Part 3: Third-Line Use of Loncastuximab for Relapsed/Refractory DLBCL

Beth A. Christian, MD (Moderator)

Associate Professor, Division of Hematology

Director, Hematology and Medical Oncology Fellowship Program

The James Cancer Hospital - The Ohio State University Comprehensive Cancer Center

Columbus, OH

DISCUSSION QUESTIONS

• Under what circumstances would you be most likely to use loncastuximab tesirine (Zynlonta) as third-line therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL)?
• What do you view as the pros and cons of loncastuximab as compared with other alternatives such as tafasitamab (Monjuvi)/lenalidomide (Revlimid), polatuzumab (Polivy)/bendamustine (Treanda)/rituximab (Rixutin), and selinexor (Xpovio)?
• Do you foresee any barriers to using loncastuximab?
• If loncastuximab were covered by insurance, would you use it in the second line for patients who decline stem cell transplant?
• Would you use it for patients who may be eligible for chimeric antigen receptor (CAR) T-cell therapy?
• Would you use it for patients who you consider not to be eligible for CAR T-cell therapy?
• Consider the 46% response rate to CAR T-cell therapy in the 15 patients who received CAR T-cell therapy after loncastuximab.¹ How does that factor into your opinions on sequencing therapeutics?

BETH A. CHRISTIAN, MD: For the participants that have used loncastuximab, what’s your experience like?

YAZAN SAMHOURI, MD: We’ve used loncastuximab in 2 patients who had rapidly progressing disease. This was in the inpatient setting, and we were desperate to gain some control over the disease [to take them to CAR T-cell therapy after failure of other bridging therapies]. But we were unlucky in both patients; 1 patient received 2 cycles [of loncastuximab], and the other patient received 1 cycle before passing away.

CHRISTIAN: It sounds like the patients were on treatment for a relatively short time. Did you encounter any issues with edema or myeloid suppression?

SAMHAHOURI: They experienced myeloid suppression for sure. As for edema, they had already been in the hospital receiving a lot of fluids and had the usual iatrogenic fluid overload. I don’t remember there being any pleural effusion, or anything outstanding that [we could attribute to] loncastuximab.

NEENOS ALNOOR, MD: Did the patients die because of cancer progression or adverse events of the drug?

SAMHOURI: They died from the disease, which was just very refractory to everything, and we couldn’t really control it. It was one of those DLBCLs or high-grade B-cell lymphomas.

CHRISTIAN: In what circumstances would you be most likely to use loncastuximab as third-line therapy for a patient with R/R DLBCL?

ANEEL CHOWDHARY, MD: I haven’t used most of these therapies, and I think the reason for that is that I use R-GemOx [rituximab plus gemcitabine plus oxaliplatin] in most of my patients [who develop refractory disease] after first-line therapy. If the patient has an activated B-cell lymphoma then I am more likely to use zanubrutinib [Brukinsa] or lenalidomide. But the majority of my patients have had germinal cell [GC] disease.

In these patients, I generally use [a combination with] rituximab [Rituxan]. I think a platinum drug is important here. That’s when I go for a second-line [therapy] if the patient is not transplant-eligible. By then I’ve referred the patient for CAR T-cell therapy and they go on to our lymphoma team. But I know that I’m going to be getting some of these patients back. And for various reasons, some of them will go on to third-line or post-CAR T-cell therapy. There are all these [late-line] regimens, and we’ve seen some of the data. I think the polatuzumab vedotin, bendamustine, rituximab is something I lean towards, but I don’t completely grasp where and when to sequence these late-line treatments.

In your decision-making for sequencing, where are your inflection points in terms of using tafasitamab versus a polatuzumab-based regimen? How are you sequencing these in the late-line setting, [both in patients who have and have not received CAR T-cell therapy]?

CHRISTIAN: Some of the things I take into consideration are [the R/R DLBCL setting is] evolving and changing, and it’s really challenging right now to manage this condition.

For my patients who have undergone prior CAR T-cell therapy; [these are usually] younger, fitter patients who weren’t eligible for autologous stem cell transplant or who relapsed after autologous stem cell transplant and received CAR T-cell therapy. One challenge that I encounter with these patients is that they often have prolonged cytopenia, whether that’s from transplant or from CAR T-cell therapy.

In my own practice, I’ve found that [cytopenia] can be somewhat of a barrier to using rituximab plus polatuzumab vedotin. I have had some patients where I started that therapy and then ultimately, I ended up converting it to polatuzumab alone, and I’ve seen some responses there. But I think low blood cell counts can be a challenge with that regimen.

One of the things that I take into account with tafasitamab/lenalidomide is the cell of origin. So, although the data in the phase 2 L-MIND study [NCT02399085] included patients with both non-GC and GC DLBCL, the responses [to lenalidomide] favored non-GC type disease.² That is something that plays into my decision-making. I also find that the full dose of lenalidomide with tafasitamab/lenalidomide is not necessarily easy on blood counts. That’s something that I also consider when I am making choices about these treatments. And then finally, I think when it comes to loncastuximab, [one has to consider] the tolerability of it, in terms of the dosing schedule, and having to talk with patients and counsel them about the edema [associated with this drug]. There can also be some issues related to myelosuppression, but the dosing schedule does tend to be a little bit kinder [for loncastuximab] than for tafasitamab/lenalidomide.

I don’t think there really is an optimal sequence [for late-line therapies for R/R DLBCL], but [when I make sequencing decisions] I try to take into account patient factors, [such as blood] counts, peripheral neuropathy, prior lines of therapy, [and] cell of origin.

TSUYNOSHI INOSHITA, MD: For the second line patients who are not transplant candidates, how do you select between, R-GemOx versus BR-pola [polatuzumab vedotin plus bendamustine plus rituximab] versus tafasitamab/lenalidomide.

CHRISTIAN: If I have a patient [with non-GC DLBCL] who is elderly and unfit, and I don’t think they’re eligible for transplant or CAR T-cell therapy, that is where tafasitamab/lenalidomide was approved in and has showed good results with sustained responses in some patients.

Patients with high-grade large B-cell lymphoma were excluded from L-MIND of tafasitamab/lenalidomide.² But these patients were included in other studies, and so that is something I might take into consideration, as well as how rapidly I need a response, or how sick the patient is.

In terms of myeloid suppression, at least in my experience, the BR-pola can be a little bit of a tougher regimen if the patient has baseline cytopenias or is elderly or unfit, and I’m concerned about tolerance.

_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}