CD19-Directed Antibody-Drug Conjugates for DLBCL

Part 2: Selecting a Non-CAR T-Cell Treatment in Third-Line R/R DLBCL

During a live virtual event, Jason Westin, MD, discussed with participants the choice of third-line treatment for relapsed/refractory diffuse large B-cell lymphoma for a patient who declines chimeric antigen receptor T-cell therapy.

DISCUSSION QUESTIONS

  • How might you sequence the various available therapies for third-line relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL)?​
  • When you think about each, what patient comes to mind as a “perfect fit”?​
  • Would you use any of these therapies, on or off label, as second-line treatment?​
  • How do you think about these therapies with respect to CAR (chimeric antigen receptor) T-cell therapy?​

JASON WESTIN, MD: Considering the clinical trial data for polatuzumab vedotin [Polivy] plus bendamustine and rituximab [Rituxan], tafasitamab [Monjuvi]/lenalidomide [Revlimid], and loncastuximab tesirine [Zynlonta], what are some individual patient characteristics, both clinical and pathological, that might make a difference in your assessment? Is there a particular patient that you’d view as a perfect fit for one of these therapies? Dr Reddy, tafasitamab was something you were considering. Is there a perfect fit for any of these therapies for a given patient?

BRAMHAM REDDY, MD: Honestly, I do not know if it is the best for each patient because I practice in a small-town community practice. [When dealing with patients with] lymphoma after the first and second line, I refer them to an academic center. I live about 2 and a half hours from Houston, so it’s going to be a tertiary center that is going to decide. From what I have been learning about, tafasitamab seems to be the easiest therapy that I could use. Anything beyond, I’d probably let the tertiary center decide. It would be very difficult for me to learn how to implement the other agents.

WESTIN: Yes, there is a muscle memory that develops when you don’t have unlimited time to learn all these things. It’s helpful to [review] some of the data. But getting that experience with 1 or a couple therapies and using those as your go-to is a practice a lot of us have.

Dr Huang, are there any thoughts you have about sequencing therapies? Is there a particular agent you would use as your backup plan? What are your thoughts about how you’d structure this treatment algorithm?

QUILLAN HUANG, MD: I’ll be honest, I don’t really know. Obviously, CAR T-cell therapy [should be used] if we can, and then I think among all the CD19-targeting choices out there, it really is hard to sequence them. We have done tafasitamab in post-CAR T-cell patients. We checked the CD19, saw that it was still positive, and we gave it a shot. It’s worked some of the time, not amazingly. Otherwise, we haven’t yet had the chance to try loncastuximab. I think it’s just newer, and we haven’t gone quite to that point yet. Again, the tafasitamab data look good. I was wondering what you think—tafasitamab seems to have a plateau to the curve.1 That was also the big idea of CAR T-cell therapy, that there was a plateau to the curve.2 They’re different populations in different trials, but I’m just curious to see what you think about that.

WESTIN: I think that’s exactly right. They both look great, however they’re not in the same pool. One of them is a population of no double-hit disease, no refractory patients, and non-transplant eligible population, and the other’s playing in of a more chemotherapy-refractory zone. So, I think it’s hard to know without a direct head-to-head comparison, but I think if you had a 45-year-old in your clinic who runs marathons, most of us would consider that person for CAR T-cell therapy, and not for something like tafasitamab/lenalidomide if they could have the options all in front of them.

But real life happens, and people sometimes can’t travel to CAR T cell centers, so there’s definitely a role for those for some patients that potentially could get CAR T-cell in the future, and I think there are questions about CD19 loss or targeting CD19 that we don’t yet know. We don’t have a lot of data of doing these CD19 therapies ahead of CAR T-cell therapy, except for some anecdotal experience from the LOTIS-2 trial [NCT03589469] showing that patients who’d had prior CAR T-cell therapy could respond to loncastuximab, and patients who had received prior loncastuximab could respond to CAR T-cell therapy.3

DISCUSSION QUESTION

  • Under what circumstances would you be most likely to use loncastuximab tesirine as third-line therapy for a patient with R/R DLBCL?​

WESTIN: Is there a patient that you’d view as a perfect fit for loncastuximab tesirine? Does anybody have an opinion on that, seeing that it is relatively well tolerated, with a response rate of around 50%?3 Is there somebody in particular that you’d say, “This is the kind of patient I’d tee up for loncastuximab?”

I think the data in both double-hit patients that was expressed in the Kaplan-Meier curves, showing that a decent proportion of the patients had double-hit disease, were more heavily pretreated, and had the prior CAR T-cell therapy, all of those I think were unique and might be somebody that would be a good fit for using this. But, knowing that you are not necessarily burning a bridge for CAR T-cell therapy, at least in the anecdotes that we’ve seen thus far, I’m not sure that the idea of saving loncastuximab for only a non-CAR T-cell patient makes a lot of sense. I think this is something that as we get more experience with, and figure out how to manage the toxicity profile, physicians will get more comfortable and familiar with that.

DISCUSSION QUESTIONS:

  • If loncastuximab tesirine were covered by insurance, would you use it in the second line for patients who decline autologous stem cell transplant (ASCT)?​
    • For patients who may be eligible for CAR T-cell therapy?​
    • For patients who you consider not to be eligible for CAR T-cell therapy?​
  • Do you foresee any barriers to using loncastuximab tesirine? ​

WESTIN: If loncastuximab is covered by insurance, how would you use it for second-line in patients who decline transplant? Dr Lee, if there was a patient who’s potentially eligible, or non-eligible, for CAR T-cell, how would you figure loncastuximab into the algorithm?

HUN LEE, MD: My experience with loncastuximab is in the post-CAR T cell setting. I do have concerns about targeting CD19 prior to CAR T. Do you decrease the efficacy of the CD19 CAR T cells if you use it before? We do see downregulation from Hodgkin lymphoma when we use brentuximab [Adcetris]. When we do a re-biopsy on these patients who have been exposed to brentuximab, they clearly decrease or downregulate CD30.4 So, I am concerned. I do use loncastuximab in post-CAR T-cell therapy, just like tafasitamab. I’ve spoken with many physicians, and we like to have a virgin CD19 for the CAR T-cell therapy, because many of the patients are going in to CAR T-cell therapy with the hope and prayer that they will be in that 30% to 40% of patients with a possibility of a cure. So, I want to give them the best opportunity to get that 30% to 40% chance of durable long-term remission, and a possible cure.

I use polatuzumab for bridging. I agree with you. I don’t like using bendamustine along with the polatuzumab, because I have not harvested the T cells at that point. But after I harvest them, I give them bendamustine, but not much, because they’re going to get high doses of cyclophosphamide soon. I’m trying to work this very fine line of bone marrow toxicity because we do have significant cytopenia after CAR T-cell therapy.

WESTIN: That can certainly be a problem, no doubt about it. Dr Luu, do you foresee any barriers in using loncastuximab? I know this is new, and maybe you haven’t had a chance to use it yet, but is that something you’d foresee as a barrier in your practice, or is it something that might enter the pantheon of available treatments?

CHU LUU, MD: Yes, I think the biggest barrier would be knowing how to use it and anticipating the adverse events of it. But I think with better experience, I don’t see any barriers.

References:

1. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

2. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7

3. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

4. Al-Rohil RN, Torres-Cabala CA, Patel A, et al. Loss of CD30 expression after treatment with brentuximab vedotin in a patient with anaplastic large cell lymphoma: a novel finding. J Cutan Pathol. 2016;43(12):1161-1166. doi:10.1111/cup.12797