Updates on the biology and treatment of T-cell lymphoma

Francine Foss: Hello, I’m Francine Foss, and I’d like to introduce you to my colleagues here at the iwNHL at our T-cell session, Francois LeMonnier, my co-chair, Laurence de Leval, and Dr Steve Horowitz. So I would like to ask my colleagues here to summarize briefly what they thought the important points were from their talk. You talked a little bit about the background of mutations and T-cell lymphoma, and what’s going to be important to us as clinicians. Could you tell us a little bit about that?

Laurence de Leval: Yes, of course, Francine, so I provided some overview of the entire accumulated past ten years and genetic sub-stratification and characterization of lymphomas. I talked a little bit about the historical group, that of anaplastic large cell lymphomas ALK positive versus ALK negative, that distinction still matters. But, the question now is: what is the significance of the genetic variants of ALK negative ALCL? And the situation is not so clear on the relevance of the testing for DUSP22, while rearrangement, while TP63 rearranged cases are generally aggressive, but they’re very rare. They seem to be other variants like JAK2 rearranged which are less well characterized, so there’s still a way to go. In addition, those cases have frequent mutations in the JAK-STAT pathway. That’s another way of looking at the mutations and abnormalities- by pathway rather than by entities. And among the signaling pathways that are important in pathogenesis with potential therapeutic intervention are the JAK-STAT signaling pathway often activated by mutations or rearrangements, and the T-cell receptor NF-κB pathway, also supposedly mostly activated by rearrangements. These abnormalities you see in various PTCL entities. That is the background for constructing clinical trials that are entity agnostic but based on the molecular alteration. And I think the JAK-STAT pathway has the best characterized inhibitors. So that was developed further by my colleagues.

Francine Foss: Yes- Steve- you spoke some about JAK inhibitors. You gave us some clinical data from some of your studies.

Steven Horwitz: Yeah. So what I talked about today was really looking at a couple of signaling pathways JAK-STAT, PI3-kinase, ITK, and then some of the preliminary clinical data. So, in targeting the JAK-STAT pathway, we did a Phase II study of ruxolitinib, and we were able to see that there is some activity with targeting that pathway. Activity is most in patients that have alterations of that pathway, with mutations or elevated phospho-STAT signaling. So it looks like, by targeting that pathway, you can have responses, you enrich responses. A lot of work is looking at trying to correlate how much we can predict who’s likely to respond, who’s not going to respond, so we can individualize the strategy.

Francine Foss: Francois, you talked a little bit about the whole epigenetic landscape and how we could potentially target that.

Francois Lemonnier: Yes, indeed. Actually, we know that for more than ten years, I think, between 10 and 15 years, there are very recurrent mutations in T-cell lymphomas, especially in the [inaudible] T-cell lymphomas, with mutations in TET2 in more than 80% of patients which is an important epigenetic change, especially in the DNA methylation and hydroxymethylation. So it makes a rationale to develop epigenetic drug therapies, including with azacitidine. So we met with the French group, LYSA, but also with other collaborators in the UK and with the Nordic Lymphoma Group, in Japan, and we made a Phase III study that randomized the oral form of azacitidine (CC-486) in the experimental arm, randomized against the control arm with drugs at the choice of the investigator between romidepsin, gemcitabine or bendamustine. So, the trial showed interesting results with an increase in overall survival and PFS, progression-free survival, which was the primary endpoint, actually, was not reached, likely due to a lack of power of the study, because there was only 43 patients treated with azacitidine. We observed some sustained response because some patients are still on therapy now, four years after the initiation of the treatment. And, so, we want to try to understand better how to improve those results. The safety profile of the drug was really good actually. And so that is space for combination. We really want to investigate again this drug in combination in those lymphoma patients.

Francine Foss: I talked a little bit about valemetostat which is also is an epigenetic modifier of some sort. It looked like the response rates were very high with Valemetostat across different subtypes, which is something that we haven’t necessarily seen with some of our other therapies. And I know this touches on something that Steve talked about, which is that we’re now starting to dissect and look at specific subsets- rare subsets- and identifying pathways forward for some of those. And Steve, if you want to briefly just tell us a little bit about maybe some of these orphans that you have seen activity for in some of these new drug trials that you have been doing?

Steven Horwitz: Yeah, And I think the best example we have of that right now still is with targeting JAK-STAT. So, not us, but others, have identified that some of these tumors are really characterized by these frequent fusions, particularly in JAK2. And there’s a whole class of tumors that have this, including some rare cutaneous T-cell lymphomas, the aggressive epidermotropic. We’ve seen them in some PLL, other kinds of PTCL, and we see these sometimes in LGL. These rare or ultra rare subtypes that have these specific mutations, it looks like some of those patients, not all, are exquisitely sensitive to JAK inhibition. So, we talked about this idea that there may be molecular genetic subtypes where there may be a very effective, specific, on-target treatment. And I think the ruxolitinib data is sort of proof of that concept. But there’s probably other ways of identifying these and other ways of going about that. Then there’s a lot of discussion about the challenges in T-cell lymphoma, and how do we generate good enough data in these ultra-rare subtypes to generate either clinical use or payer support or even approval. And that is, of course, a big challenge.

Francine Foss: Right, yeah. And Laurence, if you want to summarize for us some of the data with animal models and how pertinent they are to us in the future, and also whether or not you feel we’re in the era where every patient with aggressive T-cell lymphoma should have deep sequencing done to identify these mutations.

Laurence de Leval: So it’s many questions in one Francine, I assume that you’re making reference to the talk that was provided by Dr Inghirami from Cornell. So, he presented us an update of data he has already partly explained a few years ago. As I understand, they have constructed a multi-dimensional platform using human samples and trying to create patient derived xenografts in mice, that was the basics. He has explained to us that by doing so, there is a high attrition rate with at least 30% attrition from what he explained. But they successfully obtained multiple PDX models of angioimmunoblastic T-cell lymphoma, for example, which is really the disease that is very common and that has no cell line, but also a lot of microenvironment that is retained in those mice. So that really provides a good experimental substrate to test for drugs. I’m taking the liberty because I’m sitting by Francois. I believe that he has a similar approach and has also successfully constructed some xenografts for drug testing in ex-vivo and can make additional testings. Giorgio Inghirami also explained that he could manipulate native human cells with specific mutations and create tumor models in humanized mice. He explained the complementarity of these different models in the platform. Now, to what extent this platform can really be used in real life to adapt therapy, that so far he has not really shown to us that this was done on a daily basis, or could be done in due time on a daily basis. Maybe you want to comment on that, Steve, because it’s close to you.

Steven Horowitz: Yeah. We’ve worked a lot with Giorgio. I think Giorgio has been fantastic at developing these models, and then we can test them. We haven’t done it real time concurrent with developing model, testing drugs, and then going back to the patient. What we’ve seen is, if you look at what happened to the patient in terms of sensitivity or not to therapy, you can often recapitulate that in the PDX, but not yet providing real time clinical information yet.

Laurence de Leval: And Francine, there was another part to your question. Do I believe that patients with T-cell lymphoma should undergo genetic testing? I would say I believe so, yes. I mean, it’s also my interest, but I do it at diagnosis. I think we learn from that approach, to learn about those patterns, to find out some associations. I think any single observations have value in this group of diseases that are very heterogeneous, the same way as Steve said, sometimes there’s very limited response, but it’s one element, it’s one data point. Similar in diagnosis, we see a lot of variability, and I think it matters. We accumulate data and then maybe find, relevant subgroups or limited numbers of individuals with similar patterns that may be relevant.

Steven Horwitz: If I can just add to that, I think the practical aspect that we see also is, in addition to learning more and more of our choices at relapse, they are not directed by, but informed by molecular testing. So if you get it at baseline, you have it when the patient doesn’t respond to therapy or relapses. If you wait till the relapse, you don’t have that information in real time. So we think there’s a practical benefit to getting a baseline, in addition to so much more understanding of the disease

Laurence de Leval:  And helping diagnoses.

Francois Lemonnier: Yes. I think it’s really helpful for the diagnosis because it really helps to have a better classification. And, I think we really made a huge progress in the understanding of the T-cell lymphoma pathogenesis. So I think now the molecular landscape is known. Probably, we need to learn a bit more regarding the interaction between the lymphoma neoplastic cells and the microenvironment. I think we still have a lot to learn. And now I think the emergency is to find some drugs, because now we have the mutations, we have a better classification, and a better understanding of the oncogenesis. So now, we need to find some good drugs.

Francine Foss: I think this was a really great session because we really brought the science and the clinical together and really talked about the translational elements here that are going to be important moving forward. And I’d like to thank all my panel members for their intelligent and really enlightening discussions here today, and look forward to our session next year. Thank you.

Evolving treatment landscape of MCL

Stephen Ansell: Hi, my name is Steve Ansell from Mayo Clinic, and we’re grateful to be together talking about mantle cell lymphoma here at iwNHL. I’m going to let my colleagues, all of whom are really experts in the field, share who they are. So, John, you want to get us started?

John Kuruvilla: Thanks, Steve. I’m John Kuruvilla. I work at the Princess Margaret Cancer Centre in Toronto, Canada- great to be here.

Stephen Ansell: Great, Marek?

Marek Trněný: Thank you. I’m Marek Trněný. I’m from Prague, Czech Republic.

Stephen Ansell: You, Yucai?

Yucai Wang: Yeah. My name is Yucai Wang, I’m a lymphoma doctor at Mayo Clinic, with Steve.

Stephen Ansell: So anyway, really a fun session on mantle cell lymphoma, and we’d like to just talk a little bit about your takeaways from that time. So the main focus was about biology and talking about high risk patients, but then really talking about the impact of new therapies and how it’s changing things. So, John, I’m going to start you off, because you have got the unenviable task of talking about what’s the future of autologous stem cell transplant. So your thoughts based on kind of involving data as to how that field is moving.

John Kuruvilla: Yeah, it’s an interesting time for us because we’ve seen major impact with the development of stem cell transplants, the incorporation of rituximab maintenance, intensive chemotherapy and excellent ten-year results now. So we have a really good platform, but at the same time, we have a ton of novel therapies coming to the forefront. And now, we finally have randomized trial data showing that the incorporation of BTK inhibitors, particularly ibrutinib, in terms of data that’s read out to date, now showing impressive results in front-line, both in transplant-eligible populations as well as transplant-ineligible populations.

Stephen Ansell: Right. So, Marek, you really kind of highlighted that data talking about the TRIANGLE trial. So your take on: has that changed the standard of practice or not?

Marek Trněný: Yeah, I think that there are two things. One, I think that the role of the stem cell transplant is going to disappear. So we are not yet saying to everybody, okay, do not go to transplant, but I think that we are on the way. The other issue is that the BTK inhibitor ibrutinib is not reimbursed or approved for this indication. So we are really in a tricky situation. We could rely on the data which are not mature yet- so we have to wait. But on the other hand, we do not have- really- approved medication for the first line for this setting, so this is something we have to discuss. But I think that for the low-risk, for instance, we are already discussing with patients the option to skip the stem cell transplant, the toxicity, et cetera. For high-risk patients, it’s a more difficult issue because the high-risk TP53-mutated patients, they have a poor outcome. So there is no plateau for the stem cell transplant as well. And if you see the brexu-cel data, they are the highest high-risk population, which is failing from a long term perspective as well.

Stephen Ansell: Right. And you, Yucai- we had this conversation about do we treat younger patients and older patients differently. And in the old days, we did, based on our transplant plans. But do you think that’s changing? And in your practice what are you doing?

Yucai Wang: Yeah. With the TRIANGLE data showing that transplant may be omitted when you incorporate novel agents at frontline, that perspective may be changing. Because historically, first question is whether this patient going to go through transplant or not. So with the TRIANGLE data, you know the algorithm may be changing. So now, if you think a novel agent is going to move to the frontline to be combined with chemotherapy, it’s a different question: which chemo do you give for young versus old patients? So in a sense still relevant- not in a transplant sense- but in the future if the novel agent combination comes to the frontline, then eventually, probably just like in CLL, age will no longer be relevant.

Stephen Ansell: Right. Go ahead. Marek.

Marek Trněný: We’ve published a couple of years ago, data where we treated elderly patients, median age 73 years old, with alternating co-regimen R-CHOP/R-ara-C. (4.32) And currently we are treating with R-CHOP/Ara/[inaudible]. So I think that the data are quite promising. I think that if the patient is able to go through this therapy, I think that those components ara-C plus cisplatin or oxaliplatin, rituximab, rituximab maintenance. So you really can get some very interesting data.

Stephen Ansell: So I agree with you, I think things are changing a lot in frontline. John, you made a point in the meeting which I thought was very valuable, about maintenance therapy. So often, rituximab maintenance has been our standard, now potentially adding a BTK inhibitor. So, is it important to add the BTK inhibitor in the maintenance or in the frontline or both? What do you think?

John Kuruvilla: It’s hard to know at this point given how the data have developed. What we can say from a study like the TRIANGLE trial is that when you look at the magnitude of all of the effect, it clearly speaks to the benefit of the drug in both settings. When you look at the data from SHINE now, it was pointed out in the meeting as well, that the separation of those curves appears to happen with the use of maintenance, as opposed to during the induction phase when it’s being given in combination with chemotherapy. Part of that may also be that we don’t have good enough tools to really appreciate the depth of remission- a PET scan may not be adequate, and MRD may not be assessed routinely in clinical practice. So I’ll say the jury is out there. But we certainly know even looking at rituximab, the magnitude of the benefit certainly was mostly with maintenance. And so, if you’re limited in terms of how you may access the drug, building it in wherever you can. If it’s only in the maintenance setting, that’s better than not at all.

Stephen Ansell: Yeah. So, Marek, I just want to ask you a question. You mentioned a number of different regimens that you’ve been using, and we’ve mentioned about the BTK inhibitors and how they are really bringing promise. Do you think it matters whether you add the BTK inhibitor to R-CHOP or the BTK inhibitor BR? So in other words, does the backbone that you’re adding the novel treatments to make a difference?

Marek Trněný: Yeah, I think that for us, we do not use BR very often, only for patients who are compromised. So, for the patients up to 70, 75 and maybe some more, we use combination with R-CHOP. And I do not have the answer to the question if it does matter- but I think it’s very interesting that from the TRIANGLE study, the patients didn’t receive ibrutinib in each cycle. They got the six cycles of the chemotherapy, but they got the ibrutinib only with R-CHOP, which means three cycles out of six. And the response rate, the complete remission rate was really improved. So, from 36 to 45%, in relative ways it’s almost a 30% increase in the complete remission rate. So I think that I would be very cautious to say that it’s only the maintenance part. I think that it really plays a role as a part of induction.

Stephen Ansell: I think you make some good points. So maybe moving on a little bit, and Yucai, I will try to bring you in too- where do you think in this changing environment, are we going with the cellular therapies? And specifically you and others highlighted a little bit of data about the different CAR-T cell products. So your thoughts on: where do they fit? Are they going to make it all the way to frontline? And is there a preference on how you manage and which one you use?

Yucai Wang: Yeah a great question, Steve. So, so far, brexu-cel was approved by the FDA, but they did not specify how many lines of therapy you should have received in the relapsed setting. So, you can use it as early as the second line. But in practice, most of us I think, still use brexu-cel in the third-line setting, most frequently after a BTK failure in the second-line. So, definitely, there are data emerging when you use brexu-cel in the second line, outcome might be a little bit better, but limited by small numbers- it certainly needs to be confirmed. So, in high-risk patients, you can certainly try to get insurance approval to use brexu-cel in the second-line because in the NCCN guidelines, interestingly, they say that you should use brexu-cel in the third-line. So that made it a little difficult, although the FDA label was that you can use as a second-line. But yeah, for high-risk patients, you should certainly try. Will they eventually land in the frontline? There are studies going on. So, there are single arm studies in Houston and MD Anderson.(9.20), they’re doing a so-called WINDOW-3 study. They are leading with acalabrutinib, and then adding a CAR-T cell very early for high-risk patients only so far. So it will be very interesting to see what that data shows. Our European colleagues are doing randomized studies comparing BTK/chemo versus BTK followed by CAR-T cell therapy- again for high-risk patients. Very exciting trials! We await the data. The other CAR-T cell product that’s coming is liso-cel. We saw exciting data at Lugano this year. This product uses a 4-1BB setting (9.54). It seems to have a better toxicity profile- a higher response rate as well. We just need to see, when used in standard of care practice, whether the duration of response is similar to brexu-cel, because in the pivotal trial, it seemed to be a little different compared to ZUMA-2 data, although different trial population.

Stephen Ansell: So, John, it seems to me CAR-T cells are in the ascendancy and autologous transplant may be descending a little bit. Do you think the one’s going to replace the other?

John Kuruvilla: I would think so, Steve- eventually. My sense with auto, one of the questions that comes up, much like we think about this in the similarities to the myeloma world, as novel therapy has come there and was heavily dependent on transplant. Will it become a relapse setting treatment, autologous transplant? And I would argue there, if we already have something else that’s quite effective, I think it will be less likely to be used. And given all the other novel agents that are available in combination and new ones coming down the pipe- I personally think I’m okay with saying that a therapy from 25 years ago has probably had its day, and we’ll move on.

Stephen Ansell: So, Marek, what I want to ask you: do you think we’re going to start curing mantle cell lymphoma? We’ve always said these are to give us durable responses. You presented some very nice data that there’s an autologous transplanted subset of people who may have a very long-term outcome. Now that we’re bringing cellular therapies and novel treatments Marek, are we going to fix everybody?

Marek Trněný: Yeah, I think it’s a very good question because the patients usually ask us if I could be cured. I think that definitely for low-risk patients, low and some intermediate-risk, we really see very long-term survival, and we almost see the plateau for those patients. But I think that we still have a challenge with the high-risk patients because they are going to relapse. And at least in our hand, there is no plateau. And I think that for mantle cell lymphoma, although we have some subsequent treatments available already, treating patients who are failing the BTK inhibitors by CAR-T cell, it’s not very easy because sometimes they are progressing very quickly and you do not have so much time to do something. So I think that we should afford to balance the toxicity and efficacy, but to give the best we can in the first-line, because then we can proceed to the cure. I really do not believe very much in being cured in the second or the third-line.

Stephen Ansell: Right. So Yucai, you get the last word here. So thinking about the novel things that are in the pipeline, as Marek mentioned, what are you excited about and what do you think is really going to contribute to the curative potential in this disease?

Yucai Wang: Yeah, so there are different classes of drugs that are in development showing promising data. I think a few classes to highlight: one is the bispecific antibodies, like glofitamab, a CD20xCD3 bispecific antibody showed very high response rates, and seems to be durable in trials. They are now going to randomized trials. I’m sure this agent, just like CAR-T, will probably move to the frontline in the future. So if it has a better toxicity profile than CAR-T, it can be used in the community setting. Maybe this holds the promise for the future frontline with bispecific antibodies, whether with or without other novel agent or even chemotherapy.

Stephen Ansell: Right. Well, just to say thank you very much to my colleagues for their comments on the session. It was a great session, and thank you very much to you, the audience, for listening to this discussion.

New therapeutic targets in DLBCL

Ash Alizadeh: Hi there, I’m Ash Alizadeh from Stanford University and with my colleagues, Dr Laura Pasqualucci from Columbia and Dr. Ken Young from Duke. We had an exciting session to hear about three very different topics. We heard first from Dr Laura Pasqualucci about co-operativity between chromatin regulatory factors and chromatin modifying mutations in large cell lymphoma and follicular lymphoma. That was quite an interesting body of work that you’ve summarized for us. Also heard from Dr Young about new ways to think about therapeutic targeting of large cell lymphoma looking at the landscape of somatic mutations and new opportunities. I shared some ways we might look at both of those types of phenomenon using cell-free DNA to see what may be going on when we try to tackle these therapeutic vulnerabilities. I first had a question for you, Laura. One of the things I was intrigued by was should we be looking at these genetic alterations in these factors like CREBBP and KMT2D through a lens outside of histones and chromatin? In particular, thinking about the difference between lymphoma types for where the mutations occur, do you think there is anything that we may not be aware of for activity of these proteins on non-histone proteins? Any opportunity to see if there are new functions for the mutations, particularly in CREBBP?

Laura Pasqualucci: Well, I think that we certainly should look at that. We know very little as of now in the context of lymphoma, but both for CREBBP and KMT2D, also more recently we know there are non-histone proteins that are modified. I agree totally with you that there may be differential functions that could be related to these proteins in the different subtypes of DLBCL. Unfortunately, I don’t have much to say, but proteomic analysis, taking advantage of the models we have in our hands, many of us, would shed light on that. The KMT2D acetylation by CREBBP is an example that certainly this thing is happening.

Ash Alizadeh: Right. But do you think that the key, the central role is still histones, that’s the way in which these things are perturbed to deregulate gene expression through histones?

Laura Pasqualucci: Well, I think histones is important because clearly you do see a correlation between the expression of these genes and the localization of the proteins. But the other protein factors that may be recruited to these loci together with CREBBP or KMT2D or even the compensatory mechanisms that could come into play when CREBBP or KMT2D are lost will have an equally important role. In fact, that’s one area we’re trying to pursue as probably many others.

Ash Alizadeh: Great. Ken, you told us about very different ways of thinking about therapeutic vulnerabilities in large cell lymphoma, looking beyond, even within, specific hotspot mutations. A number of different ways of thinking about it, among those, if you had one to pick as the top of your list in terms of prioritizing, which are you most excited about of those strategies? Can you tell us a little bit?

Ken Young: Yeah, thank you. I think the most appealing to me is the P53 pathway. I think that this is people are already working on for 50 years. All attempts from pharmaceutical company, academic centers failed in the past 50 years efforts, including Roche that spent million, billions of dollars. I think this is probably the first priority because this is present in any type of human cancers. If we are able to make one single breakthrough going to be applicable in any cancer type, even individual mutations happening. Those are probably the first things that we’re going to moving forward and we’re looking for advice and opinion from all the experts, and looking for partners for collaboration in this area and moving into the clinical investigations.

Ash Alizadeh: Great. Now not all the folks that are watching had a chance to see your talk. Can you tell us how you would approach tackling P53 – as what is the unique way in which you’re tackling it in lymphomas?

Ken Young: You have three different approaches. One is artificial intelligence which is driven smaller molecules screening. We already screen 20 million compounds. We already find three compounds, they are very effective, able to inhibit tumor cells carrying these particular mutations. The second thing I feel is that now we are moving into immunotherapy centuries. I think the bispecific antibody targeting P53 mutations engaged with normal surrounding T-cells probably could be more even powerful. Now, certainly combination could be, to think about it. The third one is vaccine. We’re developing a particular injection, intramuscular injection, use of vaccine and they’re able to achieve quite a reasonable response. So I think these three approaches, but particularly antibody-based could be very powerful tools that in the future to think about it the same we follow for myeloma patients, for the DLBCL patients, bispecific antibody treatment. FDA approved five bispecific antibodies targeting myeloma and lymphoma. I think for P53-based bispecific antibody treatment could be a breakthrough consideration in the future.

Ash Alizadeh: Great, great. Laura, you mentioned the importance of these mutations in the key chromatin modifying genes as early events in the development of lymphomas and as kind of ways of defining the progenitors of – what’s your vision for how that knowledge would have us pursue therapeutic vulnerabilities. You talked about ways of playing one chromatin modifier off the other when there’s a deficit. Can you talk us through that process and how a therapeutic pathway development may work?

Laura Pasqualucci: First of all, I think therapeutic approaches may be different if you want to try and target the precursor cell, or if it’s a vulnerability that is maintained by the tumor cells and which therefore the tumor cell can remain addicted to. Because if we want to develop approaches to eliminate the precursor cell or maybe even to predict or prevent relapses when we can detect this mutation as you showed in patients when they are still healthy, that would be quite complex. Obviously, we would have to look for approaches that are not toxic and that would provide true advantage to patients.

If it’s a vulnerability that is maintained by the tumor cell as we showed for P300, I think that that obviously may, I think, would be worth it to explore. We don’t have drugs at the moment if we talk about P300 that are specific, as you know, and probably one would have to play with dosage. But there are already compounds so that though not being specific, have shown limited toxicity in clinical trials and, therefore, I think that that could be suggesting a therapeutic window. Obviously, there’s a lot of work to do, I think for identifying other vulnerabilities, and there’s a lot of efforts academic and companies. I hope again we’ll have a better answer next time. But maybe since this is meant as a conversation, I think this is a good opportunity for me to ask you instead, since you also gave this very, very informative and amazing talk as usual on the use of circulating tumor DNA for predictive and maybe even decision-making processes. I think I would like to know your answer to these related questions.

Ash Alizadeh: I showed data on applying circulating tumor DNA through the timeline of a treatment of a patient with aggressive lymphomas from diagnosis through early prediction of response through the course of therapy to measuring residual disease at the end of therapy. Of course, these tools show a lot of promise, but for lymphomas, I think the key questions that came up after the session are the big ones, which is how do we take this information and actually make a difference for patients. As some of the folks in the audience mentioned, there are now clinical studies being designed and executed for taking patients with specific types of alterations and giving them therapy. For instance, we have a risk-adapted trial in large cell lymphoma where patients who are not responding quickly get treatment escalation through the course of therapy, adding, for example, a bispecific to the backbone, logistically difficult to execute as an interim assessment.

There are now other ones being talked about. Some people asked about the end of therapy milestone and early CAR administration or early bispecific administration as T-cell engaging type therapies that would help clean up the leftovers after chemo-immunotherapy have not achieved a cure. Then the other point that was brought up is CAR as a dramatic therapy that we now rely on for our patients, doesn’t work in every patient. The treatment failures after CAR are more prevalent than the successes. So, how do we overcome those failures with ctDNA? The ability to measure it is the first step. The second, third, fourth steps are building a study to intervene, administering it successfully, getting a response, and then showing that you improve outcomes. Each of those steps is a big lift and we’re working on them. I guess the one challenge that we haven’t really addressed, and I think some related work in CLL and myeloma have shown us is that circulating – MRD, I should say – MRD can be different in the context of different subtypes of the disease and different therapies in the subtypes. It becomes kind of a little bit complex in terms of designing and executing a study. Just imagine if CREBBP mutant large cell versus EP300 large cell are as different as, say, mutated versus un-mutated CLL, for example, in their MRD responses. How do we design the clinical studies to address these questions? But I think we need to walk before we run and that process is just getting started.

Laura Pasqualucci: Why do you think P300 is in fact sort of counter-selected as a mutation in relapsed/refractory?

Ash Alizadeh: I was hoping you would tell me. I was hoping you would tell me. One, we don’t really understand – another pathway that we see as a pathway involved in B-cell homing to germinal centers that you may have seen where different members of that pathway are on two different sides of the volcano. We’re just trying to understand that with working with Jason Cyster, P2RY8 and S1PR2, are on opposite sides. One is selected for and one is selected against. We don’t totally understand why these things are happening. If you have good ideas, we can measure it, but we don’t necessarily know what it means.

Laura Pasqualucci: It’s certainly one thing that is emerging from these studies in general at any level is that the interaction between the genetics and how genetics instructs the environment with lesions that many genes that are important in fact for the delivery of signals from T-cell or from the microenvironment will be very important in the future, or currently, right.

Ken Young: This pathway you present is very interesting. Now, we are not only seeing in lymphoma, but we’re also seeing in myeloma, particularly in the myeloid neoplasm MDS/AML. Do you think it will be a different, they play different roles in the biology in oncogenesis or maybe in MRD testing or maybe drug targeting?

Ash Alizadeh: I guess, I think, in the myeloid malignancies we’ve learned that not all mutations are created equal for MRD detection. That the FLT3-ITD versus NPM1 versus t hat the gene matters for what you’re measuring. Often when using tools that don’t target the therapeutic vulnerability of the pathway. Right? It’s not BCR-ABL by ABL inhibitors. It’s not FLT3 targeted therapy. In lymphoma, I have to say that we’ve seen much less dramatic evidence of clonal selection at the level of mutations and pathways surprisingly. I was wishing we would see more, but at the moment, I think linear rather than branched evolution, at least in large cell lymphoma, seems to be the rule… with the branching being an exception or the fraction of the genome that’s branched is small. But maybe things will be different as we do more of these things over time. And maybe it’s because of the things you showed that the types of mutations that we’re tracking probably reflect very early events. Aberrant somatic hyper mutation happens as B-cells become B-cells and become crazy B-cells in the germinal center as early events. If we have a hold on that, it’s unlikely that changed dramatically through the course of treatment.

Ken Young: I see. Many physicians still have questions now. Now, MRD testing has become a routine standard practice for myeloma and leukemia, but not well accepted by physician on lymphoma. How are we going to position MRD testing in the future for those patients and how are the healthcare systems going to support this kind of testing?

Ash Alizadeh: It seems like lymphoma’s stuck somewhere between the solid tumors which have already moved on and there’s now clinical, and actually active use, of ctDNA, for example, in colon cancer after colon resection for choice of adjuvant therapy decision-making, and the leukemias and myeloma as you said, where we, I think, have been very married to our PET scans and seeing the disease on a scan. A lot of that, of course PET scans have been transformative and super important, I don’t mean to take anything away from it, but I think we have used images whereas leukemia and myeloma were more used to treating numbers and cells that you could see under a microscope. When CR rates started to go up, it was natural that you try to use more sensitive ways of measuring it. I think we need to move towards that. I think we just had a symposium organized by the Lymphoma Research Foundation around ways of getting there. I think there is a path, but unfortunately a slow path.

Ken Young: We have to merge easily with the solid tumors while FD-LC-MS already have proof of five types of solid tumor fully covered, but the lymphoma left out. Why?

Ash Alizadeh: Actually, diffuse large B-cell lymphoma last summer was – we protested and they did cover. They cover for CMS, not in FDA, and so diffuse large B-cell lymphoma MRD testing by clonoSEQ can be paid for. But the challenge is what you do with that information right now, and it’s mostly a prognostic discussion with patients.

Laura Pasqualucci: Probably standardization will be critical when one thing sets, extending this worldwide.

Ken Young: Also, you see the myeloma already have MRD-driven clinicals trial going. Is that going to be a duplicate in the lymphoma in the future? I think that might be worth consideration into design, really a qualified patient population.

Ash Alizadeh: I think patient selection based on MRD and lymphomas is already pretty far underway; using MRD as an endpoint like in leukemias and myeloma is emerging.But I don’t know the lymphoma clinical trial that has had MRD as a true endpoint, a regulatory endpoint for approval. For myeloma, a couple are going and CLL has a couple. Great. Any closing thoughts about the session and what your takeaways are, Laura?

Laura Pasqualucci: Well, continue to invest significantly in basic research, both applications and knowledge of fundamental mechanisms that we all know are important to develop and push the field forward.

Ken Young: I completely agree, Laura. I think today and Riccardo’s presentation, I think are really inspiring me. We should be thinking about regulatory non-coding genomic components and how that impacts cancer and lymphoma pathogenesis. They may become important diagnostic, predictive and therapeutic targets. This area we have never explored in the past. Now when all the technology comes up, I think this area, we should think about it now.

Ash Alizadeh: I agree. I think seeing the mix of things, the diverse topics that we talked about, I agree with you, Laura, that it’s basic research that makes these things possible and from basic research to application of basic research to translation and meetings like this to bring together folks who work at the basic level to translation to the treatment of the disease, so I think it’s a bright day for lymphoma and meetings like this. Thank you, iwNHL, for organizing this.

Thank you.

Novel therapies: antibody-drug conjugates

John Gribben: Okay. Welcome again to the 20th International Workshop for Non-Hodgkin’s Lymphoma here in Miami. Again, this afternoon, we’ve had, what’s very traditional at these meetings, is a session looking at novel agents. And this afternoon, in a session put together by my colleague, Laurie Sehn, we focus initially on antibody-drug conjugates, which we’re going to talk a little bit about here. I’m joined today by three of the presenters, Sven de Vos from UCLA who is going to talk about one of the compounds this afternoon. Laurie Sehn, of course, who’s on the organizing committee from Vancouver and needs no introduction. And Andy Davies from Southampton in England. So, we heard a whole variety of talks, one after the other, all looking at different antibody-targeted therapies, all often carrying different payloads but with the same kind of approach of delivering the agent in. Some of these, of course, are already established and already part of an algorithm and part of established multi-drug compounds. And I’ll come back and talk about that in a moment, Laurie’s an obvious place to start. All the way through to agents which are in early phase, drug one development to compounds, Andy, that were in development, what looked like pauses have been held for a whole variety of different reasons. Let me start with you then, Laurie, in terms of polatuzumab vedotin, which of course, as you very rightly put out, is the first compound we’ve seen actually moving the algorithmic approach to be talking about moving beyond R-CHOP in diffuse large B cell lymphoma. So, what’s your take of where we are now? And you can just comment also on the question you made about, is R-Pola-CHP now the standard of care for diffuse large B-cell lymphoma?

Laurie Sehn: Yeah. So, POLARIX is the first clinical trial in DLBCL that really has met its primary endpoint, I should say, the first large randomized Phase III, introducing a novel agent into the frontline setting for DLBCL. And it did meet its primary endpoint, which was progression-free survival. But there’s been a lot of controversy around that, I think, because, number one, there was no overall survival advantage and we historically have seen PFS and OS very much linked in DLBCL. So, there was that expectation that PFS should lead to OS.

I think we’d all admit now that there are so many downstream opportunities for these patients, many of which have durable benefit and maybe even secondary chance of cure that the days of having the close link between PFS and OS are not there. But I would argue that, as a clinician, I still think our goal is to increase the cure rate in the frontline setting. And I think the data shows now with three-year follow-up most recently at ASH that those curves showing the difference in progression-free survival is sustained for at least up to three years. So, that, to me, is an improvement in the cure rate with the addition of the polatuzumab.

The controversial aspect, I think, is the forest plot that looked at a number of subgroups, many of which were not stratified within the clinical trial. So, it really is just a univariate look, and people are trying to pull out maybe subgroups that might preferentially benefit. Maybe we can ration what we know is an expensive drug compared to just giving people R-CHOP. But I think the difference is that, in this scenario, the toxicity is really quite comparable between the arms. And I think that it’s hard to put too much weight on those underpowered subgroup analyses that certainly aren’t controlled for the multitude of factors that could impact outcome.

John Gribben: On that, you highlighted one of those subgroup analyses, which is that elderly patient group in which there did appear to be a particular advantage. Now, we got questions from the audience about, was that associated with additional increased toxicity? I would argue that it’s in the elderly group that you have less ways to be able to salvage those patients back, and that maybe that is the subgroup analysis in whom getting to a curative approach is actually more important. And to my mind, that would be worth, and it’s some additional short-term pain to get that longer term gain.

Laurie Sehn: I fully agree. So, there was a suggestion actually from the forest plot that the elderly were not disadvantaged. If anything, might actually preferentially benefit. So, I thought it was an important subgroup for further analysis. And now, we have a subgroup analysis that’s been presented formally and we’ll see a manuscript soon. But it certainly appears the elderly population definitely benefits as well, if not even somewhat better. And I think that the toxicities, again, even in that group are fairly comparable.

What we pointed out is that across the whole group and within the elderly group, there’s a higher rate of febrile neutropenia, maybe a higher rate of low-grade infection. Those are short-term toxicities that, in general, we can manage, but there wasn’t a heightened risk of mortality because of the treatment and certainly not that was offsetting the outcome.

John Gribben: Sure. Now, of course, the other question you raised, and I’m going to come back to you on this one because you raised some issues here at the panel discussion about, is R-Pola-CHP the new standard of care? And of course, it isn’t. It’s the standard of care for a subgroup of the patients really at the moment; isn’t it? But the question then becomes, if we’re going to be doing randomized clinical trials, is our new benchmark against R-Pola-CHP or should it be still against R-CHOP? And Andy, you raised some interesting concepts in terms of the ethical issues about how you randomize a patient to receive R-CHOP when R-Pola-CHP would be an approved indication for that patient.

Andrew Davies: I think this is really important that we try and have this discussion because we’ve got many frontline trials that are either already open or in development asking the question about a novel intervention with a CHOP-like combination against R-CHOP chemotherapy. And so, of course, many territories have really adopted, at a very high penetration level, Pola-R-CHP in frontline DLBCL. And I think trying to randomize a patient into a study where R-CHOP is the standard of care then raises some significant dilemmas for the investigator and a difficult conversation with the patient. I’m not saying that R-CHOP chemotherapy is no longer an acceptable standard of care and I think Pola-R-CHP is just another choice as a standard of care, but it does make it very difficult when we’re thinking about what our control arm is going to be. And I think that’s also really important in terms of future-proofing the studies as we see perhaps even greater penetration of Pola-R-CHP in the years to come in very many territories where they’re struggling a little bit with the funding approvals. I think it’s going to be very difficult to have some studies that have compared with R-CHOP chemotherapy when they get their readouts and some studies that compared with Pola-R-CHP. It makes the landscape really quite difficult for us.

John Gribben: Sure. Sven, moving on to, you talked about an agent targeting ROR1, which of course, we’ve seen a lot of interest in as a potential compound, particularly sought first in CLL, but now across B-cell malignancies. Also, raised an issue that came across lots of the discussions we’re having today about levels of expression on the target and is it something that we look at, and is that a requirement to come into the study? And we saw in many of your studies, certainly across different histologies, that it was all-comers and then potentially a retrospective look. Is that the right way for us to go forward, or is it by looking at it in this way that we begin to understand they don’t always work in exactly the way that we thought? What are your thoughts?

Sven de Vos: Well, one is a new target to go after in oncology. It’s a very interesting target which is only expressed in normal life during embryogenesis and not anymore. So, it is expressed in the vast majority of malignancies, including hematological malignancies. And the more aggressive and faster-growing these are, the higher the expression is. So, I think it’s important initially to allow all-comers to come into a trial and then learn what the level of expression in relation to response might be. There is an indirect link right now in a more aggressive, more fast-growing lymphomas responding better and longer lymphomas are responding poorly. But I also would like to see the correlation with expression, and if you learn something from that too on select patients.

John Gribben: What was quite common in that whole variety of compounds we heard this afternoon was that there was a level… So, there were responders and non-responders, which of course, raises interesting concepts, but the response rate was often quite similar from compound to compound. Working the premise that many of these compounds are or will be in the future approved, how do you think we’re going to algorithmically think about the series in which we offer these? Or do you think almost all of them, as we’ve done for polatuzumab, are going to land up being used as part of a combination and moving more and more frontline? I think, Laurie, you raised the issue, we can’t have R-Pola-Zolo something-CHP. We can’t just keep adding and adding and adding to our algorithm. So, how do you think we’re going to be thinking about where these compounds fit into our algorithm?

Laurie Sehn: Yeah, it’s a real challenge. I mean we heard, I guess, a lot of individual compounds, lots of great science behind them. The one thing that I am being challenged by right now is that also, if you’re doing single arm studies of these single arm drugs, the bar has changed. The kinds of patients we’re putting on these trials are not the kinds of patients we put on even five years ago. So, I have many trials or proposed and they say, “We’re trying to test this in the unmet need of third line DLBCL.” And you could argue that most third line DLBCL patients are not going on trials of novel compounds anymore. They have a series of options and now, we’re enrolling patients in their fifth line and beyond. So, what is the bar now that gives you that signal of activity in those fifth line and sixth line patients that makes you want to move a drug forward? And it’s unlikely that any of these drugs are going to have a high level of success as single agents. So, we’re going to want to combine them, but it does get complicated when you think about the permutations and combinations and the number of options that we have. I think it’s going to be very challenging moving forward.

Andrew Davies: And John, I think part of this is also about how the target antigen is going to be modulated through the clinical course of the disease and perhaps how prior therapies that you may have been exposed to may modify that. We already know the story about loss in CD19 in patients who had previous CAR-T exposure. It doesn’t look from the preliminary data that patients who had lonca-T, which is an ADC target, CD19, a different epitope may not lose the CD19 expression in progression.

John Gribben: Yeah, it’s an interesting concept as to why that should be; isn’t it?

Andrew Davies: Absolutely. So, I think this is going to be a really important story in terms of our evolution of sequencing.

John Gribben: Now, the other session we had within the session this afternoon was this industry perspective on some of the things that are happening. And of course, what we heard from our industry panel this afternoon is, of course, the FDA’s moving the goalposts here in terms of exactly how we get it. And I didn’t hear anything today that made me comfortable to think that there’s going to be an easier path to approval for many of these compounds.

And in fact, what we did hear was that the move towards looking for overall survival advantage, which of course, is the goal of what we all want to do in our clinical trial developments, but particularly in hem malignancies where we’ve got multiple lines of therapy being able to be offered, it’s very difficult to see – if that’s going to become a goal that needs to be required for registration, is that too high a goal for us to see any of these compounds ever make it through in the future? Sven, let’s come to you.

John Gribben: As the American on the panel.

Sven de Vos: Thank you very much. Recognizable by my accent. Clearly, in trials that are randomized where crossovers are allowed, you basically design the trial against actually necessarily seeing survival advantage. Therefore, I think that that should not, I think, be over-emphasized in these aggressive lymphoma trials.

John Gribben: The trouble is, of course, that’s what the FDA is looking for. It was interesting to see the industry perspectives on the panel, look at how they are creatively trying to come up with ways. But in the end, they’re going to have to sit down with the regulators and find out whether their approaches are going to be acceptable to the agency. But there is the potential that with all the best intentions in the world, that we may have actually shot ourself in the foot here in terms of what it is we are looking to achieve for our patients. Andy?

Andrew Davies: Yeah, I think you’re absolutely right. I think we should be concerned that perhaps we may slow the pace of development down. We’ve had this excess of accelerated approvals. And now, we’ve seen some backward stepping on that because some of these agents that were approved under this process actually haven’t proven themselves in the Phase III setting, or the safety signal hasn’t really been confirmed. And we’re seeing a decrease in the number of agents that are getting accelerated approval. So, I think that we’ll see as a result of this perhaps some slowing of the pace of drugs and therefore, access to our patients, which I think we’re going to have to be really mindful. I think one of the commentators said, “Look, there’s this big focus now from the agency towards overall survival. The pendulum has really swung from one to the other, and we hope that that may well move back in the future to somewhere that really gives us a proof of efficacy and safety, but actually is able to deliver these new agents in a timely way for our patients.”

John Gribben: Okay. So, there you have it. That’s the end of day one from iwNHL today. We look forward to being able to see all of you tomorrow for what, I think, looks like a very exciting day two. We’ll be posting more on what we find from the sessions following this one. So, thank you very much for your attention, and thank you very much to the panel for joining me today.

Expanding the CAR platform in NHL

David Maloney: Greetings. I’m Dr David Maloney from the Fred Hutch Cancer Center in Seattle. And I’m here with my two colleagues here at the iwNHL meeting, 20th year of this meeting, Dr Jason Westin from MD Anderson and Dr David Miklos from Stanford. Jason, why don’t you kick it off here. We hear great summaries from the three different products and from second line. Give us your take.

Jason Westin: Thank you. We had a great session this morning and covered a lot of ground. We heard about the three FDA-approved products, starting with tisagenlecleucel. We heard from Dr Schuster about the early studies that showed how that product, targeting CD19, autologous product using 4-1BB showed some very good promise. However, as that trial moved from third line into second line, there were some challenges and that product is not approved in second line because of some perhaps design challenges in the BELINDA trial. Dr Schuster also shared some of his data about different lymphodepletion regimens, including bendamustine, and we’ll look forward to seeing more data about that at the ASH meeting. Then we heard from Dr Sattva Neelapu talking about axicabtagene, both in the ZUMA-1 trial as well as in now up to ZUMA-25, lots and lots and lots of trials looking at axicabtagene, a CD19 autologous product using CD28. That has shown, in the ZUMA-7 trial, to now have a superior overall survival compared to platinum-based chemo followed in responding patients by autologous stem cell transplant, which we know is the standard of care for almost 30 years. We made the case that there’s a new paradigm where now CAR-T cells should be considered a second line approach as opposed to chemo and transplant. And lastly, you presented some great data on lisocabtagene maraleucel, the other FDA-approved product, using CD19 as the target. And again, 4-1BB showing a very high response rate and a slightly favorable toxicity profile compared to axicabtagene, again in second line showing a superiority to standard of care for event-free survival and a trend towards overall survival improvement. So effectively we’ve got a new standard, which is always a great thing for treating patients with cancer, where second line now, CAR-T cells, specifically axi-cel and liso-cel are the preferred approach.

David Maloney: Yeah, I think it was a great discussion. A lot of lively discussion about how you choose products for different populations at your own center. All right, David, it doesn’t work in everybody. If we still fail and the product fails the patient, I guess in 60% of patients, what do we do next?

David Miklos: Well, we had an opening discussion of how the product may fail and what are some of the mechanisms of failure: antigen loss, exhaustion, large tumor burden, poor tumor microenvironment, inhibitory cells. So in that realm, we considered some options amongst a number of speakers. I kicked it off with a discussion of: is it possible to make an autologous product that it’s going to target another antigen? And in our situation it was CAR22. This is a study that Dr Matt Frank led at our program and has treated patients. This Phase I safety efficacy was all manufactured in-house, and the efficacy on the 27 patients treated with the recommended dose, level one, has gone forward now into a company-sponsored study and it’s open in a number of multi-sites. So that seems like it’s possible, you can still harvest from patients who’ve been through CAR and make another autologous. And the idea of choosing a new antigen might be a good idea just to avoid the idea of antigen loss.

We heard a lot by Dr Siddiqi in regards to a number of competing programs in the allogeneic or off-the-shelf space. The idea there is that time is important and getting the patients’ therapy quickly would be helpful. And if the product is in the freezer, liquid nitrogen, then moving from consent to treatment on a clinical trial space could be relatively quick. There again, we talk about what are the targets, what are the mechanisms to avoid graft-versus-host disease of therapies that are going to be immunologically different. The histocompatibility is going to lead to some immunological rejection of these products. How do you avoid this? Whether it’s TCR depletion, beta-2 microglobulin, using checkpoint blockades. What we, I think, heard though was that we need to think about the durable response evidence in order to move therapies that are not shown in large patient cohorts with thousands of real-world outcomes to a second line or to compete with the autologous CAR-T cells that have proven benefit, especially in these randomized second line. Think I’ll stop there.

David Maloney: Yeah, I think it was… I was struck by the fact that some of these alloCAR-T programs use very high dose lymphodepletion, like 60 per kilo of Cy times two plus five days of fludarabine. It’s more like a TIL type regimen. How do you disassociate the response just to that chemotherapy from your actual product? Because if you’re looking at initial responses at day 28, I guess I wouldn’t be too surprised that you’re responding to a transplant regimen, at least transient…

David Miklos: Therefore, the emphasis on durable response is being demonstrated for six month minimum and possibly even longer. And what about-

David Maloney: But I think you need biologic correlates, right? I’d like to see T-cell proliferation. I’d like to see T-cell expansion, some correlation of T-cell expansion with outcome, like we’ve seen in some of the other trials.

David Miklos: Yeah, you would think that the PK of these allogeneic products is driving the decisions to escalate dose, to change the lymphodepletion. What if you have good expansion on these really large lymphodepletion regimens now, could we pull back and have less lymphodepletion and have a more tolerable experience for long-term immune reconstitution and hopefully avoid some late infections?

David Maloney: Yeah. Well, I think that’s the next topic that we should mention, which is really… We’re treating these patients. We’re curing them, as I think of the data you showed in minority of patients.

David Miklos: Dr Westin really did make the case, and I’m going to highlight again what you highlighted. Read the paper because the discussion actually used the word cure in the-

David Miklos: … comparison of second line with overall survival benefit with axi-cel.

David Maloney: But what about long-term issues? It’s not just CRS and neurotoxicity. We have other issues.

Jason Westin: Yeah. I mean, infections clearly are a problem. And I think that that’s something that David made the case, that we need to look at outcomes, not just for the first 28 days or the first couple months, but looking at long-term outcomes including risk of infections. And I think the studies that are ongoing now, it’s incumbent on them to report these data, especially when we’re using very high doses of lymphodepleting chemotherapy, which we know increases the risk of bad infections. So I think that looking at on-target effects of hypogammaglobulinemia, that’s durable. That’s, of course, a luxury to have versus being dead of your cancer. But in the long-term sense where you’re curing more and more people, you got to look at what is the long-term outcome for the quality of life of patient. And if they’re chronically having a congested sinus and needing IVIG, that’s not a trivial outcome. I think that late toxicities need to be looked at now that we’ve moved out of the early days of CAR-T cells.

David Miklos: Yeah. And I think my message, I hope, was that collecting this data is going to be a long-term, not just for the safety or REMS consideration of what the FDA negotiated, but for the community to be able to learn how to compare the established therapies, auto and allo, with these new CAR-T cells, and I assume the T-cell engagers. It would be a shame if we took T-cell engagers forward and didn’t capture their long-term follow-ups and infectious complications in this established ecosystem of what CIBMTR helps us with already with registry data collection.

David Maloney: I think that’s a key point because James Kochenderfer also presented data from the original trials that actually led to axi-cel back in, what, 2008. And it was great to see the long-term follow-up, but I was also struck by the fact that if you have complete B-cell reconstitution, but you don’t have Ig reconstitution, IgG reconstitution, or you still need transfusion, how much of this is really a carryover from their being bathed in rituximab for years before they even get to treatment? So I think we really need comparative groups, and I really think that the Phase III trials in the second line will provide us some opportunity to look at what happened in the control group. The control group would’ve either gotten salvage chemotherapy alone, if they didn’t respond enough to get to a transplant, or they got transplanted. Well, I know that many of my patients have IgG deficiency before we even start, more than 50%. And if you’re looking at levels like 400. So it is really expensive. There was a lot of discussion about the cost of ongoing IVIG. Well, let’s make sure it’s actually due to the CAR-T cells, because if the CAR-T cells are gone, the B-cells are back, then I don’t know that there’s a good rationale for ongoing B-cell depletion related to the CAR. So interesting.

David Miklos: It’s a good place to leave it. It’s very exciting. It’s exciting to use the word cure at a large seminar, symposium. And the iwNHL did a great job of having wonderful conversations, discussions. Really wonderful to be here. I’m so glad to participate.

David Maloney: Well, I’d like to thank my colleagues. And greetings from iwNHL number 20.

Novel therapies: BTK inhibitors & degraders

Tanya Siddiqi: Hi, I’m Tanya Siddiqi. I’m a hematologist from City of Hope Medical Center in Southern California, and I have with me Dr Nirav Shah, who is a hematologist from the Medical College of Wisconsin. We just had a great session on novel therapies, talking about BTK primarily. The session is called BTK inhibitors, but we also talk about BTK degraders- which is why I just call it BTK. We started with talking about zanubrutinib, acalabrutinib, and then you talked about pirtobrutinib. So that’s the exciting new non-covalent-binding BTK inhibitor. If you want to tell us a little bit about the data you presented?

Nirav Shah: Of course! Thanks Tanya, and it was a great discussion today. So I think pirtobrutinib is a little bit different to the drugs we’ve talked about so far. It’s a non-covalent inhibitor, sort of first-in-class drug, the first in that generation to be approved in relapsed/refractory mantle cell. What’s important about it is the different mechanism of action, and so it can actually inhibit BTK even in those patients who have progressed on covalent BTK inhibitors or those who have a mutation at the C481 site, making the covalent inhibitors no longer effective. We shared some data today looking at its efficacy across B-cell malignancies- which I thought was relatively impressive, with high rates of overall response in BTK-exposed CLL, BTK-exposed mantle cell, and even difficult-to-treat diseases like Richter’s. The safety profile of the drug looks very compelling, especially when we think about traditional BTK toxicities such as AFib, hypertension, bleeding; which was very low in the BRUIN trial, which enrolled over 700 patients. So I think this is definitely a drug that has a place in B-cell malignancies, but as I showed at the end, it’s not the end all be all. Resistance mutations can occur to non-covalent BTK inhibitors, and luckily, you talked about what we can do for that group of patients.

Tanya Siddiqi: Right. So we talked a little bit about early data that we’ve seen so far from the Nurix BTK degrader trial, the 2127 program. That’s a product that basically uses the ubiquitin-proteasome pathway to degrade the entire BTK complex, but also that particular product has an effect on cereblon as well and leads to degradation of that protein as well, thereby leading to a two-target effect of this fairly well tolerated treatment modality. It’s oral therapy. The trial enrolled patients with various B-cell lymphomas, including CLL, and the responses were a modest 33% overall response rate, but all the patients had had prior BTK inhibitor therapy, including one or two with pirtobrutinib failures as you mentioned. A majority of the patients were also double-class exposed to BTK inhibitors as well as venetoclax, so BCL2 inhibitors. So it’s this growing population in CLL, especially where we don’t have a lot of good options for people who are failing our two best targeted therapy treatment modalities. The company has come up with a new product, the 5948 product, which is also an oral pill- and that basically just degrades the BTK. It doesn’t have the cereblon side effect because on the 2127 program, they saw a little bit too much neutropenia as a side effect, and we think maybe it was the cereblon effects that were leading to the neutropenia. So on this new phase of the study, it’ll be nice to see if that side effect goes away. The study is now enrolling, it’s taking all B-cell lymphomas, including primary CNS lymphoma, because they have penetration into the CNS, and we don’t have data yet. So that’ll be something we’ll discuss in the future. There aren’t a lot of other BTK degrader programs out there, but the Nurix ones are the best, most developed- both trials are enrolling still. We’ll see if the treatments are useful in a number of other B-cell diseases, not just CLL. So exciting time in CLL and lymphomas, with all sorts of new targets coming along.

Nirav Shah: Yeah, I think it’s great that we didn’t stop at covalent BTK inhibitors and say that once you’ve exhausted those, that that pathway is no longer accessible. So I think that between the non-covalent, the degraders, and whatever comes next, we can sort of re-establish BTK inhibition and prolong patient’s duration of response with- I think- well-tolerated oral agents. So that’s really an exciting development, and it was a fun conversation to have today about the future of this field, which is, which drug do you give first?

Tanya Siddiqi: Yeah, and I think some of the other discussions that occurred with the acalabrutinib and zanubrutinib showed the reason why we need so many different agents in this pathway, that there are potentially some side effects- more so than ibrutinib- hypertension, bleeding, neutropenia, et cetera. Then resistance mutation, as you talked about. So there is a need to develop all the fields further, and I think this was a great session to summarize all that.

Nirav Shah: Yeah, agreed. Thanks.

Bispecific antibodies in NHL

Martin Hutchings: Hello, my name is Martin Hutchings. I’m here at the iwNHL in Miami, joined by Marion Subklewe, by Mazyar Shadman and by Krish Patel. We have just been taking part in a very interesting session over two hours on bispecific antibodies in non-Hodgkin lymphomas. We’ve been discussing the use in large B-cell lymphomas where there is approval of two drugs, but also in other indications and in different interesting combinations including perspectives for the future. We have a few minutes to give our take home messages for the audience at home. Marion, do you want to point out a few highlights?

Marion Subklewe: Yes. So I talked about blinatumomab. So that’s first in-class bispecific that was approved almost 10 years ago, and I think there are three lessons we can learn from blinatumomab that might also be applicable to the settings of lymphoma. So first of all, I think we’ve learned that bispecifics are more successful, but in earlier treatment lines. It was first approved in relapsed/refractory and was shown that in salvage one it works better than in later treatment lines. It also has been shown with blinatumomab that it works particularly well in the MRD setting, and there’s interesting data now evolving that best responses or even a benefit is seen for blinatumomab if combined in upfront de novo BCP-ALL in the MRD negative setting. So it also indicates probably that our technology is not super, with these patients still somehow at least MRD positive. I think the third aspect is as we are still not curing all patients- there are still residual cells- that we have to look at the T-cell compartments. So I think T-cell exhaustion, T-cell dysfunction, through chronic exposure to the bispecific is an issue. And I think we need to take into account when we combine our treatment strategies with bispecifics and sequence our bispecifics, that we watch out for the T-cell compartment. That we rather enhance T-cell function than depress T-cell function. One of the things that came out from our analysis is that there is also a necessity for treatment-free intervals. So that continuous exposure to the bispecific is probably detrimental for the T-cell compartment, but that having it on and off, either through the treatment cycles or through additional drugs like dasatinib, might be beneficial to increase efficacy.

Martin Hutchings: So these considerations are relevant in the context of all the different T-cell engagers. I must ask you though, you spent very little time on blinatumomab in lymphoma. Is there a role in the future for blinatumomab in DLBCL?

Marion Subklewe: I think the original studies in 2008 were actually in lymphoma and they didn’t see the same activity as in ALL. So that’s why the company at that time proceeded into the ALL context. I think they’re still struggling with putting up the dose and side effects, but now there’s also an application of Sub-Q. So, maybe they’re upping the dose at some point, but there are so many competitors, I’m not sure how far blinatumomab is going to go in lymphoma.

Martin Hutchings: Right. Dr Shadman, you opened with a difficult task, which was a comparison of the available data in the CD3xCD20 bispecifics. Would you summarize your thoughts on this?

Mazyar Shadman: Sure. So of course for large cell lymphoma, we have two great options now, both epcoritamab and glofitamab. In day-to-day practice, we have to make a decision and discuss with patients pros and cons of each approach. So, we had a chance today to discuss clinical efficacy, safety profile, and some logistical reasons with both drugs at high levels and the conclusion with the current follow-up: there doesn’t seem to be a major difference in terms of their efficacy or even safety profile. We discussed the fact that the long-term follow-up would be extremely important, focusing on infections and cytopenias. The two drugs have differences in terms of their delivery. One, epcoritamab, is treatment until progression, and glofitamab has a fixed duration therapy. So, maybe with the current follow-up, we are not capturing some of the differences in safety profile- but this is definitely something that we need to follow. Real world evidence would be important as well; some of these drugs will be used differently to what the clinical trial or the label recommendations are. So we will learn a lot about the experience in the community in the future too.

Martin Hutchings: Absolutely, still a lot to learn and even though these antibodies are similar in many ways, there are also big differences in their structure and the way that they are given. So you, Dr Patel, had the opportunity to tell us about odronextamab and plamotamab. Would you summarize the discussions around these drugs?

Krish Patel: Sure, happy to. So I’ll do odronextamab first. Odronextamab is another CD3xCD20 bispecific antibody. It currently has been studied in Phase II trials in DLBCL and follicular lymphoma. What we summarized and saw in that trial is that- very similar to other bispecific antibodies in large cell lymphoma- for example, in patients who have had prior CAR-T cell therapy, have had more than two lines of therapy, it’s a highly active bispecific. Overall response rates look to be around 50% or so, with roughly speaking, about half of patients achieving complete responses. And those appear to be potentially durable. So, comparable to what we’ve seen from other agents. But, I think, as was alluded to previously, they have differences in dosing intervals. CRS was seen in about half of patients, mostly Grade 1 or 2 during step-up for DLBCL. In follicular lymphoma, we see a similar story but a higher overall response rate. The overall response rate was approaching 80%, with the majority of those being complete responses. Safety looked very similar to DLBCL for the follicular lymphoma patients, mostly Grade 1 and 2 CRS. Odronextamab is actually being reviewed for potential approval- at least in the US- by the US FDA. So, maybe another tool to add to the toolbox and another sort of variation on bispecifics that we’ll have to incorporate in practice. Then, plamotamab is another CD3xCD20 bispecific antibody, also with a full length Fc receptor, still in dose optimization studies in Phase I trials. We presented data again in relapsed/refractory DLBCL. Slightly different cohorts than other bispecific trials, with a slightly later line median of four prior lines, a slightly higher fraction of post CAR-T cell therapy exposed patients. But again, similar, about 50% response rate, complete response rate around 25%, and similar CRS primarily during step-up dosing- common themes across the spectrum of CD3xCD20 bispecific antibodies.

Martin Hutchings: So I myself covered epcoritamab and glofitamab, showing data that are already known to most because these drugs are approved, in third-plus line treatment of large B-cell lymphomas based on frequent and deep responses, many of which are durable. But we went a bit further in our discussions towards what’s happening next- interest in combinations because they are highly combinable. That goes for odronextamab and plamotamab as well, eventually. We also ventured on to talk about the potential use of these antibodies in first-line treatment of large B-cell lymphomas. There are studies ongoing, so we don’t really have data yet. We have a bit of safety data that looks pretty good. Is this the answer to our next steps into first line treatment? Nobody really knows, but it was an interesting discussion. We also have friends that are absent here. We had Laurie Sehn who had to leave. She covered mosunetuzumab, mainly on its use in follicular lymphoma, and Ranjit Nair telling us new words from the interesting story of TNB-486, which is a CD3xCD19 bispecific antibody, which looks very promising in both intermediate and aggressive B-cell lymphomas. So with that, I will wrap this up. Thank you very much for your participation and thank you for your attention.