Hematologist On Call: Relapsed/Refractory Mantle Cell Lymphoma Post cBTKi

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Beyond cBTKi Progression in R/R MCL: Mechanism-Based Sequencing and Community Implementation

Introduction

Dr. Toby Eyre (Oxford University): Hello, everybody. Welcome to this podcast on treating relapsed mantle cell lymphoma in the post-covalent BTK space. My name is Dr. Toby Eyre. I am a consultant hematologist based in Oxford in the UK. I am delighted to be joined by Tycel Phillips, who is an associate professor of medicine at the City of Hope Cancer Hospital.

Tycel, thanks for joining. We are going to be discussing mantle cell lymphoma and talking about how things are moving in the relapsed/refractory space.

First things first, though. How do you see things sitting in the first-line setting at the moment? Do you think covalent BTK inhibitors are sitting in that space for all patients now, or do you think it is a little bit more nuanced than that?

Dr. Tycel Phillips (City of Hope Cancer Hospital): Great question. I would be curious to get your thoughts. I feel it should be more nuanced. The way things are moving, I think we are moving to a one-stop shop where, unless a patient really has a contraindication to a BTK inhibitor, they are going to be offered that based on the multitude of regimens now that are incorporating BTK inhibitors in the frontline space, from TRIANGLE to ENRICH study, BOVen, ECHO, it is just such momentum to solidify these agents in the frontline. We are basically losing the nuanced discussion that we were having about possible sequencing versus combination. That seems to be going out the window.

Dr. Eyre: It is interesting you say that. The strength of evidence really sits in the TRIANGLE study so far. We have got a very large, robust randomized trial demonstrating an overall survival benefit using a BTK, dropping the autotransplant. That is pretty strong evidence, certainly in younger patients. The ECHO regime maybe is a little bit more nuanced. You have got three drugs versus two, more toxicity with the three than the two. In terms of BR plus acalabrutinib, the regimen is more immunosuppressive. You have the two drugs in maintenance with BTK and CD20. You have to be pretty selective about who you select that for, but you are right, there are some maybe lower-risk patients that might be better suited to immuno-chemotherapy and then subsequent BTK.

Certainly, a lot of patients moving forward will get, I think, BTK in some shape or form. None of these regimes are clearly curative. It suggests that the space for the post-BTK setting is going to enlarge over time because everybody or nearly everybody in the future probably will be getting a covalent BTK first-line, and then undoubtedly will enter an era where we have more nonchemotherapy combinations that will be attractive for patients and physicians and potentially easy to deliver.

Just in the post-BTK space, we are assuming a lot of patients will move into that at some point, and it becomes a bigger space. We see these relapses more commonly.

How do you see therapies developing there? I guess we have small molecule inhibitors being developed, but also T-cell engaging therapies in different forms. We have got really quite different strategies in development. What do you see particularly being used here most commonly?

Dr. Phillips: To the point in the relapsed/refractory space, assuming the patient has already seen a covalent BTK inhibitor, it puts us down two different paths. Is this a patient who is progressing on a BTK inhibitor or one who is having just issues? The ones that are having just issues, meaning intolerance issues, sets us up on a different timeline, where again, the pirtobrutinib would actually probably be a very good alternative for a durable response in this patient population. Ideally, most of the other drugs tend to work a bit better in the BTK patients who are not necessarily progressing on BTK inhibitor versus those who are having progression.

In the BTK progressions, we have pirtobrutinib, we have brexu-cel, at least in the US, and now liso-cel. If we look at those options, and soon to be joined by sonrotoclax. For most of us, we look at pirtobrutinib as a good option that you can quickly start patients. A minority of those patients are likely to have a durable response after failing a covalent BTK inhibitor, given the mutational pattern is a little bit different from CLL. We cannot necessarily just jump from agent to agent and expect to have durability of response.

At least in my practice and a lot of the ones I have talked to more recently, if we are starting patients on pirtobrutinib, it is as a bridge to try to get these patients to CAR T as soon as possible.

Whether sonrotoclax, because it has a different mechanism of action, will change that, I think that will be something very interesting to see when we get real-world analysis of that situation. the CAR products are there, but they, do have some of the limitations.

Brexu-cel, besides the time limitation for all the CAR products, brexu-cel still has these toxicity concerns even though it is quite efficacious. There is some concerns with efficacy with liso-cel which we will be very keen to see some of the real-world data set to see how that results play out in a real-world setting versus what we saw in the clinical trial.

At least in the US, as far as the NCCN guidelines, we can give access to the bispecific antibodies, which Mosun-Pola and single-agent glofitamab, again, are in that space with Mosun-Pola having a very impressive reduction in rates of cytokine release syndrome. The limited follow-up shows to be quite efficacious and hopefully a hint of durability. Glofitamab was more recently updated to show that we are actually getting some durable responses in some patients several years out in remission after completion of treatment, which is something we had only previously seen with CAR T-cell therapy.

Dr. Eyre: It is an interesting field because we have a range of very different therapies in development, all active in their own right. However, when you take pirtobrutinib as monotherapy, you are looking at a very straightforward, non-toxic oral palliative therapy in effect. If you compare that to brexucabtagene, you have got almost the reverse end of the spectrum, high-risk, high-reward style therapy. It just strikes me that we have a lot of drug development in this space, which is actually very interesting because we have seen very little for a long time in mantle cell lymphoma. Now you have seen this explosion of development, which is exciting.

I guess we are still learning about maybe which therapeutic strategies are optimal for which risk group. You mentioned intolerance. I suppose there is also this phenomenon of fixed-duration therapy with covalent BTK inhibitors in the first-line setting. That will, from the TRIANGLE study, of course, you get two years of ibrutinib, and then you stop. In the future, we will see patients who may be suitable for retreatment with a covalent BTK inhibitor. We do not have much evidence base for that, but that would be a possibility, certainly in the future. Whether that would be with or without a BCL-2 inhibitor, that is again for debate, but you can certainly see those patients being quite well served with re-exposure to covalent BTK inhibitors.

Dr. Phillips: A lot to be gleaned from TRIANGLE.

Dr. Eyre: Yes, for sure. Hopefully there will be longer-term follow-up of subsequent therapies from the trial population, but also hopefully real-world patients that will get re-exposure, and there will be data that will be able to support that as a therapeutic strategy. I guess most of our patients will probably become resistant to covalent BTK inhibitors.

Do you reassess patients' risk features at that point? Do you tend to rebiopsy? Do you look at their disease proliferation, et cetera, in terms of deciding which of those therapeutic options might be most appropriate? You get quite a lot of referrals from community centers with relapsed mantle cell lymphoma. It must be you must sometimes feel like you are playing catch-up from day one almost with the proliferative patients. I would be interested in your perspective on whether you would reach for oral, well-tolerated agents in maybe less proliferative diseases, or whether you do not judge patients in that way at present with the evidence we have.

Dr. Phillips: Yes. The easiest thing with the internal patients, we tend to get biopsies on those patients in general. If we can, we will run a reanalysis of mutations just to see what comes up. As I mentioned, we rarely find anything that really points to the reason why the BTK inhibitor is no longer working. In that aspect, a lot of it will depend, at least internally if we have trials or as you mentioned earlier, the fitness of the patient because not everybody is a candidate for brexu-cel, which is a little bit different from our discussion of large cell lymphoma, where we think everybody is a candidate for CAR. In mantle cell lymphoma, brexu-cel can be quite a burden for some patients, so sometimes we just do not bring it up. In those patients, if I do not think they can actually tolerate brexu-cel.

Then again, it is a discussion of pirtobrutinib now and then come tomorrow; once we actually get our hands on sonrotoclax, it will be a discussion of pirtobrutinib versus sonrotoclax. Pirtobrutinib again has its benefits because, as you mentioned, you can just start it and not worry about it. Whereas with sonrotoclax, there is still a ramp-up, so obviously, to get to the full dose will take about four weeks. The twice-a-week ramp-up is something you do not have to deal with pirtobrutinib.

As I mentioned before, I am a bit excited about the different mechanism of action, maybe potentially being a bit more efficacious in some of these patients who are refractory to a covalent BTK inhibitor and come in progressing on that medication.

Now, community patients, who progress on covalent, by the time they hit my door, they have already started pirtobrutinib. At that point, we are getting an idea of how they are responding, if they are responding. It is that transition point of whether we are taking these patients to CAR or trying to find something else to start them with.

What about in your aspect?

Dr. Eyre: Yes, it is interesting that your patients get put on pirtobrutinib almost without thinking. I guess it is an easy thing for community physicians to do as they refer to you.

From our point of view, certainly in the UK, when we are thinking about our therapeutic pathways, the key question is suitability for brexucabtagene. You have touched on some of the toxicities. In my mind, when I am seeing somebody, I look at a patient and think: how is this patient going to fare with four to six weeks in hospital and grade 3 ICANS, one in five chance of ICU admission, and plentiful immunosuppression and antibiotics, et cetera, along the way. Is this something that this patient is robust enough to manage? Because if they are not, they are not suitable.

We do not have an absolute cutoff, but pragmatically, when patients get beyond 70 to 75, they have to really be ticking the fitness boxes to be considered for this. We have that as an option. We do not have absolute age cutoffs, but I think those of us that have used this therapy, like yourself, recognize that it is not the most straightforward CD19 CAR that we have at our disposal, but it is probably the most efficacious agent we have, at least in mantle cell lymphoma. In the UK, we do not have access to liso-cel for mantle cell; we only have it for large cell lymphoma, so it is not a super relevant discussion. We do not have routine access to glofitamab; only in clinical trials at present.

I would be thinking CAR-suitable or not. Then if they are not suitable, bispecific-suitable or not in terms of access in a clinical trial, and then assuming agents like BTK and sonrotoclax were available. In essence, these are well-tolerated tablet-form treatments which represent a very reasonable palliative treatment option for older and potentially slightly frailer patients.

As you say, pirtobrutinib is easy to initiate. The data with covalent BTK resistance in pirtobrutinib, the responses are lower than you see if you have been intolerant. It makes complete sense. I think that is important to state. Whereas I do not think you tend to see that differentiation when you tease out the sonrotoclax data in quite the same way.

I think both will be potentially useful palliative options in the future, and as you say, in theory could be bridging strategies. We have no data of combinations of these two therapies. Maybe in the future that might be something of interest, but in essence, those two agents in certain future UK practice would be used for those CAR-unsuitable patients.

We do get referrals into the larger centers, perhaps slightly different practice than in the US because our community practice is managed often by actually hematologists managing quite a lot of lymphoma medicine, so it is possibly a little bit different, but I think a lot of the principles are very similar.

If we just focus on sonrotoclax a little bit more, for our listeners, sonrotoclax has been recently FDA-approved for relapsed/refractory mantle cell lymphoma in patients who have experienced the covalent BTK inhibitor. A publication in the summer of this year delineates efficacy in about 125 patients. Response rates, CR rates, and progression-free survival, very interestingly, look remarkably similar to pirtobrutinib. I suppose this begs the question here. This is a very different style of therapy. There is a different initiation pattern, as you have already alluded to, and it is clearly hitting a very different target. We have known for many years that BCL-2 inhibitors are actually very active in mantle cell lymphoma, but this is the first time we have actually got the option to use them as monotherapy.

Tycel, in terms of your practice, any thoughts about both its sequencing and then also maybe just some practical guidance around tumor lysis syndrome monitoring, what things physicians listening to this podcast might need to be thinking about when they are reaching for sonrotoclax in the future?

Dr. Phillips: I think, as far as the sequencing aspect as I mentioned earlier, a bit more excited about the different mechanisms of action. As you pointed out, we have all been quite piqued about the potential of BCL-2 inhibitors. Obviously, venetoclax never was really formally evaluated in a post-BTK space; a lot of retrospective studies.

When sonrotoclax was approved, it was quite a useful situation to see how this agent would perform, hopefully, in this space when we get into the real-world setting. As far as the lysis aspect, the risk is still there, but I do think in the relapsed/refractory space, it is much, much less than what we would expect in a treatment-naive patient population. However, the escalation and the shorter half-life of sonrotoclax does allow for closer monitoring. I would suspect, unless you really had a patient with significantly bulky or leukemic disease or horrific renal function, that you can probably follow most of these patients in a low-risk TLS management just labs every couple of hours from the 24-hour period with the appropriate escalation of day one, day four during the week.

Ideally, it should not necessarily be too onerous for community physicians, especially a lot of them will have experience with venetoclax just from the CLL space, so transitioning over to this should be a little bit – easier transition and uptake versus what we see when we actually introduce novel drugs, which they have no experience with the side effects profile.

Dr. Eyre: Yes, absolutely. From the sonrotoclax study, the TLS monitoring required, as you mentioned, twice-weekly ramp-up over a four-week period. It still took five weeks in total, a bit like venetoclax to get to the full dose. This was done slightly differently. It was twice-weekly ramp-up, but at the ramp-up levels, there was only a requirement to do a four-hour post-dose blood test for tumor lysis syndrome and monitoring, which is somewhat different to the CLL venetoclax license, which we know involves far more monitoring and is clearly somewhat more burdensome. We hope in the future this will be much more straightforward from a TLS monitoring point of view. However, as you say, you have still got to be mindful of those with very bulky disease, particularly leukemic disease, and those patients with poor renal function, and being mindful of that risk.

Do you see that requirement for twice-weekly monitoring being particularly problematic or burdensome for patients, or do you think that this will be something that once physicians have managed a couple of times, they will get quite familiar with and realize it is pretty straightforward and so forth? How do you see this playing out in routine clinical practice?

Dr. Phillips: Yes, I would only imagine that for the patients who actually need to be admitted for some reason, those patients would be an unnecessary burden. However, as you mentioned, a one-hour lab draw, a lot of patients can get those close to home. If they are dispensed with a starter pack, a lot of patients now are savvy enough where they can take a drug, go get a lab four hours later, and we look at the results. I do not necessarily see that as a big barrier per se, as long as, again, we can keep those patients out of the hospital. Now, if you have to be admitted twice a week, that is a different story.

Dr. Eyre: You are suggesting if you are managing this in the community, for example, you would expect these patients to be dosing in the community but getting a blood count done at a particular point, potentially in the community, so that they are being monitored sufficiently, but not necessarily, as you say, coming out to the hospital a lot.

Dr. Phillips: Yes. A lot of our community sites do not have blood drawing stations; they are on the facility. Patients are familiar with going to a lab anyway to get blood checks. I would assume that would still be their routine practice. As long as they can continue to do that, again, I do not think that necessarily adds too much of a burden to patients.

Now, I am sure if you laid out the options, pirtobrutinib where you do not have to do this versus sonrotoclax, I am sure the patient would say, "Just give me the pirtobrutinib," but that is where we come in as far as a more educated discussion about the reasons for possibly recommending sonrotoclax in these situations over pirtobrutinib, as why there is more benefit in some cases for the MCL versus just ease of use.

Dr. Eyre: What would you say about the argument that in the non-CAR-eligible setting in an older patient, the sequence of pirtobrutinib and sonrotoclax does not probably matter, because ultimately, it is likely that these therapies will be used sequentially one after the other, whichever way round? What would you say to that argument? Would you just say you use which one you think is most appropriate first and go from there? Because there will probably be subgroups - we know this from the BRUIN study. where you have this very durable responses. Biologically, we do not fully understand it, but if you respond with pirtobrutinib, you can get good two or three years potentially of benefit.

I guess sequentially you can certainly say if you had a super fit 80-year-old, they would certainly want to try both at various time points.

Dr. Phillips: Yes, I would agree with you. If we are dealing with that situation, I do not think sequencing really matters. As you mentioned, in the BRUIN study, there is a tail, so we do know there is a subset of patients who will have durable responses. Again, we both agree: toxicity and ease of use, pirtobrutinib is hands down the easiest thing we can start a patient on who progresses up to a covalent BTK inhibitor, so you do not really lose much. In most of these cases, you get a very early signal whether things are working or not. There is a plethora of data where you can actually ramp up a BCL-2 inhibitor while a patient is already on a BTK inhibitor without significant concern from toxicity.

Dr. Eyre: I suspect that will be quite a popular approach at some point in the future, absolutely. We have covered a lot of ground here, but just to finish up, we have not really talked about bispecifics very much. Tycel, you have been very involved in the glofitamab studies and the development of that agent in mantle cell lymphoma, and certainly probably have as much experience, if not more than anyone in the US with glofitamab in mantle cell lymphoma.

Where do you say is its place here? Do you see it being used in CAR-unsuitable patients, or how might you use it if you did have the option of liso-cel as well as glofitamab, for example? How does, for example, sonrotoclax and pirtobrutinib play into those decisions as well? Or do you see it as another therapeutic option on the table for a patient to try at the appropriate time?

Dr. Phillips: Yes. We can have a whole another hour podcast about CAR-T and bispecifics. I will not spend a lot of time there. I do think that pirtobrutinib and sonrotoclax is probably playing in a different sandbox than the bispecifics and CAR T-cell therapy, just because of what we have seen for the number of patients who can probably get a durable response, but as you have already known, glofitamab in itself also is not necessarily a walk in the park to get through the step-up dosing for the bispecific. Once you can move past the step-up dosing, it is a little bit easier, but it can sometimes give you pause, when the first 2.5 mg dose you tend to get a grade 2/3 CRS, which is something you generally do not expect to see in the bispecific antibody.

Where it will fit, obviously, a lot will be contingent on how we can reduce the rates of CRS for patients because, you would hope that bispecifics would have a little bit more reach into community spaces. However, to accomplish that, you need to keep patients out of the hospital. If we can accomplish that, then it really brings up the discussion of possibly using these drugs in a pre-CAR space and then saving CAR for later for others because we are targeting different antigens.

That being said, as of right now, bispecifics are likely to be in the same places where you have CAR, at least in the MCL space, which is academic centers or places where you can actually hospitalize a patient. A lot of that decision-making comes down to physician preference, your experience, and that regard.

Liso-cel is a little bit tough just because there was an ASCO meeting a couple of years ago where they flashed a slide very quickly. If you look at the post-BTK exposure rates with liso-cel, it did not look very impressive and actually looked a little bit worse than pirtobrutinib. That has always given me a little bit of pause with liso-cel. That is why I mentioned earlier the real-world dataset will be very impactful for letting us know whether liso-cel is really an equivalent to an axi-cel-type product like we see in large cell lymphoma, or if we will have different tiers of CAR in mantle cell, where liso-cel may only be used as a palliative approach, not expecting durable responses, and you really still reserve brexu-cel for patients who you actually want to really take the CAR, actually, who can think to get us some durable response.

Dr. Eyre: Yes, definitely. It is interesting that Mosun-Pola was presented and published as a little bit of an afterthought, but it does seem to almost tick the boxes of potentially the best of both those worlds: the efficacy that we see with glofitamab, but potentially at least a strategy to debulk and reduce the T-cell activating toxicities that we see with glofitamab. I guess we wait to see whether there is any formal plans to develop that further. Clearly, the GLOBRYTE study, large randomized global phase III, and those types of studies do not grow on trees in terms of the ease of delivery of big randomized trials in relapsed mantle. I guess we will have to wait and see whether that combination, Mosun-Pola, is developed further in mantle cell lymphoma beyond the data we have at the moment, but it certainly looks interesting.

Dr. Phillips: You are right. They seem to have threaded the needle there as far as safety and efficacy. Yes, we will have to see.

Dr. Eyre: Absolutely. Tycel, I think we have covered a lot of ground there. We are both very involved and invested in this field. Certainly, I am sure for both of us, very exciting times in mantle cell lymphoma, lots of development and some real hope for our patients, both in relapsed disease and, of course, moving forward. A lot of these agents, ultimately, we’ll be probably talking about their first-line use at some point in the future, which is certainly super exciting. For now, certainly lots of development in the relapsed/refractory space. Thank you, Tycel, for joining this podcast. I hope you all enjoyed it. Goodbye for now.