Drs Stephen Ansell (USA), Pier Luigi Zinzani (Italy), and John Kuruvilla (Canada) discuss the latest frontline lymphoma treatments, including emerging data from this year’s congresses.
- [Steve] Hello, everybody. On behalf of Medthority, I'd like to welcome you and thank you for joining this CME-accredited live roundtable. This is Leading lymphoma: Expert insights. Joining me today to provide those expert insights are Dr. Pier Luigi Zinzani, who is from the University of Bologna, and Dr. John Kuruvilla, who is a Professor of Medicine at the University of Toronto, but also Princess Margaret Cancer Centre. My name is Steve Ansell. I am the Chair of Haematology at Mayo Clinic. Thank you again so much for being part of this programme. What we're gonna do in the meeting today is that we're going to be talking about frontline treatments for lymphoma. Dr. Zinzani will give us some introductory comments and then we'll have some questions and discussion back and forth related to that. That'll be followed by Dr. Kuruvilla, who will tell us about recent advances in lymphoma treatment. This is a very rapidly moving field. And then again, we'll have additional conversation. And then finally, I will talk about emerging therapies and their potential impact. And then together, we'll again discuss how the field is changing. And then we'll have some closing comments at the end once we've addressed as many questions as we can. And just to note, this is a large field with many different topics, so we may not be able to cover everything in our conversation. And that's where the question and answer part of it comes in. So here are our learning objectives. We want you at the end of this activity to be able to understand and recall the indications for first and later lines of Hodgkin lymphoma therapies. So we'll talk about that. We also want to talk about peripheral T-cell lymphoma and specifically talk about targeted and immunotherapies and how those are impacting therapies today. Further then, focusing on diffuse large B-cell lymphoma with a specific conversation around frontline and then subsequent therapies and together really kind of highlight, hopefully, most of the major new data that are coming out of various congresses. As I said, things are happening thick and fast, and we hope to be able to address as many of these topics as we possibly can. So we're gonna start off and talk about frontline treatment for patients with lymphoma. This is a very broad topic. So, Dr. Zinzani, thank you very much for taking on this big topic. But Dr. Zinzani is gonna give us a number of his sort of opinions on the frontline standard therapy for some of the typical more common lymphomas. And then we'll have a conversation to follow after that. So, Dr. Zinzani, turning it over to you.
- Thank you very much, Dr. Ansell. So I will start with Hodgkin lymphoma. As you know, so far, for advanced-stage Hodgkin lymphoma, in the United States, Canada, and also in Europe, the most common is brentuximab vedotin plus AVD. But we are very close to a new revolution in this setting of patient because in the next 6 to 12 months, there will be the possibility to use two new regimen in the same setting of patient. I mean, the first one is Nivo plus AVD. Finally, there is a checkpoint inhibitor in frontline in combination with conventional chemotherapy. And I think it's very important to remember that one of the important inclusion criteria of this trial was the age from 18 to 80 and was in the North America trial, I mean, in United States and Canada, was a huge phase III randomised trial at the end of the day, and the random was of course versus the standard of care, BV plus AVD, so brentuximab versus Nivo plus chemotherapy, and the winner is Nivo plus AVD. And also, in term of safety profile, this kind of new combination is very interesting because in particular, also for elderly patient from 60 to 80, the activity is very good with, at the same time, a very good safety profile. At the same time in Europe, in particular in Germany, there is the new version from Germany of the BEACOPP, the BrECADD. The idea was to reduce the toxicity of the conventional BEACOPP escalated, modify some drugs and also reducing the dose, but also including the Anti-CD30 monoclonal antibody brentuximab vedotin. And at the end of the day, there was this kind of phase III trial comparing BrECADD versus BEACOPP and there are no difference in term of three years of survival. But the end of the day, in term of three-year progression to survival, for sure, BrECADD is a little bit better, but in particular, is less toxic. And we'll see in the next few months the officiality of these two new regimens. The second is diffuse B-cell lymphoma. In advanced and treated diffuse B-cell lymphoma, after several years of R-CHOP without any kind of competitors, now there is Pola-R-CHP and by FDA and also by EMA, there was official indication for IPI3 and 4 and 5 concerning the combination of polatuzumab vedotin, an anti-CD79b antibody drug conjugate, plus the conventional R-CHOP. So, in term of event‐free survival, comparing in this phase III study, Pola-R-CHP versus the conventional CHOP, the difference is statistically significant, but it's quite small, no more than 7%. Anyway, the peripheral neurological toxicity related to Pola-R is not so important because it's fixed ratio. It's not like when you use polatuzumab for several administration. But at the same time, there are very interesting preliminary data concerning the role of CAR-T in frontline, according to the recent publication by ZUMA-12 concerning the role of CAR-T. Also in high-risk diffuse B-cell lymphoma, including double-hit, triple-hit, IPI 3, 4, and 5, and for the patient in this phase II trial, that after two cycle of R-CHOP or R-EPOCH, the Deauville score at the interim PET was four or five. They moved to CAR-T and the results are really impressive. One shot and the CR is more than 80% and the response rate is more than 90%. The product in this case was axi-cel. And on the basis of this phase II study, now there is an ongoing phase III international trial called ZUMA-23. Comparing the CAR-T versus the conventional chemoimmunotherapy after one cycle of conventional chemoimmunotherapy and then there is the randomization 1:1 and we'll see. So I mean, the competition is the new combination with the monoclonal antibody such as Pola-R-CHP versus the CAR-T one shot in the setting of high-risk patients. The last one is peripheral T-cell lymphoma, peripheral T-cell lymphoma, unfortunately, the frontline is yet CHOP or CHOEP according to the age of the patient. CHOEP, I mean with the inclusion of etoposide, for a patient with an age until 65, the results are not so exciting in term of complete metabolic response. At the end of treatment, no more than 50-55%. But for the patient who obtain a complete metabolic response, there is an official, is mandatory to use the consolidation autologous stem cell transplantation. This could be a question mark because recently in the last few years there were several retrospective analysis from Asia, from Europe, from North America, where the observation versus the consolidation there was no difference in term of overall survival. And at the end of the day, to try to answer this very important question, there is an ongoing phase III trial from the LYSA in France. They tasked with comparing in the phase III trial, phase one to one R-CHOP, I mean I'm sorry, CHOP or CHOEP versus the treatment without consolidation after the induction treatment, I mean the conventional chemotherapy for both arms were observation versus consolidation inside only one histological subtype of peripheral T-cell lymphoma there are at least is three, four years. The ECHELON-2, the phase III study demonstrated that a combination of CHOP without being increased with brentuximab vedotin + CHP that is really the best treatment for advanced untreated anaplastic large-cell lymphoma. Of course, all CD30 positive, ALK positive or ALK negative. This is very important. This is the mandatory treatment for these histological subtype. For the other, in particular NOS or angioimmunoblastic. There is the same official indication by FDA using the combination BV plus CHOP. But at the same time EMA decide, don't move to this kind of combination for this histological subtype because there was no real statistical significant difference in the ECHELON-2 study. That was the trial that demonstrated this kind of new frontline treatment for anaplastic large-cell lymphoma.
- Pier Luigi, thank you very much. That was very comprehensive. A lot of territory to cover as it were. But a number of points that you brought up that I think we would like to talk about. So maybe taking it in the order that you presented. So starting maybe with Hodgkin lymphoma, John, I wanna bring you in and ask you your thoughts. Is there a space for patients with Hodgkin who just get ABVD or are we done with ABVD entirely in the face of all of these new drugs that are showing up?
- Yeah, thanks a lot Steve. It's I think one of the most relevant questions that we're dealing with right now. And I think for the audience as Pier Luigi mentioned, the data that we have available incorporating novel therapy, be it nivolumab or brentuximab, the randomised studies have come out of treating advanced stage disease. And so, in that setting I think we have a lot of information to show that ABVD has been surpassed, we have long-term follow-up data, we have good outcome data supporting moving beyond that. That being said, I think if you're in an environment where for whatever reason you may not have easy access to the drug, it's something to consider in that we still have very good outcomes with ABVD, particularly in lower risk advanced stage patients. But I think where the data are still open and where we lack randomised trials with available data are in localised disease. And so that's where again, there are studies that are ongoing. Such as the one led by the UK group called RADAR that's looking at incorporating BV in limited stage disease. And we also know that there are single arm studies that speak very well to the efficacy of adding a checkpoint inhibitor or BV. But I think, you know, the randomised data is generally driven how we treat Hodgkin's lymphoma for a few decades now. And so there's still space there to better define a role in localised disease.
- Yeah, thanks very much, John. So Pier Luigi, just to ask you, you touched on this Nivo AVD really looking promising BrECADD showing less toxicity and greater efficacy than escalated BEACOPP. How are we gonna decide between those two therapies and what are you thinking at this point?
- Yeah, thank you for this interesting question Steve. I mean, as I said before, the age for the new ABVD trial was 18 to 80. I think it's very important for the elderly patients. At the same time the BrECADD was only from 18 to 60 years old and this could be active only for young patient. But so there was several modifications in term of dose change of drug, the inclusion of BV, but the end of the day, it's quite toxic when you compare with Nivo AVD and everybody know very well the management and experience using checkpoint inhibitors in pretreated patients and they think that my opinion Nivo AVD could be the best treatment, the frontline treatment not only for elderly patient but for all patient independently by age.
- Yeah, so I think it's an interesting time and that's gonna need a randomised trial to really prove that so we'll need to see if there's an appetite to move that forward. But I kind of smile, it's sort of back to the old days where we were comparing ABVD to escalated BEACOPP, now we're comparing Nivo AVD to BrECADD, but certainly as I say, great to see progress moving forward. So we're gonna move now to the second topic that you spoke about that's diffuse large B-cell lymphoma. I'm gonna keep this, we're just gonna stick on this for a few more minutes. Talk a little bit about your thoughts John, about are we just gonna give polatuzumab vedotin, diffuse large B-cell lymphoma to everybody? So Pola-R-CHP, are we gonna give that, pretty much to all large cell lymphoma patients or is there a subgroup that we should be thinking about?
- Yeah, again, another great question Steve. So I guess there's a couple of different ways that I like to think about that when discussing with patients in the clinic. Firstly the way the trial was designed, POLARIX, it did not include everyone with DLBCL. And so again it was IPI driven and included patients with an IPI of two or greater. And so from a clinical decision making standpoint, firstly you don't think about patients with lower risk disease, when you start to get into the nuance of the trial. I think that's where again, we experts and clinicians will be debating a lot of these points from subgroup analysis and so we know maybe more of the effect is seen in the patients with an IPI of three or greater. And so that's certainly where you may want to use a treatment that comes potentially with more cost but for patients that are more likely to derive some benefit in subset. And I think the other thing, increasingly there's data translationally that speaks to the idea that ABC subtype, if you're able to do the testing or if it's done routinely, at least non germinal centre with immunohistochemistry, that might be the patient population that again derives most of the benefits. So again, we have some clues, we have retrospective subset analysis, but again as I was taught during my training, hypothesis generating the trial basically said IPI two to five.
- Yeah, thank you. Very valuable. Pier Luigi, maybe the last point of discussion, now turning to T-cell lymphomas, you know you made a great case there that for example, anaplastic large cell lymphoma patients getting brentuximab vedotin plus CHP chemotherapy has clearly been shown to be superior to CHOP chemotherapy. You spoke about in some patients, giving etoposide, particularly the younger patients where that's an effective therapy. Is there a space to give brentuximab vedotin CHP chemotherapy to patients that don't have anaplastic large cell lymphoma but more just PTCL with some degree of CD30 positivity? And if so, how much positivity is positive?
- I think so. I think so, unfortunately I'm unlucky because I'm living in Europe but for United States it's easier, at the end of the day, as you know, there are several data concerning that positivity, CD30 positivity range between 30 to 50-60% in patient with NOS in patient with anaplastic and angioimmunoblastic. And I think this could be a very important point for this patient to use the combination of BV CHP and in particular independently by the CD30 positivity because could be active also with 1% of CD30 positivity. It's another important point to remember for our patients.
- Alright, well thank you both of you for great comments. So we're gonna move to the second portion of this. And so now talking about novel therapies, moving to the next slide here, let me do that. So this is now recent advances in lymphoma treatment, kind of also thinking about, not only frontline but second line. So John, I'm gonna turn this over to you for you to give us a little bit of context here.
- Thanks a lot Steve. So I'm going to build a lot on what Pier Luigi mentioned in his first session where we've seen changes in frontline therapy really driven by the incorporation of novel agents that were tested and initially approved based on single agent clinical trials. And so the first one I think that really is game changing in the treatment of non-Hodgkin's lymphoma is in the setting of relapsed and refractory diffuse large B-cell lymphoma, where again, glofitamab was tested in a randomised control trial called STARGLO. So this was a study that built on the data that led to the registration of glofitamab as a single agent. Again, I think the audience are hopefully familiar with the drug. So this is a bispecific T-cell engaging antibody targeting CD3 and CD20, that in a multiply treated cohort, at least two prior lines of treatment, the single agent showed an excellent complete remission rate of about 40%. And although the median PFS again was modest at under six months, those patients that achieved CR, and again this is a fixed duration regimen, were able to derive significant disease control with progression-free survival now well over 12 months and again a median overall survival of better than two years. And so with those data and we've seen similar data from a compound called epcoritamab to also targeting CD3 and CD20, these drugs have really revolutionised the third line and beyond approach for DLBCL. So STARGLO looked to move the drug further and was a randomised control trial that used the control arm of rituximab with gemcitabine oxaliplatin for eight cycles in total compared to that same regimen in combination with glofitamab. Again the typical step up dosing was employed with glofitamab to minimise early cytokine release syndrome. And what we saw with the clinical trial ultimately in its conduct, this was an ambitious trial, it was powered to look at overall survival, again, uncommon for us but we saw an overall survival endpoint to read out favouring the experimental arm. Highly statistically significant, very clinically meaningful in terms of its benefit. And beyond that, not surprisingly, progression-free survival was better, when you look at toxicity, what we saw was the signal that was also present from bispecific antibodies as monotherapy where infectious toxicity can be a major concern. And what we're seeing with many trials that were done during this time period, unfortunately during the COVID pandemic, we did see deaths from COVID, as a consequence. We saw COVID infection. But even despite those events being at a higher rate in the experimental arm, the overall survival benefit driven by disease control strongly favoured the bispecific antibody. And so thinking about this study, it was done in a population not eligible for autologous stem cell transplant in terms of the patient population and by proxy we might say that includes patients typically not eligible for CAR T-cell therapy, which again is a well established standard in this setting. I think we'll be debating these data and figuring out where it fits in in terms of how we manage our patients moving forward. I think the other study I'll just highlight really quickly is also in relapse/refractory diffuse large B-cell lymphoma and also builds on brentuximab vedotin where again we talked a lot about its CD30 targeting and how that's been studied in peripheral T-cell lymphoma and Hodgkin's lymphoma. But there is also a study in relapse/refractory diffuse large B-cell lymphoma. And in this setting, ECHELON-3 looked at a combination of lenalidomide in combination with brentuximab vedotin compared to lenalidomide in the control arm. And again this was a regimen initially developed by Nancy Bartlett, again very good data sort of behind it in a phase II setting. But you might argue given the other advances we'd seen in DLBCL with CAR-T and bispecific antibodies, now perhaps an older concept with slightly older drugs. That being said, when the trial was conducted, again, in a randomised study comparing the two arms, we interestingly saw another trial that also looked at overall survival and what did we see? We saw a trial favouring the experimental arm incorporating brentuximab vedotin, again showing an overall survival advantage for this regimen. Now fascinatingly, the control arm also performed a little bit better than what we tend to see in relapse/refractory diffuse large B-cell. So it'll be great to to hear what you both think about this in the context of interpreting the trial. But the other thing that really stands out here is again, it's a very user-friendly regimen. The toxicity profile is quite favourable and CD30 expression wasn't really an important part of this study at all. Getting to the point again that was brought up earlier how we're using this regimen and what it may mean in terms of its disease control and how that happens. And so it's nice again that we see another option here. This was in a post-transplant, post CAR-T or never transplant, never CAR-T patient population. So good to have options for these patients that we don't expect to be able to cure with standard therapies. But looking forward, we now, once again, much like we have in Hodgkin's lymphoma, we have some choice, we have multiple options available now defined by randomised trials. So making it a very interesting time for clinicians and nice to have options for patients as well. So I can stop now Steve.
- John, yeah, no thank you very much. So Pier Luigi, it's very hard to ignore overall survival data and so you know, I think just like the phone's ringing, hold the phone, this is really important information. They want you badly but the thing I think that's really important is just the fact that at this time with overall survival from both the regimens that John just mentioned, how are we gonna incorporate that information into how we manage patients with diffuse large B-cell lymphoma? And I guess I'll put one more little wrinkle in there. I would tell you that they're not that many people in my practise that couldn't get a CAR therapy. So the question is, just when you say CAR ineligible, it's probably ineligible due to logistics more than the patient. So the question is just as we kind of get these therapies moving more and more into the real world, is that gonna change how we do things?
- Well this is very tricky question because every time it's more complicated. The therapeutic algorithm in the relapse/refractory patient with diffuse large B-cell lymphoma. For example, in terms of autologous stem cell transplantation ineligibility of the STARGLO where the Glofit plus GemOx is roughly the survivability is close to 60% and you compare with the another trial, the the L-MIND in the same setting of patient, autologous stem cell transplant ineligibility is only 42%. So I mean I think is quite incredible also the data of the ECHELON-3, I mean I remember 8-10 years ago there was the advent of brentuximab vedotin also in relapse/refractory diffusive B-cell lymphoma. But now they come back with this kind of combination and the CR is more than 40%. Unbelievable, is the double of loncastuximab tesirine, same setting of patients, is the same of Pola-BR, it the same of Tafa-lena I mean and is less toxic than Pola-BR. Is less toxic than loncastuximab tesirine the same situations STARGLO in term of Glofit. It's a classical very good, very, very good safety profile of of bispecific and GemOx were quite very well tolerated because at the end of the day, so you have a new potential therapeutic option in the same setting of relapse/refractory patient increasing the CR rate with a very interesting data concerning also the the median progression for survival for STAGLO when you compare with the classic treatment. I mean classic but quite new of Tafa-lena, loncastuximab and also Pola-BR.
- Pier Luigi, thank you. John, just to ask you what you think. So is it gonna make a difference as we think about these regimens and probably where they may fit relative to CAR-T and transplant. As we think of STARGLO data, as we think of ECHELON-3 data, is that gonna impact whether we do a CAR therapy versus a transplant as the next line after this or you know, 'cause again, I can't imagine this is purely gonna stay in the non-CAR, non-transplant population.
- Yeah, I think you're right Steve, it's really difficult to forecast how things are gonna look in the end. But you know, firstly I'll just go back to first principles and say the longest term follow-up that we have for cure and overall survival advantage still remains with CAR. And I think when you made the question earlier to Pier Luigi, what stands out to me is people have gotten really good at managing toxicity. We have 4-1BB products, we have early intervention for CRS and so you can do a CAR incredibly safely. That being said, I think a lot of people still wanna optimise responses and we're now seeing in some environments now the use of bispecifics even as bridging and then it leads to a question, do you really need to consolidate with a CAR and might you consider it for later in treatment lines? So I think it's gonna be a place where ideally clinical trials will better inform what we're gonna do. But I think in the meantime, I think a lot of this is gonna be driven, as you said, by access and a little bit by patient preference with the idea that, do you really wanna have to go to a CAR centre if you live very far away from one? Do you have enough family support if you need a caregiver for that first month when you might see acute toxicities, or again in a patient that might be a little older but still would be eligible, is the choice to maybe stay at home to avoid some of the complexity of the care and perhaps not have to worry about that. I think we're all gonna be struggling with that one.
- Yeah, thanks. Pier Luigi, I'm gonna change gears and talk a little bit about Hodgkin for a moment, but also the transplants and second line kind of approaches, some interesting real world data that came out that showed that as you looked at the use of novel therapies prior to an autologous transplant, it really did seem that PD-1 blockade seems to be making a difference if you do that before you go to transplant. Your thoughts on whether that's just a artefact of the study or if that's real and whether that's something we should be thinking about more specifically?
- Do do you mean allotransplant in relapse/refractory patient?
- I think it's actually autologous transplant. So basically getting a PD-1 blocking antibody-
- I mean the real problem concern is the advent of Nivo plus AVD. When there is a relapse/refractory situation, normally in Europe we cannot use Nivo plus AVD such as for example in United States or Pembro plus GVD, we are using conventional chemotherapy in particular bendamustine gemcitabine and vinorelbine. And for the patient who obtain a complete metabolic response we move to consolidation with auto stem cell. When you use auto stem cell after checkpoint inhibitor, I don't think that there is a real problem. The situation could be quite different when you are using a relapse/refractory patient Nivo or Pembro as a single agent and then you can obtain a very good partial response or why not a CR and then you can move to allogenic bone marrow transplantation. In our experience if you wait at least six, eight weeks before to move to allo, you can really reduce the potential risk of graft versus host disease after the allo stem cell transplantation. But I think that advent in frontline of Nivo continuous regimen could be a real, is not a real problem for the potential role in the setting of relapse/refractory patient of the stem cell transplant. I don't know concerning the situation about the re-treatment with another checkpoint inhibitor in the second line. For example, if you use Nivo plus BV in patient treated before with Nivo AVD in the frontline, there are some anecdotal cases, in the relapse/refractory patients that could be active again in the second time and another kind of of a checkpoint inhibitor. But we have to see the future, what happens in these kind of patients.
- Yeah Pier Luigi, I think you're right, this is such a rapidly moving space and it's actually complicated because as the frontline treatments and then the salvage treatments keep changing so the data then obviously becomes different. So even though we saw some data that by using a PD-1 blocking antibody right before an autologous transplant seems to have the best outcome, now we are giving the PD-1 antibody right in the frontline. So it actually becomes a little more difficult to dissect that.
- Everything is really dynamic.
- Exactly, which is good. I mean it's good for patients-
- Yeah, absolutely.
- I think resulting-
- For the patient overall. Yeah.
- Yeah. John, one last question on this segment coming to you in T-cell lymphoma. Your thoughts about, we've touched on it earlier, but just to maybe some additional endpoints on, if you have a peripheral T-cell lymphoma, you get standard treatment and you have a good response, just stopping, doing an autologous transplant, doing an allo transplant? what do you do and what do you think about that?
- Well it's still a difficult question when you look at what the evidence-based tells you. And we all are aware that there are very good data speaking to long-term consolidation with an autologous transplant upfront. We were interested in exploring graft versus lymphoma effect with an allo transplant and unfortunately the randomised trial that was ultimately ran in Europe did not show longer term benefit. And there is a recent follow-up, I think in the JCO very recently. Speaking to the randomised comparison there, right now I think the untold question is very much like one that used to be prevalent in DLBCL, does consolidation in first remission with an auto add benefit? And there are again groups, both in Europe and in North America trying to ask that question right now. So our standard of care, at least where I work, is we don't tend to consolidate these patients in first response if they have standard T-cell lymphomas, we think about the less common higher risk patients. If that's gamma delta or ATLL or other variant subtypes, we might consider such a dismal outcome with standard therapy to think to consolidate those patients. But we're really hoping that the randomised trials will at least sort out the role of auto. But my concern is that since chemo resistance seems to be the challenge here, the problem with most of these data is that is not transplanting or not, it's getting the patient to the transplant and what we really need are novel tools to help us control disease.
- Yeah. So I think that's an excellent point. And that actually is a great segue to our last segment talking about those novel therapies if you like. So gonna move us here to the next slide 'cause I think this just highlights emerging therapies and their potential impact. So that's my turn to talk a little bit about it and I guess I would make the case that there are five categories and it won't be enough time to really kind of dive into the all of the details, but then I think we'd like to really talk about it afterwards. So the five categories that come to mind for me, the first one we've already spoken about to some degree and that's chimeric antigen receptor T-cell lymphoma, T-cell treatments, so CAR-T ways in which they've really now become standard of care and actually migrated right up the course of treatment in large cell lymphoma, follicular lymphoma also in mantle cell lymphoma. So we're seeing that becoming more and more standard, particularly the CD19 directed CARs. But I think the technologies are now getting better and better where CARs in other diseases are going to be coming along, there've been CARs in Hodgkin, those data are less mature and maybe not quite as impressive but we're looking to see how those improve. And then there's a whole body of armoured CARs where CARs that are really prevented from being shut down or actually have key receptors that would inhibit them downregulated or cytokines that are added to promote them. Those are all now coming along in clinical trials. So the second then would be the bispecific antibodies and we've touched on a few of those but there are multiple others. I think the predominant family has been the CD20, CD3 targeting antibodies, but now we're seeing actually quad- and tri-specific antibodies. The so-called TriKEs and quad-BiKEs and heaven knows what all, that are actually looking at different ways of engaging more than one molecule on a T-cell and more than one molecule on a target cell to really get greater efficacy. And a number of us have been part of clinical trials which actually are bispecifics targeting to, for example immune checkpoints rather than even targeting the tumour itself. So a huge family of those. And we've just discussed some of the data around glofitamab, epcoritamab, odronextamab, rituximab, all of those have been highly effective and very promising. Plus very promising in the context of CAR T-cell available to patients where a number of these studies have actually looked at whether a bispecific can rescue patients and we see pretty good results in that space. A third category then would be what I would call small molecules. And this is a very broad generalisation but in lymphomas we have a number of those. Dr Kuruvilla who's kind of one of the lead people on selinexor for example an XPO1 inhibitor, that's an agent that's been used in large cell lymphoma, particularly there's been EZH2 inhibitors targeting that mutation, particularly in follicular lymphoma. And tazemetostat has shown a number of good results. BTK inhibitors broadly used in a variety of different lymphomas, specifically CLL, mantle cell, marginal zone, often in combination. And then probably a further category, PI3 kinase inhibitors kind of hit a little bit of hard times because of some of their toxicity issues. But we do see a bit of a resurgence and I think we see some pretty interesting data in T-cell lymphoma where as we made the comment earlier, we are desperate for new drugs and potentially that could be something that may be coming in the future. Fourth category we touched on a little bit and that's the antibody drug conjugates if you like. So loncastuximab, Dr. Zinzani, you mentioned that just a little bit ago, already an approved agent in relapsed large cell lymphoma, a recent approval for a Denileukin diftitox, re-imagined molecule in T-cell lymphomas, particularly cutaneous T-cell lymphomas. So that I think again is an antibody drug conjugate with obviously now becoming approved and useful in that space. And then finally we touched on this a little bit, we can expand a little more, and that is kind of 'naked' if you like antibodies, but antibodies targeting CD19. So we mentioned tafasitamab as an agent that's used in combination but in the T-cell lymphoma space for example mogamulizumab targeting CCR4 is an agent that is commonly and standardly used in T-cell lymphomas. So as you can tell, multiple different agents often and many of these being used in the kind of third line post-CAR, post-transplant relapsed patients. So John, I'm gonna start with you. With all of those things going on, how do you think, let's make it large cell lymphoma 'cause many of these drugs is in that space. If you've had somebody who's come through frontline therapy who's gone through a second line, maybe a CAR and now relapsing, what's your kind of thought on how you manage those patients with this plethora of different options you could pick?
- Yeah, unfortunately it's still something we have to do enough of in clinical practise despite having highly effective frontline and relapse therapies. So it's a question that still is highly relevant. Based on available data, it comes down to what do you think is the best choice for the patient in front of you based on fitness, performance status, comorbidity. And I think at least in large cell lymphoma, the agents that have risen ahead of the class after standards is now the new standard, which is a bispecific antibody. Philosophically we still don't understand enough about what is driving mechanism of resistance. We know a few points about antigen expression as an example and loss thereof that may influence choices. And so it's important again to think about doing biopsies in this setting because if you are using targeted agents, we know that antigen expression, even with bispecific antibodies with early data might be important. But I think the other issue here also speaks one to ease and tolerability and if we're saying that we're largely managing a patient population that might be considered palliative and if we're dealing with patients that are also older, we should also think about how easy it is to administer the therapy from a toxicity and convenience standpoint. And when you look at some of the things you were thinking about there, Steve, like I go back to can we do this and deliver it early? What's the toxicity profile like? But also is it a fixed duration IV therapy, are the toxicity's reasonable? And some of the things that that we've mentioned, even if it's Pola-BR, if those are agents that a patient hasn't been exposed to, it's very tolerable, very easy to give, closer to home, the likelihood of being admitted to hospital is quite low. But is that really gonna be a major solution for the patient that is refractory post CAR and post frontline therapy? Probably not, but it might make an effective palliative regimen.
- Thanks, and Pier Luigi, you've had a lot of experience with CAR, you had a lot of experience with bispecifics. Tell us a little bit about your approach in the real world. So real world CAR versus bispecific, what do you see? What are you thinking?
- I mean I will start from the role of CAR-T versus bispecific in follicular lymphoma from the third line. And if you come back to the two updates at the last large meeting concerning three years of the last study with the T-cell versus three years of MOZU in the same setting of patients. There are no real difference in term of a plateau that you can obtain after 36 months. And there are some differences because at the end of the day, MOZU is active in every kind of subset. I mean relapse/refractory patient, patient received prior CAR-T as John said before. And I think elderly and young patient, even pretreated that is another important point because we know that after with CAR-T, even pretreated patients can obtain a very bad result when you compare with the third line. I mean at the end of the day I think that there are no real statistical significant difference, I mean is indirect evaluation, but I think right now my opinion in the setting of relapse/refractory follicular lymphoma from the third line, 20% I will treat with CAR-T in particular for double refractory POD24. I know that this is not the best but we have not CAR-T second line and also young patient who relapse after auto stem cell transplantation in second line, these represent more than 20%, the remaining patient potential with bispecific response. Diffuse B-cell lymphoma, third line FLOFI or EPCO, the result are quite similar in term of complete metabolic response, in term of three years follow up, when you compare with CAR-T cell in third line, this could be a real problem. I mean actually the plateau that we can observe after five years with CAR-T is unbelievable, is absolutely better than than bispecific. But where we need a longer follow up, but I don't know, in United States or in Canada, could be more difficult in Europe and also in Italy to convince the referral centre to move the patients for CAR-T to the CAR-T centre for this setting of a third line of CAR-T.
- Yeah, good points. And so maybe John, we're gonna move now to the question and answers, but a few of these questions really fit very nicely with what we've just been discussing here. So maybe you would like to comment John on, you know obviously CAR-T and bispecifics really look exciting and very promising, but what do you think are the barriers to really moving those into common practise outside of academic centres?
- Right, so you know, cell therapy I think, comes with its own complexities and you need a lab, you need to be able to apheresis, you need to be able to store cells, you need a lot of personnel, you need accreditation in many countries to be able to do this. And so, if this is a transplant centre as an example in the community, that might be an easy step to move into the CAR-T space and lots of safety, lots of efficacy, longer term follow up and lots of expertise to share with protocols. I think the bigger role or the bigger question is around the use of bispecific antibodies. And so, there I see lots of opportunity for these to be used in the community. Now certainly concerns raised when you look at the rates of acute toxicities such as cytokine release syndrome, but in most studies, certainly in lymphoma, we know that they tend to be fairly predictable in their timing they tend to happen early. Often with the first dose as an example with glofitamab or potentially with the first full dose with epcoritamab. And so the opportunity for a clinician to recognise when it's coming to be prepared is there. And then secondly, thankfully the high grade toxicity rates are quite low. So this is typically grade one, which is fever or grade two, which is often with a bit of mild hypotension. And so this can be managed quite effectively with steroids and/or the use of tocilizumab. So I think for a clinical practise in the community where you're used to giving antibodies, you're used to giving chemotherapy, if you know how to manage fever and how to deal with an infusion reaction, I think that will generally be fairly easy to translate. It's just bringing the clinicians on side, understanding that tocilizumab needs to be available, steroids need to be available, How do you access those things after hours? How does the on-call team know about that? Is your emergency room prepared? And I guess, rarely is the ICU prepared and knows what to do? But I think much like what we've seen with other therapies, the time will come to move these into the community and we have learned a lot about how to manage toxicity acutely.
- Yeah, very good points. And so Pier Luigi gonna go to you. There's a question here in the question and answer chat to say, you know, you mentioned in Hodgkin how you are thinking of Nivo AVD particularly benefiting elderly, et cetera. But if you think about frontline treatment, let's say in large cell, what are your thoughts about comorbidities and age, and how that impacts your choice of treatment?
- Only for elderly patient with with comorbidities. I think you have to avoid BrECADD, but also it's quite easy because there is no indication for patient with an age more than 60. And I prefer in older life, Nivo plus AVD for sure. I mean-
- And how about in large cell, what do you do in diffuse large B-cell lymphoma?
- In diffuse B-cell lymphoma, this is another important point, I think the future, because normally there are at least 50% of patient in frontline that are anthracycline-containing regimen ineligible. This could be a real problem. There are some preliminary data concerning the role in frontline of MOZU or also epcoritamab with fantastic result in this setting of patient 50-55% of CR. I think that the future could be a chemo-free regimen including bispecific plus, I mean lenalidomide or tafasitamab or something that this could be the future for this setting of frail/unfit patient with comorbidities and they represent 15% of all diffuse B-cell lymphoma. This is a very important point.
- Maybe just to piggyback one more question that comes from the chat here. With all these exciting new therapies and combinations. How do you, Pier Luigi, balance the giving people standard treatment with proven outcomes compared to the novel therapy that you go, "Maybe we don't know if it's gonna be that good."
- I think that the future in terms of chemo-free regimen also in frontline will be in follicular lymphoma. The preliminary result in second line of EPCO plus R squared or MOZU plus lenalidomide are really unbelievable. More than 85% of CR, no toxicity. This could be the future. I mean if we are quite ready to the second attack to the relevant trial, if you remember 10 years ago there was the R squared versus CHOP-R or BR and now we have a very close. I hope and I think in the next three, four years, the treatment for follicular lymphoma from in frontline second line, third line, will be only chemo-free.
- You know, I think that's a good point. One of the things I find a little challenging as I'm thinking about follicular lymphoma, you know there are a subset of follicular lymphoma whom if you observe and they don't progress in a year or two, they have the same outcome as the national average as far as survival is concerned. And so one of the challenges is jumping in and giving new treatments to some of those patients, recognising the long-term problems with infections and the like, will we do more harm than good? So I think that's a space where we really need to be watching closely. John, maybe a last question for you. This is completely in a different direction, but it comes out of the chat. It's a good question here. You know, back in the day of Zevalin and Bexxar, we had these radioligand-type therapies and do you see anything new coming in that space for lymphoma?
- I think it'll be a very difficult space to get back into given all of the logistical issues that we know about using radiotherapy, even when it's targeted. You know, that being said, a few years ago, there was an agent that had made it into the phase II setting and was looking at the potential of registrational studies. I don't believe that was followed through on in the end. And I know some of our colleagues have been approached recently about, again, early phase trials. So when it's a concept that has worked before, and we know radiotherapy remains a very active therapy in lymphoma, it's hard to walk away from it. But looking at how many other options we have available, I think it's gonna be challenging for one of those new compounds to really make it into the routine clinical practise.
- Well, thank you. Just to say big thank you to Dr. Kuruvilla and Dr. Zinzani for excellent insights and commentary. We're gonna now go back to the question and answer to the answer the questions session. So really encourage you, if you would, to please go ahead and specifically answer the questions. I just wanted to say thank you to Medthority for hosting this. Thank you so much to Dr. Zinzani and Dr. Kuruvilla for their inputs. And please, if you would go ahead and fill out your questions, we'd be very grateful. But most of all, thank you for participating.
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