Part 2: Sequencing Loncastuximab and CAR T-Cell Therapy in DLBCL

Ann LaCasce, MD, MMSc (Moderator)

Director, Dana-Farber/Mass General Brigham Fellowship in Hematology/Oncology

Dana-Farber Cancer Institute

Boston, Massachusetts

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 (R/R DLBCL)?
• What do you view as the pros and cons of loncastuximab tesirine as compared with other alternatives such as tafasitamab (Monjuvi) plus lenalidomide (Revlimid), polatuzumab (Polivy) plus bendamustine (Bendeka) and rituximab (Rituxan), or selinexor (Xpovio)?
• Would you use it in the second line for patients who decline transplant?
• For patients who may be eligible for chimeric antigen receptor (CAR) T-cell therapy?
• For patients who you consider not to be eligible for CAR T-cell therapy?

ANN S. LACASCE, MD, MMSC: Any thoughts on how you would sequence polatuzumab, tafasitamab/lenalidomide, loncastuximab, and CAR T-cell therapy? Or any thoughts about using these drugs?

JOSEPH ANTIN, MD: I think it’s interesting that the definitive trial is going to be an anti-CD19 plus an anti-CD20 monoclonal antibody. That’s not something that we usually do, Other than making it symmetrical with the chemotherapy arm, it seems a little [unusual].

LACASCE: Well, it’s an antibody-drug conjugate, so I think they’re considering it to be more of a chemotherapy drug than an immunotherapy drug. I agree, I think rituximab, gemcitabine, and oxaliplatin [R-GemOx] is now the de facto comparator for a number of these relapsed/refractory settings, and it’s relatively active, but I think the question we really want to see is how do you compare these options to each other. They’re very different, yes.

ANTIN: I agree with you. And why wouldn’t they use it with lenalidomide, for instance? Although it is somewhat myelotoxic. That would be another semi-rational combination, at least.

LACASCE: Right.

HEATHER BENJAMIN, MD: This seems to offer the patients a lot more opportunity in terms of potentially going to autologous stem cell transplant [ASCT] or CAR T cell afterwards, as opposed to the tafasitamab/lenalidomide combination, where it seemed like it would be difficult to go on to receive ASCT or CAR T cell. It seems like this may open doors.

LACASCE: Yes, I think that’s true, and maybe if you had a patient who had a poor performance status, and for whatever reason you thought they were not transplant-eligible; and then, by treating their disease, they looked better, and then they became eligible. I think we need more experience with lisocabtagene maraleucel CAR T-cell therapy [Breyanzi; liso-cel] to see, is it really a tolerable product for our elderly, infirm patients. That will probably have a big impact on how things are sequenced, because we are testing that in patients we would not give axicabtagene ciloleucel CAR T-cell therapy [Yescarta; axi-cel] to. Having a few patients who went on to CAR T-cell therapy and responded isn’t enough data yet to make physicians feel comfortable about giving [loncastuximab] before CAR T-cell therapy. And I think people are using polatuzumab without bendamustine more commonly, so they do not have to worry about that issue.

ANTIN: Yes, since there is a proportion of people who relapse from CAR T-cell therapy because the CD19 has been lost from the cell surface, you may wonder whether this is a logical approach if you’re planning to move on to CAR T-cell therapy, or any of the CD19 antibodies.

LACASCE: Yes, we worry about that, and I think there’s been a lot of opinions about whether that’s a major mechanism of failure in CAR T-cell therapy. I don’t know those data terribly well, but I’m sure that there is some loss of CD19.

ANTIN: It’s not all patients, but there certainly a measurable proportion of patients who either have the mutated CD19, or have downregulated CD19, and then relapse in that context.

ROBERT KOCH, MD: So, I’m curious, with respect to the non-transplant eligible patient who has failed first-line therapy, you will then look at gemcitabine/oxaliplatin [GemOx] versus polatuzumab? What are the discriminating or important clinical and laboratory factors that would help you decide which of the 2 would be the most appropriate therapy?

LACASCE: If I had a patient that I thought was not going to be eligible for CAR T-cell therapy, or for high-dose chemotherapy, I would probably want to give them whatever I thought had the most durable remission, or longest progression-free survival [PFS] in the second line. So, I would tend to give that patient polatuzumab/bendamustine/rituximab and give the whole combination.

We use R-GemOx when we have a patient who has relapsed, and we want to get them to CAR T-cell therapy or a primary refractory therapy. This may be an even better situation, where the patient is primary refractory. We don’t have a lot of faith that they’re going to respond to salvage chemotherapy to get to an ASCT, so we want to give them something gentle, to make them eligible for CAR T-cell therapy. So, that’s where we use GemOx, because people tolerate it quite well, with the exception of the neuropathy. Then we get them to CAR T-cell therapy.

I think the 3 studies [TRANSFORM (NCT03575351); ZUMA-12 (NCT03761056); BELINDA (NCT03570892)] that looked at the group of primary refractory, or early relapses after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or frontline therapy with the 3 CAR T-cell products [liso-cel, axi-cel, and tisagenlecleucel (Kymriah; tisa-cel)] have been presented at the American Society of Hematology 2021 Annual Meeting and Exposition, and 2 of them [TRANSFORM and ZUMA-12] have positive results; 1 [BELINDA] was apparently negative.^1-3

So, it will be interesting to see if those data may change our practice patterns. Hopefully it will be a moot point because the POLARIX [NCT03274492] study of polatuzumab/R-CHOP versus R-CHOP is a positive study with an improvement in PFS.⁴ Hopefully, that will become our front line therapy. It’s going to be pretty exciting since it is the first time we’ve had any change in up-front therapy for DLBCL since 2002. So that [will mean] we’ll have a lot fewer relapses, but we won’t use polatuzumab later.

KOCH: Is that study in first-line therapy for patients across the board, patients with germinal center B-cell, activated B-cell, double-hit, triple-hit, all patients?

LACASCE: I believe you could not have an International Prognostic Index score of [0 or 1] in order to be enrolled on the study. So, whether that will apply to our relatively healthy patients with localized disease, I’m not sure. I believe it was open to patients with double- and triple-hit disease. I think the question will be, were those patients referred to that study, because in the control arm they would have gotten R-CHOP. So, I suspect there probably weren’t a lot.

But there’s been a lot of discussion lately about how much worse double-hit disease is, and the thinking is that the MYC/BCL6-positive are not the same as the MYC/BCL2-positive; and, that the rearrangement partner for MYC/BCL2 is very important. And, if it’s a non-immunoglobulin partner, that those patients probably do not have the really bad prognosis, such as double-hit disease with circulating disease and extranodal disease around the body.

_References:

_{1. Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen reception (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pts) with relapsed or refractory (R/R) large B-cell lymphoma: results from the randomized phase 3 TRANSFORM study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 91. https://bit.ly/3rZa5Ar}

_{2. Neelapu S, Dickinson M, Munoz J, et al. Primary analysis of zuma-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients with high-risk large b-cell lymphoma (LBCL). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 739. https://bit.ly/3AE61cN}

_{3. Bishop MR, Dickinson M, Purtill D, et al. Tisagenlecleucel vs standard of care as second-line therapy of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma: Analysis of the phase 3 BELINDA study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract LBA-6. https://bit.ly/3o9I0VL}

_{4. Tilly H, Morschhauser F, Sehn LH, et al. The POLARIX Study: polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy in patients with previously untreated diffuse large B-cell lymphoma. Presented at: 63rd Annual American Society of Hematology Meeting and Exposition. LBA-1. December 14, 2021. https://bit.ly/34hikzm}