Experts Discuss Breakthroughs in Large B-Cell Lymphoma at ASCO Annual Meeting

At the recent American Society of Clinical Oncology (ASCO) annual meeting, groundbreaking advancements in cancer therapy were highlighted, particularly in the treatment of large B-cell lymphoma. These advancements include updates on chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies, which have significantly affected treatment protocols and patient outcomes.

MedPage Today brought together three expert leaders in the field for a roundtable discussion: Moderator Loretta Nastoupil, MD, from the University of Texas MD Anderson Cancer Center in Houston, is joined by Catherine Diefenbach, MD, from NYU Langone’s Perlmutter Cancer Center in New York City, and Mazyar Shadman, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle. This final of four exclusive episodes looks at how having more options will affect treatment decisions.

Click here to watch the other videos from this ASCO roundtable series in diffuse large B-cell lymphoma (DLBCL).

Following is a transcript of their remarks:

Nastoupil: So we’ve talked about CAR T-cell therapy and how it’s changed the treatment landscape in large cell lymphoma over the last 5 years. And generally at these meetings we see sort of new data emerge and maybe changing how we practice somewhat. We’ve also seen this emerge in mantle cell lymphoma in the form of liso-cel [lisocabtagene maraleucel; Breyanzi], a new option for both of those diseases. And at this meeting we saw some updates, particularly with liso-cel in mantle cell lymphoma. What’s your take on having more options, or maybe access to better tolerated CAR-T?

Shadman: Great news. In the past few weeks, we now have access to lisocabtagene maraleucel, an anti CD19-targeted CAR with a 4-1BB co-[stimulatory] molecule. And this CAR has been approved for large B-cell lymphoma in as early as second line for primary refractory patients, or for patients who are not tolerant or were not considered to be transplant candidates. So now we have access to liso-cel for follicular lymphoma in patients with two or more prior lines of therapy and also mantle cell lymphoma, as just a few days ago it got the approval.

So I think for mantle cell lymphoma it will be, in my opinion, practice-changing in many settings. Brexu-cel [brexucabtagene autoleucel; Tecartus], the first approved CAR-T therapy for mantle cell, has great efficacy but it comes at the cost of high toxicity, both cytokine release syndrome [CRS] and more importantly neurotoxicity, which is not always predictable. We have patients with low disease burden still going through times with neurotoxicity.

The data from liso-cel for mantle cell from the safety standpoint looks much better. So I think in practice we will be increasingly using this. So in that regard, I think it was great news for our patients. And for follicular lymphoma it’s nice to have another option. Now we have all three CD19-targeted CARs approved for follicular lymphoma and it will just add to the portfolio we have to offer to our patients.

Nastoupil: I think that’s a key part. Catherine, what’s your take on, particularly in follicular lymphoma and we saw some data with glofitamab [Columvi] in mantle cell lymphoma at this meeting. So how do we really sequence therapy in this disease?

Diefenbach: I think this is such an important question, right? And I think this is going to drive the field because although they’re both considered immunotherapy, bispecific antibodies and CAR T-cells have really different trade-offs. So bispecific antibodies have a low incidence of cytokine release syndrome and potential neurotoxicity. It’s usually only in the step-up dosing in the first cycle and then no more. And most of the time with step-up dosing, this is grade 1 to 2. And mosunetuzumab [Lunsumio] can be given outpatient, epcoritamab [Epkinly] can be given outpatient, and glofitamab will soon be allowed to be given outpatient. So these are given as an infusion in outpatient. There’s no cell preparation, there’s no targeting of stem cells with conditioning therapy with stem cell-toxic agents. It doesn’t impair fertility for younger patients. Glofitamab, which is a 2:1 bispecific, is given for 12 cycles. The other, epcoritamab, which is a bispecific for DLBCL, is given indefinitely.

So the issue with bispecifics in mantle cell is that it’s a treatment that is either given for 12 cycles or indefinitely, but it’s the treatment that you have to come to the infusion center approximately once every 3 weeks to get. Now the toxicities with bispecifics once you’re out of step-up dosing are very mild, a little bit of myelosuppression, but not really anything above the fact that you’re going to have targeting of your B cells, which is similar to both agents. So your immunity to COVID and other viruses is impaired the whole time you’re on a bispecific. But it’s impaired globally from a CAR T2.

So really, bispecifics are an extremely well-tolerated therapy for mantle cell, for follicular lymphoma. And I think the really striking thing is that the mosunetuzumab data in follicular showed extremely long progression-free survival [PFS] for the patients who had a complete response.

The CAR-T data in follicular lymphoma, the liso-cel data and the axi-cel [axicabtagene ciloleucel; Yescarta] data, and for mantle cell as well, shows that there are absolutely durable responses. For mantle cell, it’s probably similar to the large cell. You’re not curing everybody, right? You’re curing about 40% of the population in mantle cell. It’s higher in follicular, but I think the issue in follicular is how do we know with 24-, even 36-month follow-up if these patients are cured because these are the patients that are going to relapse at 5 years. I think in mantle cell it’s different because obviously there a 24- or 36-month PFS is meaningful. But I think it’s always going to be a balance, a trade-off of toxicity and efficacy.

I think the issue in large cell when people say do we do bispecifics before or after, is that we don’t know how durable the PFS is with bispecifics. We also don’t know if you’ve had your T cells stimulated for a year with a bispecific if the CAR’s going to work less well with these chronically stimulated T cells or if it’s going to work better. And we don’t know where to sequence these two. But I think, in large cell, it’s pretty clear that there’s a survival advantage to doing CARs second. So I think bispecific sort of slot on behind.

I think in follicular it’s the reverse. When you have patients who are not that sick who have an indolent disease, even if they have a high tumor burden or they’ve relapsed within 24 months and you have a therapy that can cause really durable progression-free survival and has very low toxicity, why wouldn’t you give this first when the CAR T-cell still, unfortunately the way we give it has the toxicity of conditioning therapy plus the CRS and the neurotoxicity, which are significantly higher than they are for bispecifics.

So I think in all three of these diseases — large cell, follicular, and mantle cell — there’s going to be a real trade-off between risks and toxicities and durable benefits that is going to make the field really exciting over the next 5 to 10 years. And I for one, and I hope you guys too, are really excited that we have all these options for our patients that we can sit down and talk about which one is better. Because 5 years ago we didn’t have any of these things available to our patients and to me that’s why it’s such an exciting time to be in the lymphoma field right now.

Shadman: I totally agree. In follicular lymphoma, I think we have a good problem. We have access to a number of effective treatments with different modes of action, CAR-T therapy, bispecific therapy, we now have BTK [Bruton’s tyrosine kinase] inhibitor in combination with anti-CD20. We already had lenalidomide [Revlimid] and anti-CD20. So as lymphoma investigators will have a busy time ahead of us to come up with trials and other research methodologies to really look at the right sequencing or combinations. So exciting times for patients and more work for us.

Nastoupil: I agree. And again, meetings like this, it’s really nice to sit down and reflect back on all the work and progress that’s been made. Also lessons learned from negative studies. So how do we prevent those moving forward and make sure that we prioritize our patients and their family members are giving of their time and potential risks so that we can continue these discussions and learn and continue to inform the treatment landscape. So once again, I really want to thank both of you for joining. It’s been a great discussion and I’d really like to thank the audience for participating.

Diefenbach: Thank you so much. This has been really fun to do.

Shadman: Thank you.

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