CD19-Directed Antibody-Drug Conjugates for DLBCL

Part 3: Barriers to Loncastuximab Before CAR T-Cell Therapy in DLBCL

During a live virtual event, Paolo Caimi, MD, discussed the barriers to using loncastuximab tesirine for diffuse large B-cell lymphoma preceding chimeric antigen receptor T-cell therapy.

DISCUSSION QUESTIONS

  • Do you foresee any barriers to using loncastuximab tesirine (Zynlonta) in diffuse large B-cell lymphoma (DLBCL)?​
  • If loncastuximab were covered by insurance, would you use it in the second line for patients who decline transplant?​

DEVA NATHAN, MD: I have different question. Are you willing to replace R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone] as the first line? Do you think at some point R-CHOP is going to be passé?

PAOLO CAIMI, MD: I think it probably will be improved upon. There are some [aspects] of R-CHOP that will stay. I still think that cytotoxics have a space for these diseases, and we have to be respectful of their role. I don’t think it will be completely passé, but maybe vincristine is not the most important drug. So, it’s a good question. I think at some point we’ll replace some of the parts of R-CHOP.

DIVIS KHAIRA, MD: I think it’s very important [to note] that the NCCN [National Comprehensive Cancer Network] doesn’t put everything into 1 slot, so then you’re arguing with the insurance company. Last week, I was trying to teach the insurance company person some hematology. It was an addiction specialist who was telling me how I should practice hematology. We’re getting more and more insurance companies [saying] “Peer review this and peer review that,” and “NCCN said only use 1 drug, and not 2 drugs,” and that’s become a nightmare in daily life. You went from maybe 1 peer review a month to 4 or 5 for everything, and you’re talking to a non-oncologist on the other side.

CAIMI: When you say that they don’t put everything in 1 slot, you mean that they include the drugs that you use?

KHAIRA: What they do is, they have level 1, 2, and 3. So, what the insurance company does deny is the level 2 and 3. Level 2 and 3 evidence is no evidence to them. For example, they won’t give you obinutuzumab [Gazvya] with bendamustine [Bendeka]. They won’t give you this, that, and the other. You’re not going to get JAK2 inhibition unless the patient has more symptoms.

A lot of it is driven by the NCCN, and that’s a nightmare now. They make things way too specific. And maybe that’s good, because advanced practice providers and nurse practitioners can practice like that, but the rest of us oncologists who have experience can wade through some of this information and make our own decisions. But that’s now being driven by the NCCN, and this needs to stop, in my opinion.

CAIMI: I think it’s still important to bring this up.

DISCUSSION QUESTION

  • Consider the 46% response rate to chimeric anitgen receptor (CAR) T-cell therapy in the 15 patients who received CAR T-cell therapy after loncastuximab tesirine.1 How does that factor into your opinions on sequencing therapeutics?​

CAIMI: Would you consider loncastuximab either while you’re waiting for CAR T-cell therapy, or in a patient for whom you’re deciding for CAR T cell since it’s been demonstrated that they can have a response to CAR T cell afterwards?

YAN JI, MD: I do think these data provided peace of mind. I can see that although the study is small, at least there’s a signal that a patient still can respond to CAR T-cell therapy after receiving loncastuximab.

KHAIRA: The question is: What’s the response to CAR T cell after fourth-line therapy? While 46% responded [to CAR T-cell therapy after loncastuximab], if they receive loncastuximab in the fourth-line and they go for CAR T cell therapy afterward, what’s the response?

CAIMI: True. I don’t think we know that. We know the patients who have more advanced disease tend to have worse [outcomes], and I think that’s why comparing loncastuximab to the other 2 drugs that included patients on just 1 line of therapy is not necessarily a fair comparison, because they were sicker patients. I think we’ll learn more as we start treating patients with less advanced disease with these drugs.

NATHAN: To answer your question, how about if you see 24% complete response and 24% partial response? That’s 48% compared with 46% on CAR T-cell therapy, they’re basically equivalent response rates. Can I say it in that way?

CAIMI: Yes, that’s true.

NATHAN: Either the patient is too sick to go through CAR T-cell therapy or they are waiting for CAR T cell, then maybe you can use it before. I can see this can be transposed before or after. It makes it a more reasonable drug option.

CAIMI: Yes. So it would potentially be a bridge to CAR T-cell therapy. That’s 1 of the things we’re looking for, drugs that can get us a patient that can be using CAR T cells afterwards.

[In regard to the] phenomenon where people lose their CD19 expression, how much does this concern you—people who are getting repeated CD19 drugs?

KHAIRA: I’m not so concerned if you have a 46% response. You’re looking at loncastuximab in patients who have been treated with multiple other drugs. The real question is going to be, does it make a difference if you use it earlier?

CAIMI: You’re using drugs that target the same surface markers, which is something to be concerned with.

LYLE GOLDMAN, MD: We’re getting away from lymphoma biology, germinal center and non-germinal center. Where do those things factor in when you’re thinking about second-, third-, and fourth-line therapies? In the [L-MIND] study of tafasitamab [Monjuvi] and lenalidomide [Revlimid], I noticed that two-thirds of the patients were not classified in terms of germinal center versus non-germinal center subtype.2 And we know that lenalidomide is principally active in the non-germinal center subtype. But how do these other therapies factor in, considering that?

CAIMI: Good question. First, I think that you can see that these studies are reporting it less and less. The second thing that you’re seeing is that the drugs are working in both subtypes. And the third thing that you can see is from the large phase 3 studies, that when they tested for cell of origin, those studies were either inconclusive or they weren’t positive. For tafasitamab/lenalidomide, it seems that it works in a proportion of patients that have the germinal center subtype. It may work a little bit differently; it may not work as well.

Then, it seems that both loncastuximab and polatuzumab [Polivy] are agnostic to the subtype. Which, at least in my opinion, is a good thing, because I think the ‘cell of origin’ is a square box that we’re trying to fit our round peg into. I don’t think it explains the whole biology of the disease, and I think, sadly, we’re still stuck with the outside of the cell instead of the inside of the cell. I think that will probably change soon. But thankfully, I think targeting the surface antigens allows us to move away from that thinking, and it works in both scenarios. At least in terms of efficacy for loncastuximab, there’s no real difference between non-germinal and germinal.1 The results were comparable.

References:

1. 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

2. 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