Dr. Armitage discusses the role of CAR T-cell therapy in the management of multiple myeloma and lymphoma in a conversation with his colleagues Dr. Holstein and Dr. Lunning.
James Armitage: Hello, I’m Jim Armitage from the University of Nebraska Medical Center. I want to welcome you to The ASCO Post Video Roundtable Series featuring the Appropriate Management of Challenging Cases in Patients with Myeloma and Lymphoma. In this installment we are going to be talking about where CAR T-cell therapy fits in to these diseases, and I am joined today by my two friends and colleagues who are experts in this business, and I will let them introduce themselves. Sarah Holstein: Hello. My name is Sarah Holstein. I’m an associate professor at the University of Nebraska Medical Center, and I specialize in the treatment of multiple myeloma and related plasma cell disorders. Matthew Lunning: Hello, I’m Matthew Lunning. I’m associate professor at the University of Nebraska Medical Center. I specialize in lymphoma and cellular therapy. Dr. Armitage: Okay, so this is a bit different than talking about a specific disease situation, and first I would like both of you to just briefly tell us which patients really need to have this thought about and offered to them. Matt, which patients? Dr. Lunning: Sure. So, right now in the commercial environment for the two constructs which are approved, which are axi-cel and tisagenlecleucel, is for patients who received two prior lines of therapy for large-cell lymphoma. Where do I see it used? Across all spectrums. Patients who have responded to first-line therapy and then recurred and had an intent to go on to get transplant and were refractory to their second-line therapy, blew right through their second-line therapy, those patients would get CAR T. The double-refractory patients we’ve seen, and we’ve seen patients who have had prior autologous stem cell transplant as second-line therapy and the disease has recurred and have received CAR T cell. I think there’s a lot of clinical trials going on right now with CAR T also and in other diseases. Probably the one that’s furthest along is in mantle cell lymphoma, in relapsed/refractory mantle cell lymphoma, but that’s not commercially available. Dr. Armitage: And the other things that people might think about were follicular common disease. And just to address the T cell because people sometimes ask that. Dr. Lunning: So I think T-cell lymphoma is – there are trials coming out namely against CD30, so anaplastic large cell lymphoma. There is also being tried in Hodgkin’s lymphoma because of the expression on the Reed-Sternberg cell. There are other constructs using the immune system which are still under the cellular therapy umbrella, but you have to worry about fratricide when you’re developing T-cell CARs against T-cell lymphoma, and I think that’s an inherent potential barrier. Do I think that we can get around that? Well, CRISPR-9 technology is now there. They are CRISPRing out things left and right in CAR T cells. They’re also looking at potentially using other parts whether or not they’re NK cells or even myeloid-derived cells as a form of cellular therapy to get around this. Dr. Armitage: But no commercial follicular product? Dr. Lunning: Well, no, I believe ZUMA-5 is – that’s the follicular component with axi-cel, that’s data that I don’t think is out there yet but it’s data that when it gets out there, we will be excited to see the activity. There was early data from the group at Fred Hutch: eight patients, I believe seven of the eight responded and the overall survival curve is flat, meaning flat at 100%, not flat at 0. And then the other area that we talked about which has transformed lymphomas, follicular lymphomas: recently at ASH, Jeremy Abramson gave a beautiful talk talking about liso-cel, which is, I think, the third CAR T-cell construct that is in late development. And what really struck me was the first time that they parsed out the disease subtypes, and I hadn’t seen that in the other two constructs and when they reported their pivotal data. But what surprised me in that is that the transformed follicular lymphomas were doing quite well, and there were quite a few of them on that trial, but it also buried in that trial the Richter patients that were allowed in the TRANSCEND trials, and those people were hovering down around your double-hit, triple-hit lymphomas, but I think that is another unmet medical need that hasn’t necessarily been addressed with the other two approved constructs. Dr. Armitage: Now, one of the flavors of the month, because you’ve got a different target that seems to work, is trying to do this in people with myeloma. What do you think about it? Dr. Holstein: I think CAR T-cell therapy is very exciting for myeloma. We’re a little bit further behind than in lymphoma of course, so we currently don’t have any commercial products available, although I hope that that is going to change in 2020. Right now what’s first out of the gate in terms of being the most successful is BCMA-targeted CAR T-cell therapy. For me, I think the two populations that are of most interest or most relevant for CAR T-cell therapy are first the heavily relapsed/refractory, so those patients who were penta-refractory, meaning refractory to lenalidomide, bortezomib, carfilzomib, pomalidomide, and daratumumab. So you’ve ran out of all the best options, and what do you have left? That is where many of the US-based CAR T-cell studies, that’s the population that has been looked at, and we’re seeing response rates that really have not been anywhere close to the response rates that traditional drugs have achieved, so much, much better in the CAR T realm. So if you look at selinexor, melflufen, other agents, iberdomide, you’re getting maybe 25% to 30% response rates, but in the CAR T-cell therapy for that same patient population, you’re seeing response rates of close to 100%. So that’s extremely exciting. Dr. Armitage: Both of you, I would like you to address the issue of do you see this replacing autotransplants, so they wouldn’t be done anymore? Replacing allotransplants, so they wouldn’t be done anymore? Part of the upfront therapy for particularly high-risk patients, where do you see it? Either one of you can start. Dr. Lunning: I think from the lymphoma standpoint we can – I’ll march it backward. So, you know, the trials are going on right now, and I think high-risk patient population, so those patients who were refractory or relapsed within a year of their therapy or within a year of the start of the therapy or within a year after an autotransplant, those are the randomized trials that we are looking for those results and still accruing to some of the trials. So that would replace autotransplant in that population. Then the question is this: do we do it in patients who go beyond that, so patients who have had a relapse beyond a year from their therapy. Upfront therapy, I think we’re going to have to find the right patient population to study it in first. Who is that patient? Well, you could argue high IPI, double-hit patients, but those patients don’t come along very often. You could use PET-adapted responses, so those patients who haven’t achieved a CR by some time point. I’ve looked to the PETAL study, which looked at a PET after two cycles. We tried to give more intensive therapy with an ALL-like intensification, and those patients didn’t do any better. So I would think, and I think ZUMA-12, which, again, is using the axi-cel construct, has it right. They’re doing kind of that approach. I think it will be interesting to see – that data has not come out and that will be interesting data to see if that strategy is working. But there are patients with double-hit IPIs that can go into remission and can have durable remissions so I think it’s going to be tough. We really have to nail down that disease. If you can’t nail down in that situation, then it’s going to be very hard to go to the frontline setting, and not too many things have beaten R-CHOP and nothing in North America today. Dr. Armitage: So, you have to do more speculating because you have less data. But do you see this, for example, replacing the autotransplant that most people with myeloma that are relatively healthy still get? Dr. Holstein: I don’t see it replacing autotransplant. I definitely see it replacing allotransplant where we would use it, perhaps in those patients who relapse very quickly after an autotransplant. And in that case, you might have thought about allo. Now I think you think about CAR. What I’m more excited about is the potential for a tandem auto-CAR approaches, which is going to be studied. I think it makes a lot of sense. I think it is great to collect your T cells and your stem cells all at the same time and move forward. So I think of that as being a potential. I think in myeloma, the billion dollar question is whether or not CAR T-cell therapy is a curative approach. Right now we have no data to suggest that it is, but again we’ve been studying it in the primarily heavily relapsed/refractory setting. If this becomes the first therapy that truly cures patients, then absolutely it moves upfront, and in that case, we can do away with autotransplant potentially. If not, if it simply significantly prolongs disease remission period, then I think it makes sense to do in concert with auto. Dr. Armitage: Now you can make an argument that if it works, it ought to replace allo, because it is kind of like an allotransplant without graft-versus-host disease. But there’s some new treatments that are coming along, these bispecific antibodies, that look like they might be the same thing without cellular therapy. You guys want to comment on this? Dr. Lunning: Yeah, I think that we have to learn from the ALL. While in adults, you can’t get CAR T cells, at least not in the commercial environment, if you’re older than 25. But blinatumumab – we’re going to be in this situation where that targets CD19, and there have been potentially CARs done after blinatumumab, and we need to learn from that data. It’s really going to take time for the BiTE data to mature to see if they can generate the curves that ZUMA-1 is generating, that JULIET is generating. We will have to see with longer follow-up for the TRANSCEND dataset to see if there are plateaus, because it’s the tail that will wag the curve from the CAR T cell. That’s what got everybody excited when you start to see those sensor marks going beyond 24 months and plateauing. How are we going to use them in diffuse large B-cell lymphoma? Is it to bridge people? And what do you do to the CD19 engaging of the CAR T cells if it’s already been kind of perturbed? I think that will be a discussion with drugs like tafasitamab, or MOR208, in combination with lenalidomide. And we did not talk much about the polatuzumab plus bendamustine/rituximab in the CAR T-cell environment. Coming back—I didn’t realize I didn’t answer your allo question—when would you use an allo after CAR T cell? I think that’s a pretty interesting question because before a lot of patients were not coming off the CAR T-cell trials to go to allotransplant. I think the data is starting to show that maybe higher bulk disease or bulky sites of disease if they go into a CR or overall metabolic tumor burden, would those be the patients who get in CR that aren’t going to have the durability that you would expect? Maybe those are the patients that you could consider an allotransplant in. I’m just starting to think about radiating those sites of bulk after. So I don’t think there is a clear-cut answer. I think we’re going to have to let data drive us towards that discussion. Dr. Armitage: Sarah, bispecific antibodies in your business or something else that you can see it passing up CAR T cell? Dr. Holstein: Potentially. Right now there are four therapeutic strategies under development that all target BCMA. We have the BCMA CAR Ts. We have the BCMA bispecific antibodies, BCMA bispecific T-cell engagers, which are slightly different than the bispecific antibodies, and then the antibody-drug conjugate approach. We know with the latter that the response rates and PFS in fairly similar patient populations appear to be inferior to what we’re seeing with CAR T. We just don’t have enough robust data for the middle two, so the BiTEs and the bispecifics, to really know whether or not that’s ultimately going to beat CAR T. From a logistical perspective, the bispecifics and the bispecific T-cell engagers are definitely therapies that could be administered in the community, whereas CAR T cell cannot, and so I think it might not be the case of one versus the other, but perhaps just trying to find out which is the best fit for an individual patient. Dr. Lunning: I guess that’s a good point about access. So access to CAR T cell when you have other therapies that could be used instead of CAR T cell. And I think that that is probably going to be one of the biggest barriers to CAR T cell moving forward as other drugs move in, beyond if you’ve already targeted BCMA from a different agent, what is the BCMA expression, or what BCMA expression do you need to go to CAR T cell? Same thing goes for CD19 from that standpoint. We haven’t even gotten, when the patient hasn’t even gotten to the CAR T-cell center; we’re still having that gap of access. I think it’s different if it’s curative intent therapy versus not curative intent therapy from that standpoint, because there are still logistical challenges when you get to the CAR T-cell center of getting what I call “brain-to-vein” time, from the standpoint of when you’re first seen, when you really want to do a CAR T cell, to actually getting the apheresis product. There’s a lot of time in large-cell lymphoma and even myeloma when it’s meeting with seven lines of therapy and bb2121, and your time is of the essence, and so how do we shrink down that brain-to-vein time so that we aren’t having patients progressing or not able to even get apheresed? Because I think one of the challenges right now is we have no idea what the intent-to-CAR outcomes are when we really want to do CAR T cell to actually getting the patient through CAR T cell. We haven’t learned that in the clinical trials. We haven’t really learned that in the retrospective real-world experiences. That can only come down to the single-institution data and the willingness to share the data amongst each other about really this is our intent-to-CAR population that they are going to go and this is how many people, the true denominator and the true long-term survivors. Dr. Holstein: And I think another factor here is right now, at least in myeloma, is CAR T as seen as you get the therapy and you’re done. And we don’t have anything like that otherwise. Everything else we do is treat until progression, but having said that, there is already studies that are going to be looking at doing, for example, lenalidomide maintenance after a CAR T, so it’s no longer going to be the one therapy and you’re done, which might be attractive to some people because they are finally, finally done with therapy. If we are simply turning this into another therapy but then you have to continue on something else indefinitely it might be that they say, “well, the CAR part of it isn’t worth all the risks of neurotoxicity and having to be in a hospital or have to be away from home for a certain period of time,” and they might choose instead a BiTE approach. Dr. Armitage: Thank you. I appreciate that. That was wonderful both of you. We really appreciate you taking the time to do this, and I would like to thank you for joining us. Stay tuned for more installments of The ASCO Post Video Roundtable Series exploring other disease types, but once again you will find on ascopost.com.
