CD19-Directed Antibody-Drug Conjugates for DLBCL

Part 2: Loncastuximab as a Third-Line Therapy for Relapsed/Refractory DLBCL

During a live virtual event, Paolo Caimi, MD, discussed the toxicity and dosage of loncastuximab tesirine as a third-line therapy for diffuse large B-cell lymphoma before receiving chimeric antigen receptor T-cell therapy.

DISCUSSION QUESTIONS

  • Under what circumstances would you be most likely to use loncastuximab tesirine (Zylonta) as third-line therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma (DLBCL)?​
  • What are the pros and cons of loncastuximab tesirine as compared with other alternatives such as tafasitamab (Monjuvi) and lenalidomide (Revlimid), polatuzumab (Polivy) plus bendamustine (Bendeka) and rituximab (Rituxin), or Selinexor (Xpovio)?​

PAOLO CAIMI, MD: Under what kind of circumstances, and what type of patient, would you consider using loncastuximab?

DEVA NATHAN, MD: Based on what I’ve seen so far, it is probably more like a fourth-line treatment than anything else, at this point.

PRIYA KUMAR, MD: What about a patient who has neuropathy, or renal insufficiency, where you can’t use lenalidomide?

CAIMI: I think that’s 1 of the specific aspects of this drug, that it’s somewhat different in terms of its toxicity. What is interesting is that as a CD19-targeted treatment, it can [produce] good responses. It was tested up to 2 or more lines of therapy, including patients with prior chimeric antigen receptor [CAR] T-cell therapy, but it doesn’t cause neuropathy. The patients who have peripheral neuropathy from bendamustine or polatuzumab are [patients] to consider. Or lenalidomide, as well.

YAN JI, MD: The dose is more convenient compared with the other 2 regimens and does not involve oral pills. I think some of the patients will probably prefer using this.

CAIMI: Do you find that it has a similar schedule compared with polatuzumab/bendamustine/rituximab? Or maybe polatuzumab is a couple more days, because it’s 2 days in a row versus 1 every 3 weeks? But an intravenous therapy every 3 weeks seems to be easy.Any barriers that you can see for giving loncastuximab?

JI: There are too many options.

CAIMI: Too many options, and it is difficult to compare them because the studies seem to be a little bit different.

PAVAN KUMAR BHAMIDIPATI, MD: I would like to comment that this is a single agent antibody-drug conjugate, which seems to be much easier administering to an outpatient once every 3 weeks. If [a patient was] rituximab refractory, if they progressed in the second line on rituximab-based therapy, and you are looking for alternate agents while you’re waiting for CAR T-cell therapy—that takes at least a month, in terms of logistics. [Loncastuximab] is something that is available right off the shelf. The only caveat is that the CD19 positivity, which you probably need to get a repeat biopsy, unless the patient hadn’t received a CD19 [treatment] prior and you could presume the patient is still CD19 positive.

CAIMI: First of all, you’re right, it’s off the shelf. The patient doesn’t have to be CD19 positive, and they don’t have to be tested for CD19 expression if they have never had a CD19-targeting agent before. It’s primarily CAR T cells; it seems that the pressure of CAR T cells is greater to lose the antigen than other drugs. Tafasitamab doesn’t seem to do it. With loncastuximab, it’s not really clear whether patients lose CD19 expression. This seems to be something that happens more with CAR T-cell therapy. So, if you have somebody who failed CAR T-cell therapy, I’d check CD19 expression if you’re considering loncastuximab. But, if they’ve never had anything like that, that targets CD19, you don’t have to check it.

BHAMIDIPATI: That’s one of the things I faced—when I refer patients to CAR T-cell therapy, they would say, “Oh, don’t give the patient tafasitamab, because we’re planning for CAR T cell,” whether on trial or off trial. So, we tend to reserve the tafasitamab for later. It sounds to be more like loncastuximab could be used before CAR T cell, and CAR T cell could be pushed later.

CAIMI: It’s not yet that scenario, for you to have patients who are progressing beyond the second line. It can be considered. We did have those patients that went on to have CAR T-cell therapy, and they had responses that were comparable with what you would see in such a high-risk population. These patients were receiving third or fourth line; this wasn’t CAR T cells on the second line, so you’re right.

BHAMIDIPATI: What about patients with neurological involvement, like CNS lymphoma and leptomeningeal carcinomatosis? These patients are excluded from CAR T-cell therapy. Can we use loncastuximab in these patients?

CAIMI: They were also excluded from the trial. That is a patient population that is definitely in need, but they were not included in [the loncastuximab] study. Like most of these trials, they don’t include patients with CNS involvement.

DIVIS KHAIRA, MD: I think this is a very durable drug in private practice. After all, a lot of our chemotherapies currently tend to give some of these horrible AEs, like horrible skin problems with panitumumab [Vectibix], and third-spacing with paclitaxel. Once we have knowledge of how to take care of these AEs, I think it can be given.