In this podcast, 2 experts explore the evolving role of CELMoD-based strategies in lymphoma, with a focus on the biologic mechanisms and emerging clinical evidence for golcadomide in diffuse large B-cell lymphoma and follicular lymphoma. Listeners will hear how CELMoDs differ from established immunomodulatory and immune-based therapies, review evidence from ongoing and early-phase studies of golcadomide as monotherapy and in combination regimens, and consider practice-relevant issues including efficacy, toxicity, treatment sequencing, combination strategies, and the experts’ thoughts on how emerging CELMoD therapy can be adopted into community-based lymphoma care.
Treatment options for patients with lymphoma are rapidly evolving. In this podcast episode, Alex F. Herrera, MD, and Marc Hoffmann, MD, discuss cereblon E3 ligase modulators (CELMoDs) as potential treatment options for patients with aggressive diffuse large B-cell lymphoma and follicular lymphoma, with a focus on golcadomide, an investigational, oral, first-in-class CELMoD therapy. Topic areas covered include:
Presenters:
Alex F. Herrera, MD
Chief, Division of Lymphoma
Professor, Department of Hematology and Hematopoietic Cell Transplantation
Director, Toni Stephenson Lymphoma Center
City of Hope
Duarte, California
Marc Hoffmann, MD
Director, Lymphoma Program
Medical Director, Lean and Quality Improvement
Associate Professor
Division of Hematologic Malignancies and Cellular Therapeutics
University of Kansas Cancer Center
Kansas City, Kansas
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CELMoDs on the Horizon: A New Chapter in Lymphoma Care
Hello and welcome to the Decera Clinical Education’s Oncology podcast. I’m your host, Hannah Powell. Today’s episode features
Dr. Alex Herrera from City of Hope and Dr. Marc Hoffmann from University of Kansas Medical Center.
They are going to be discussing the scientific understanding and clinical readiness around emerging CELMoD strategies in lymphomas, such as ongoing clinical trial data, combination strategies, and future implementation into practice, specifically for community-based centers.
This episode is part of a larger educational program titled, “Emerging CELMoD Strategies in DLBCL and FL: Interpreting the Data and Preparing for Practice” For more information about the presenters along with a link to the larger educational program, please visit the show notes for this episode.
Now let’s get started and hear what the experts have to say about this important topic.
Introduction
Dr. Alex Herrera (City of Hope): Well, I'm here with Dr. Hoffman today and the goal is to discuss CELMoDs based strategies for the treatment of diffuse large B cell lymphoma and follicular lymphoma. Now Marc could you start by telling us a little bit about what CELMoDs are, how they differ from the current treatments that we have available for the treatment of lymphoma, and kind of how they may differ biologically from the other treatment approaches that we have.
Dr. Marc Hoffman (University of Kansas Medical Center): So CELMoDs are an interesting compound, And historically have been around for some time. So just for the audience, the - the original set of compounds that led to protein degradation was with thalidomide, which a lot of people probably know from some of the birth defect conversations that happened when it was given as a sedative in the '50s and '60s to pregnant women. We realized during that time when it was given to those ladies that certain ones of them that had hematologic malignancies that there was response.
And so thalidomide was used in multiple myeloma and then went on to get developed and further refined into Lenalidomide and pomalidomide. And those drugs are classified largely as being IMiDs or immunomodulatory drugs. And they lead to some degree of protein degradation through the cereblon E3 ligase system. But their predominant mechanism of action is immune activation.
So they are leading to T cell activation, NK cell activation, and they have a couple, a variety of non-desirable side effects, which I'm sure most of the audience that's given them has experienced. And so CELMoDs are sort of a further iteration of those. And I think they distinguish themselves in a couple of specific ways. And the first is, is that they just lead to significantly more potent protein degradation, And so the one that's pertinent in lymphoma is golcadomide.
And so compared to about 20% reduction in protein in Ikaros and Aiolos that you see with Lenalidomide, you get nearly 100% degradation with golcadomide. And those proteins are directly part of the lymphomagenesis pathways within a variety of - of lymphomas, but predominantly in follicular and large cell lymphoma are where we see a lot of this activity. And so that's where they've largely been developed. And so that increased protein degradation appears to overcome some of the resistance of those lymphomas to Lenalidomide.
So it seems to overcome some of the cell of origin based resistance, which we've seen in some of these studies and appears to overcome some of the just direct resistance. You still get some of the immune stimulation, which is a nice added bonus to this. And the distribution So the other characteristic that's very different is that the distribution can be targeted.
And so the couple of compounds that are CELMoDs that are developed in myeloma largely work within the marrow space, and they concentrate in the marrow and blood space, whereas golcadomide is largely in lymphoid spaces. So the spleen and lymphatic compartments. And so I think those are the big differences from a biological standpoint compared to prior compounds that we've had and that we've used.
Dr. Herrera: That's really interesting, Marc. And you know, of course, you mentioned that there's this immunomodulatory effect. And - and right now in the treatment of lymphoma, we have a lot of immune therapies, right? So there's - there's some certainly some parallels with the way that treatment of - of non-Hodgkin and Hodgkin lymphomas has evolved by kind of harnessing the power of the immune system. But here there seems to be more kind of direct influence on - on the cancer cell itself.
Now, I guess one interesting thing here is that CELMoDs are - it's an oral therapy, right? It's a pill based therapy as opposed to something like bispecific antibodies or CAR T cells where you're, you know, either engineering cells or you know, giving an antibody that’s harnessing kind of bringing the immune system to the fight with the cancer.
So, you know, certainly some ease of administration, and it's an off the shelf therapy, you know, as opposed to some of the other immune therapies that we use nowadays. What are the data so far showing that these CELMoDs and golcadomide, you know, in the case of lymphoma, have some promise? What have we seen so far when we've used this drug in - in the treatment of non-Hodgkin lymphoma?
Dr. Hoffman: Yeah. So I mean, I think there's a couple of good data sets to highlight. First in large cell lymphoma and the relapsed setting it was studied both as monotherapy and then in - in conjunction with rituximab. And among a pretty heavily pre-treated group of patients, many of whom have had prior CAR T cells or prior bispecifics they saw high response rates. So the response rates were around 45% in that group with complete response rates, over 20%, which were quite promising for just giving rituximab, which every single one of these patients had - had previously.
And the majority of which of whom were refractory to rituximab given in conjunction with the golcadomide. And so then it moved forward and as is typical, we started giving it with chemoimmunotherapy. And so there's two data sets in the frontline setting. One with R-CHOP, one with R-CHP plus polatuzumab. And both of those data sets indicate high CR rates, well over 90% for both compounds.
The two year PFS rate with R-CHOP was right around 80%. And among those patients that did have ctDNA based MRD assays, the MRD negativity rates were quite high in that context as well. We saw similar findings in the R-CHP-pola data sets. They don't have the two year PFS. I think that's going to be coming out. But the response rates, the MRD negativity rates also looked quite high.
From a toxicity standpoint, the Ikaros and Aiolos, which are the proteins that are degraded by golcadomide, are involved in neutrophil development. And so we did see cytopenias, which were not surprising. It did not compromise the capacity to give the chemotherapy backbone, but the cytopenias were the dominant toxicity. I think the biggest thing just from giving the drugs and sometimes what I think one of the challenges and I - I'd be interested in your thoughts on this too.
You know, one of the challenges when you read through a toxicity diagram is - is that you're often getting grade three and higher toxicities or persistent grade 1, 2s, but that doesn't capture the picture of what it's like for somebody that's on Lenalidomide on a long term basis. Where they get, you know, rash, they get diarrhea, they get that weird feeling where they think their head is on fire. And those types of things are hard to capture, right?
It's hard to present those at a formal presentation and the drug just doesn't cause any of those. So it's just a much more straightforward drug to give, and you don't get a lot of those sort of nagging, low grade toxicities with it. And I think it's one of the things that's hard to capture from a data standpoint when we're presenting, somebody has to take my word as having given both drugs that - that you see these differences, but it's hard to - to actually capture that in a specific report.
Dr. Herrera: Absolutely. And I think it's - it's a really great point. A lot of times when we capture data in clinical trials, you don't really get that granular kind of over time toxicity, you know, picture that you get as a treating clinician and so, I do agree Lenalidomide can often have these kind of nagging toxicities. And it's a range of strange stuff that it isn't often dose limiting.
Sometimes the rash is bad and you need to stop, but it is not the most pleasant. And I agree so far with golcadomide we have seen a lot less of that. I agree the neutropenia is the primary issue. But it's been reassuring so far like you said, when we've combined it with chemoimmunotherapy, it hasn't limited our ability to give the chemo.
I think one interesting thing that I've noticed when you and others have presented the golcadomide data is that there's efficacy in patients who have previously exposed to Lenalidomide. Again, really arguing that the mechanism here, really you're getting a lot deeper suppression of targets and still killing cancer cells, even if a patient has some resistance to prior lenalidomide.
We earlier were talking about immunotherapy a little bit, and I know that golcadomide it's been combined with bispecific antibodies with mosunetuzumab in follicular lymphoma and glofitamab as well in - in large cell lymphoma. And so far, even though it's been in a small number of patients, I know that the therapies combine, they played well together. They had their known toxicities, but there wasn't any increase or unexpected toxicities.
And, certainly there was anti-tumor efficacy seen. So, you know, it's an interesting time in the treatment of lymphoma, like we've been talking about there's a whole range of new therapies. And so far golcadomide it seems to be able to play well with other therapies despite, you know, the toxicity that it has of neutropenia. What are your thoughts?
Dr. Hoffman: Yeah. No, I think that's true, One of the basic principles of oncology and developing combination regimens is having non-overlapping toxicities. And so I think the toxicity profile is two things. It's both narrow, right? It's not a broad toxicity profile where you have a large number of things to worry about, and it's also predictable. So when you see studies, they repeatedly show the same sets of toxicities that we're accustomed to seeing.
And so I think that you know, as it starts to expand and we start thinking about if - if some of these phase 3s end up being positive, which I think a lot of us hope that they are and we think about how these are going to be used in a community setting and in combination. And then how the drugs are going to get developed as we start to come up with new regimens for you know, follicular up front and that may include golcadomide. I think the community barriers are going to be things that community doctors are used to dealing with, right? It is cytopenias which we're accustomed to working with.
And so I don't think that we're going to end up with a lot of - of significant challenges from a toxicity standpoint, and the combinability is often good, right? And when you have a drug with a predictable safety profile that's usually quite helpful. So I mean, I think that it's going to make a lot of sense. There's a lot of studies that are going on right now that are phase 3 studies in large cell lymphoma and we don't have the data.
The studies have largely been completed. If all of those studies were positive today. We knew that the CAR T, the frontline CAR T study were positive and glofitamab were positive and epcoritamab were positive and golcadomide was positive, right? The drug that would be most easy to implement tomorrow would be golcadomide. All right. You write a prescription, you get it.
Now, ostensibly, you'd get it probably with cycle two, just in the way that everything seems to work in the world from a drug approval standpoint. But you'd get it and you'd be able to do it. Some of the questions that I think will be really interesting to look at in the phase 3 and that we don't have clearly answered, you know, how many cycles of golcadomide do you need? Right? Do you need all six? Is it something where if you're running into problems and you either discontinue or dose reduce, do we see similar outcomes?
These are some of the questions that are sort of noodling around in my head. As you mentioned toxicities, you know, what's the age limit? Like, at what point do we start worrying about increased rates of febrile neutropenia? We treated older patients on these studies, at least on the early phase studies. And they didn't seem to have differential outcomes, but again these are early phase patients.
So I'll be really interested to see what those data show and whether there's any age related restrictions and whether we can get away. Do you need all of the six cycles of the golcadomide?
Dr. Herrera: I think you've hit on a really key kind of topic or key point here. Where patients and as providers, we're really fortunate to have this - this kind of increasing armamentarium of - of drugs that we can use for the treatment of lymphoma that's really effective. But what we run into now, which is, for decades in large cell lymphoma, we didn't have a regimen that could beat R-CHOP, for example, right?
So now - now we're starting to see phase 3 studies that are randomised that are showing that you can achieve better durable disease control with other regimens you know, compared to R-CHOP. But what you see is that in practice, these regimens are still used in a minority of patients. And - and so I think you've hit on a really key topic, right? We have studies with, you know, these bispecific antibodies and CAR T cells.
We were talking earlier about even a Lenalidomide, right? An IMiD based regimen in the frontline study with tafasitamab and len plus R-CHOP that again, was a positive randomised phase 3 study. But the question is, how often are these regimens going to be used?
Now, in the case of that frontline study that, you know, perhaps a limitation is - is the weekly visits for tafasitamab as opposed to the Lenalidomide which folks are pretty comfortable giving. But you know, presumably as long as the - the early data that we saw with golcadomide combined with R-CHOP or pola-R-CHP hold up and the dose intensity is - is able to remain high or similar to what you would give without it.
You can imagine a world where, like you said, golcadomide it does have some preference or at least some ease of use in the community because people are comfortable with this kind of drug, and it doesn't have this unique kind of safety profile. Now, it may be a little early because we don't have kind of positive randomised studies, but what are the kinds of patients?
I guess maybe we can start with golcadomide you know, as - as a monotherapy or combined with rituximab, let's say, what are the kinds of patients who you're already starting to think you'd like to give the drug to, or at least make sure you find a clinical trial since it's not available standard of care yet? What kind of patients are you excited to use golcadomide in? Or do you want to make sure that it was certain drugs or certain regimens we think about particular patient populations just based on things like that?
Dr. Hoffman: I think it's a really important question that I mean, in obviously relapsed large cell patients that have - you know, have burned through CAR T cells and probably have had some exposure to bispecifics. I would love to give golcadomide in combination with a bispecific. You know, the bispecifics in general don't cause cytopenias, and the fact, as you mentioned, that in those early phase studies that we saw with mosunetuzumab and glofitamab, the golcadomide did not seem to potentiate any of the immune toxicities associated with those drugs.
And so we're always worried that if we combine a bispecific with a BTK inhibitor that, you know, may increase immune function or golcadomide which increases immune function, is that going to lead to increased rates of ICANS or CRS? And it did not. So I think that's - that's a really critical finding. And so that's something that I'm really interested in seeing.
I think the other pivot I would take is - is that in follicular lymphoma because of the challenges that we have with bendamustine and pairing later T cell efficacy with T cell engaging therapy and CAR T cells, I - I still give bendamustine in the frontline setting to some patients, but I've started giving more Lenalidomide. Just because if they end up refractory or a POD24 with an early relapse and I'm going to be thinking about doing CAR T cells.
I don't want to worry that I've compromised potential efficacy. We have frontline data showing that, you know, len-R and - and BR are equivalent. So I think that's a setting where I'd really love to have golcadomide there and available where I would not have to give Lenalidomide anymore.
And you can get people through their Lenalidomide and I've generally been doing a short course of Lenalidomide for the SAKK data. But I think golcadomide would be a very welcome addition there. There's potentially some trials that we'll have in development that will include frontline golcadomide. Obviously, there's Golseek-4 that's pending. That's looking at golcadomide R versus R chemo in the frontline setting and then Golseek-1 looking at the golcadomide R-CHOP versus R-CHOP.
So those two trials should read out at some point in the future. And I think we'll have a good idea of where to go, but I think it's going to have fairly broad applicability if those phase three trials are positive. And I think people will be interested in giving it. I think the biggest challenge is going to be making. And this is not just a challenge for - for you know, the manufacturer, right? The company has a challenge of trying to make sure that the drug is differentiated from Lenalidomide.
It's also a challenge for us, right? As referring physicians to explain to community physicians that these are not the same drugs and that you can use this and give it a try and sort of develop some of those things and make sure that people don't think of this as just a slightly better version of Lenalidomide with similar problems and toxicities. It's really a different drug. It's differentiated in that way.
Dr. Herrera: That's a good point. And you know, I think one of these trials, for example, one of these Golseek trials is looking in at relapsed refractory follicular lymphoma. And it's - it's more or less golca-R versus R squared. It looks like a direct replacement of Lenalidomide, which - which is a natural way to think about it but it has its differences.
But - but as you said, I think that those are the places where we would love to have, you know, this drug available. I think, like you said, follicular lymphoma you know, in early treatment in the places where we potentially use Lenalidomide or chemoimmunotherapy, it'd be great to have - to have golcadomide. It's interesting, I think, when we as a really big differentiator. You know, in a patient who has failed aggressive lymphoma, a patient who's failed CAR T cells and bispecific antibodies, I don't tend to expect a lot from lenalidomide in that - in that setting, right?
Whereas, you know, I think with golcadomide or rituximab with golcadomide we've seen some nice responses. And so again, these - these are differentiators and those are the kinds of patients that we're going to want to you know, be referring for CELMoD therapy in the future potentially. Any thoughts about kind of collaborating with community physicians and thinking about, you know, kind of a pathway for referring patients for CELMoDs.
One thing that comes to mind off the bat is like, actually, geez, you know, this is - these are actually drugs that lend themselves well to be used in the community. So I don't know that patients necessarily need to be referred to the main center, but what thoughts on kind of collaborating across networks and collaborating with community docs about CELMoD use?
Dr. Hoffman: I think it's a great point. One of the things that - that we often have as a challenge is you refer to patient and you may have something interesting to offer them. And for whatever reason, whether it's a logistical barrier or a social barrier, that patient is not able to come to your center and you're trying to come up with effective therapy that they can receive locally.
Like this is high on the list. It's a pill, you take it, you can just prescribe it, and - and I think many of our community physicians are so accustomed to giving oral therapies that it just makes things much easier. And I think if - you know, if there's wider adoption of bispecifics and we have a combination that would be really attractive. And then, you know, if it's - if it's approved with R-CHOP, it becomes really easy, right?
There's nothing extra that has to get done, right? You give the R-CHOP people are used to giving R-CHOP or you know, the emerging safety data with R-CHP-pola, I think is - is pretty compelling. It looks like it works just as well. And the safety profile is quite similar, and so you can pick your poison in terms of the chemotherapy backbone and then you just add a drug to it.
And so I think it - it is a particularly attractive drug combination for a variety of patients that either - for out of necessity or out of desire, want to be treated in a community setting. I think it makes a lot of sense.
Dr. Herrera: And yeah, again, thinking about differentiators, thinking about its use in the community and these, you know, kind of education around these drugs. I mean, you're - you're extremely experienced in the use of these drugs so far in clinical trials. You know, some of the things that we think about with len, you know, is having to use aspirin because of DVT risk. And, you know, the REMS program and all the challenges associated with getting Lenalidomide.
I don't know that we know exactly how this is going to look for golcadomide in the future with CELMoDs, but at least my understanding and you can, you know, chime in is that we haven't really seen blood clots on the trials using golcadomide, if that's - if that's correct.
Dr. Hoffman: Yeah. The - the clot risk. I mean, there have been some clots, but they've largely been thromboses around catheters. We've not seen this sort of later DVT type phenomenon that we've seen with Lenalidomide in - and certainly when you're giving it just with rituximab and you're not giving any chemotherapy backbone at all. We saw very, very low rates of VTE.
The studies have varied in terms of the thromboprophylaxis. So in the pola data R-CHP plus polatuzumab data, they mandated use of low dose rivaroxaban and did not see many clots with that. We did not have many thrombocytopenia events either, so there was no significant bleeding. And then when given with R-CHOP, it was investigator's choice. And so in that - and that's the way the phase 3 will be run as well. So I think the thrombosis risk is lower, and they will still, I mean the similar challenges you have from a pregnancy standpoint exists.
And so I think they will probably still require a REMS program. But I don't think that'll be a major impediment. I think most folks are accustomed to dealing with it. Would you prefer not to have one? I think, of course. But I think given the risks that are associated with it, I would highly doubt that if in the event of an FDA approval, they were able to escape a REMS program.
Dr. Herrera: Well, thank you so much, Marc, Dr. Hoffman for connecting with me today. You know, I've learned a lot. It's been awesome to - to kind of think about the role of - of CELMoDs and - and the treatment of lymphoma. You know, looking forward to all these ongoing clinical trials and what these data show about how - how we might be able to use these drugs to, you know, to treat lymphoma in the future and how we include these drugs in the treatment paradigm. Thanks so much. Appreciate it.
Dr. Hoffman: Yeah, it was absolutely my pleasure.
Thank you, Dr. Herrera and Dr. Hoffmann, and many thanks to you, our listeners, for joining us. As a reminder, to view the full program “Emerging CELMoD Strategies in DLBCL and FL: Interpreting the Data and Preparing for Practice ” please click the link in the show notes. And be sure to check back frequently for more episodes on important Oncology topics!