Bispecific Antibodies in Relapsed/Refractory DLBCL

Follow-up data from the EPCORE NHL-1 trial lend further support to the efficacy and safety of single-agent epcoritamab (Epkinly) in the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.

MedPage Today brought together three expert leaders in the field: Moderator Ian Flinn, MD, PhD, from the Sarah Cannon Research Institute in Nashville, Tennessee, is joined by Caron A. Jacobson, MD, from the Dana-Farber Cancer Institute in Boston, and Jason Westin, MD, from the University of Texas MD Anderson Cancer Center in Houston, for a virtual roundtable discussion. This is the third of four exclusive episodes focusing on bispecific antibodies in DLBCL and the real-world evidence of these treatment options.

Following is a transcript of their remarks:

Flinn: I want to switch now and talk about bispecifics. We’ve seen the FDA approval of epcoritamab recently in the United States. This is one of the many different CD20 monoclonal antibody bispecific antibodies that’s under investigation. This is the first to be approved in large cell lymphoma. Of course, we previously saw mosunetuzumab [Lunsumio] be approved for follicular lymphoma.

I guess the idea here is — the hope when people originally developing this was — that this would be an off-the-shelf CAR [chimeric antigen receptor] T-cell that could be generally applied to people everywhere. I mean, not exactly CAR T-cell, but the same idea. Caron, you buy into that? Do you think this is going to be a major player in the treatment of large cell lymphoma and by the mechanism of action? And maybe talk a little bit about some of the adverse events that are associated with this.

Jacobson: Yeah, so I’m very excited to have bispecifics available for our patients. Obviously, the biggest unmet need I think in large B-cell lymphoma right now are patients who are either refractory to or relapse after CD19 autologous CAR T-cell therapy. And so it’s very clear to me that bispecifics offer the highest benefit for those patients. And so, to not have to try to find a clinical trial for those patients to go on, I mean, we still will try to find clinical trials for those patients to go on, but to have something available when a clinical trial doesn’t exist is really pretty spectacular.

I don’t think that these are going to compete with CAR T-cells though, in terms of a line of therapy. First of all, we just heard about the approval of axi-cel [axicabtagene ciloleucel (Yescarta)] and liso-cel [lisocabtagene maraleucel (Breyanzi)] in the second line, based on the randomized studies and bispecifics. So far, epcoritamab is approved in the third line.

But we have very limited follow up of the bispecifics, and although [it looks] like there are durable responses, we have limited follow-up after the completion of the dosing of these bispecifics. And so it’s hard to know if this is going to be a definitive therapy for any patients, or what proportion of patients it could be definitive for. And I would always reach for a definitive and potentially curative therapy over one that has not proven to be definitive or curative.

But you asked about toxicities, and of course the bispecifics do come with a risk of cytokine release syndrome [CRS] and a lower risk of immune effector [cell]-associated neurologic syndrome, but not a 0% risk. And the rates of CRS do appear to be lower than with CAR T-cells, but they’re, again, not insignificant. But they are generally low-grade toxicities.

But it doesn’t make it easy to get patients started on these drugs. So although they’re available off-the-shelf, you generally have to employ step-up dosing with multiple doses within the first couple of weeks before you can get patients to the full dose. And then once they do get to the full dose, that’s when you do see these toxicities. So it can take people a month to get through that initial step-up dosing to the recommended dose.

And I think for some community oncology centers, that’s going to be a difficult task. And I think we are going to see referrals into tertiary centers to get patients through that first month of dosing, and then they can go back to the community where they can continue to get their dosing.

So, I think some of the logistical ease that we were hoping to see with bispecifics may not actually be fulfilled, given some of these logistics of getting patients to [the] full dose in the first month.

Flinn: Yeah, I mean, it’s definitely an issue for us in Nashville and in the surrounding areas. And a lot of the hospitals don’t admit people who are [on] chemotherapy or other intermittent [therapy], any kind of oncologic needs other than basically surgery. And so, I’m really wondering how this is going to play out. If and when we are able to do these fully as an outpatient, maybe that would increase the utilization of them.

But I guess, Jason, we now have a lot of different treatment options in that same space, in the multi-relapsed large cell lymphoma. There was some real-world evidence presented at ASCO this year looking at these different treatment options, and trying to see how that compared, perhaps, in the second line or third line or beyond. And maybe just sort of historically how they compare to the previous clinical trials. So I guess I was pretty impressed. I mean, I guess we always think about that the real world never does quite as well as we see in clinical trials, but there was a significant drop-off in this real-world evidence. What did you think about that?

Westin: Yeah, the abstract presented by Dr. Crombie and colleagues looking at real-world evidence of CAR T-cells, polatuzumab [Polivy]-based regimens and tafa-len [tafasitamab (Monjuvi)-lenalidomide (Revlimid)] was intriguing. These real-world, and I put loose quotes around that term, evidence are important. They are sometimes our best way to see the non-clinical trial population. But they’re always a challenge to compare across treatments because, of course, these aren’t randomized, patients aren’t given, you know, treatment A or B without reasons. There may be reasons why a patient received a CAR T-cell or a patient was deemed not to receive a CAR T-cell.

Tafa-len is not a therapy that we’ve put [on] equal footing versus CAR T-cells. Tafa-len, in the real-world datasets that were looked at at the ASH [American Society of Hematology] meeting this past year, was used in patients that would never have qualified for the clinical trial. I think it was 11% of patients in a previous real-world data cut would’ve qualified for the … clinical trial. Many of those people were refractory to initial treatment, didn’t receive lenalidomide, had all types of other comorbidities, and therefore they didn’t do as well. Surprise, if you use imatinib in blast crisis, it doesn’t work that well.

And so, it’s always a little bit in the details about who are these patients that are being treated in the real world. And I think, as you mentioned, Dr. Flinn, seeing outcomes be a little bit lower than what we expected in the clinical trial is not a big surprise because of those eligibility criteria for getting folks on studies.

Dr. Jacobson and my colleague Dr. Nastoupil previously published on real-world outcomes for CAR T-cells. And I would say that is probably the one example where real-world outcomes look very similar to clinical trial outcomes. And I think that just speaks to the efficacy of CAR T-cells, that the patients who get on trials look a lot, outcome-wise, a lot like the patients who didn’t get on trials. And in many of those data cuts, half of the patients wouldn’t have qualified for the clinical trial. And yet, outcomes still look very similar.

So, I like seeing these real-world-evidence abstracts, but I think they’re always a little bit of grain-of-salt of who are these patients and how do we interpret that cautiously against the clinical trial data we’ve already seen.

Flinn: Yeah, that was a nice analysis there, and I couldn’t agree with you more. But Caron, do you — taking that data, it was done by your colleague at Dana-Farber — do you, with that information, would you restrict now who you gave, say, tafa-len to? [Would you give it] to only the people that were on the clinical trial? I mean, that was one to three prior regimens rather than multiple prior regimens. How do you interpret that?

Jacobson: I mean, I think ideally, yes. Ideally, I think we’ve seen, well in this series that Dr. Crombie presented, she looked at outcomes for second and third line and actually saw very little difference, I think, between the outcomes. So actually, moving it to second line didn’t seem to solve the issue. But definitely, in also speaking to colleagues, the experience with tafa-len definitely seems to be restricted to the patients who went on that study, which ultimately are going to be patients that you wouldn’t consider for CAR T-cell therapy, which are not that many patients actually in real clinical practice.

But what I think this helps with is — now that we have multiple agents available to patients in the standard-of-care setting following CAR T-cell relapse — it helps you prioritize which regimen you might pick for those patients. And I think we haven’t seen real-world data for epcoritamab, but I suspect we’re going to see it similarly hold up in the real world, or at least closer to the clinical trials because of the mechanism of action being pretty similar to CAR T-cell therapy. And because it is a very powerful therapy. And so, this data does help me help support the use of epcoritamab for these patients over something like pola-BR [polatuzumab and bendamustine-rituximab (Rituxan)] or tafa-len.

Flinn: Great.

Click here to watch the other videos from this ASCO roundtable series on diffuse large B-cell lymphoma.