so far, the progression free survival is not yet reached and suggests that it may be in line with what we might see with some CAR-T products. Time will tell and obviously we have to take into account that populations may be different, but the results are very encouraging. And then we also talked about other targets, because as we know, unfortunately, unlike our lymphoma colleagues, we have not reached the plateau and we’re not seeing cures as of yet for most patients. And so we need alternatives to targeting BCMA. So we talked about talquetamab, which is targeting GPCR5, and it’s showing activity as well, high response rates, very manageable toxicity profile with low-grade CRS and ICANS including responses or I shouldn’t say responses because that data wasn’t presented, but at least some of the patients, a third of the patients enrolled in the study had had prior BCMA. So encouraging that, we will see responses with this new target in that patient population. And then I specifically spoke about cevostamab, which is another bispecific that targets Fc receptor H5. Again, this differs from the BCMA target in that is expressed through multiple lineages of B cells. In addition, it’s not secreted. So we don’t have issues with soluble levels and drug sync effects. So in those studies again, we showed at the higher doses overall response rates around 60%, very manageable CRS, almost exclusively grade 1, 2 and similarly with ICANS. So a good safety profile for that bispecific and it looks like we’re seeing durable responses. And again, that study had about a third of the patients that had had prior BCMA. So it looks very opportunistic that we will have additional drugs that we can use in our patients who are getting what’s probably now being considered the fourth pillar of myeloma therapy, anti-BCMA targeted therapies.

Yi Lin:

So we anticipate having FDA review and hopefully approval for teclistamab later this year. So we would have another option in the clinic. What are you guys thoughts in terms of how you might consider patients for teclistamab versus BCMA CAR-T, assuming we have access to both?

Krina Patel:

Right. So that’s what I was going to say at the beginning. It’s going to be all my patients that are on a list waiting for a CAR-T are likely going to get the bispecific. And as we get more slots, I think for us, it’s really going to be those patients, hopefully in this next six months to a year, we’ll have more data to say who are the patients that really are optimal for CAR-T in terms of their cells, manufacturing, especially after fourth line, it’s a lot harder for these patients to get to CAR-T, make cells and then have disease that still responds without horrible toxicity because their disease is exploding. So I think hopefully we’ll have some data on which patients to select, but I think right now we have so many patients that need therapy and it’s great to have these, we’re trying to get whatever we can for them.

Suzanne Trudel:

Yeah. I think I would agree completely with what you said. I think as we get more and more data about who are the patients who do really well with CAR-T, those patients I think would be certainly be patients that we’d preferably put on CAR-T and then who are those patients who can’t wait for the manufacturing at this point in time, we’re still not readily available to get rapid products out. So, those are the patients who might go on a bispecific. And then there are patients who may just opt for one choice over the other who may want care closer to home, as opposed to relocating for a month to an academic center for CAR-T for example or may not have the supports to manage to get through a CAR-T. So it’ll be lovely for the patients to have those choices available.

Yi Lin:

Yeah. So Dr Locke, we heard real world data is mantle cell lymphoma, which took brexu-cel and also some emerging data with ide-cel in real world and it was very encouraging to hear despite, more than half right? 75 more percent of the patient who would not have met registration trial requirement, those patients still seem to have done well with these CAR-T in the real world. You’ve talked a little bit about, in the second-line setting with the positive study and how would this gets adopted in the practice? And it’s something we discuss a lot in terms of, “Oh gosh, will you take on the patient that wouldn’t have been on a ZUMA-7 study for CAR-T in a second line setting,” and then also, we’ve seen some data in first line setting too, that may be potentially practice-changing lymphoma. Do you foresee that potentially changing the patient population being considered for earlier use of access out in lymphomas?

Frederick Locke:

Yeah, I think the results are really clear that CAR-T therapy can work for patients with refractory disease and as we move it up earlier and earlier lines of therapy, we’re actually seeing slightly better durable response rates, not wildly better, but we’re also as we move it up into earlier lines of therapy, actually, pre-selecting the patients most likely to do poorly with chemotherapy. So I think we like to broaden that and treat more patients earlier. The label for axicabtagene ciloleucel was updated to allow for second-line therapy and those who progress within 12 months of initial frontline treatment. So that means that there’s a whole number of patients who are going to be in the relapsing more than 12 months, who will not be on the FDA label and we won’t be able to use it most likely. But I think that also you mentioned the real world data, whether it be for axicabtagene ciloleucel or brexucabtagene or ide-cel, we’re seeing that we are able to administer CAR-T therapy to patients who maybe have comorbidities or wouldn’t have been perfect trial candidates, but we’re able to collect cells. We’re able to get them CAR-Ts and the results are equal and in some cases, even better than the pivotal trials, because these patients may have more of a relapsed disease phenotype, at least in large B-cell lymphoma, as opposed to a refractory disease phenotype. And I think that disease difference actually impacts CAR-T response as well. So we’re just excited that we have CAR-T therapy for our patients and we encourage referring providers to refer the patients in and it’s unfortunate about the myeloma CAR-T that we can’t treat enough patients, but I’m excited that there’s going to be some of these bispecific options, but it’s clear that the results are impressive with ide-cel. You guys talk about the envy, what is it, the plateau envy, but I don’t know, look, these are patients who really are without other good treatment options. I have patients who are eight months, nine months out of standard of care CAR-T therapy for myeloma who are cruising around the world. They’ve never gone without therapy for eight months in 15 years. It’s pretty remarkable treatment opportunity. So we hope that we can give it to more of our patients soon.

Yi Lin:

Absolutely. All right. Well, thank you everyone for sharing your data, any last thoughts or things you’re looking forward to for this coming year until we meet again for iw-23.

Suzanne Trudel:

Well, I think I’m looking forward to seeing some of the combination data that will be coming out with the bispecifics combining with IMiDs and Dara to see how the tolerability and the efficacy data from those studies, and then learning more from the correlative studies from the CAR-Ts and not trying to understand a bit more about who fails, who does well to better inform our treatment decisions.

Frederick Locke:

Yeah, I agree. Why are patients not having optimal responses to CAR-T? How are we going to sequence the bispecifics in CAR-T therapy? Or how are we going to choose those patients? And then do the allogeneic CAR-Ts work particularly for myeloma, because we’re not able to give enough autologous CAR-Ts, so we’re looking forward to it.

Krina Patel:

Yeah. And I think I can just add the real-world data for myeloma. We’re just starting with that and I think having a second product now to be able to look at responses and toxicity, et cetera, is going to be very telling and then how to sequence all of this, that we’re getting all these new treatments and wonderful opportunity, but I don’t know which target to use when or the combination, which ones are going to be the best. So I think that translational data that hopefully we’ll be getting from all the CAR-Ts and bispecifics will hopefully help with that.

Yi Lin:

Yes. That would be a good problem we would like to have.

Krina Patel:

Exactly.

Yi Lin:

More work to do. Thank you everyone for your time.

Krina Patel:

Thank you.

Frederick Locke:

Thank you.

Suzanne Trudel:

Thank you.