Jacobson Discusses Second and Third-Line Options for DLBCL

Caron A. Jacobson, MD, MMSc (Moderator)

Medical Director, Immune Effector Cell Therapy Program

Senior Physician

Dana-Farber Cancer Institute

Associate Professor of Medicine,

Harvard Medical School

Boston, MA

EVENT REGION New England

PARTICIPANT LIST Paul S. Unger, MD | Barrett Newsome, DO | Robert K. Koch, MD | Ahmed J. Nadeem, MD | Prabhsimranjot Singh, MD

DISCUSSION QUESTION

• How do you assess and define noncandidates for chimeric antigen receptor (CAR) T-cell therapy in your practice?

JACOBSON: Other than patient preference, is there a patient for whom CAR T cells are not appropriate from a clinical and biologic standpoint in your practice? Do you refer patients even if you think they’re borderline and let the CAR T-cell center decide?

UNGER: We tend to try to refer. Clearly, if someone has a very poor performance status or substantial comorbidities in terms of some other organ dysfunction, cardiac, kidney, something pulmonary, that might precipitate a phone call to the center and saying I’m assuming this person’s ineligible. I don’t want to waste their time or the patient’s travel time…. I don’t feel like we have enough of these patients with relapsed disease and [we don’t] use all the treatments enough to get a sense of who should get what or which might be best, so I tend to use my colleagues to whom I refer to help sort that out.

NEWSOME: I agree with Dr Unger. If there’s any question, I send to the CAR T physicians, and they help me determine. I had a patient who was 92 years old who had a cardiomyopathy and underlying renal problems, so I didn’t even consider CAR T-cell therapy. He got tafasitamab [Monjuvi] plus lenalidomide [Revlimid] and did great for over a year and died from something unrelated. He relapsed [after first-line therapy;] he didn’t get anthracycline because of his cardiomyopathy, but he relapsed within 8 months of his [prior] treatment and did remarkably well.

JACOBSON: If you did have a patient who refused referral for CAR T, at least in your current practice, they might also refuse referral for bispecifics. That leaves you with some of the other regimens, like tafasitamab/lenalidomide.

KOCH: There are some patients I’ve seen who have had a difficult time tolerating initial chemotherapy, and when you present them with an option that consists of additional chemotherapy, they’re very resistant. There are those patients, especially if they’re older and have a lot of comorbidities, who are just done.

JACOBSON: When we’re using polatuzumab out on the front line, that takes the polatuzumab-based regimens out of the second line. If we’re not doing CAR T cells because of financial or logistical constraints, that makes the bispecifics difficult, at least…in the short term, unless your practices start doing the ramp-up dosing, and that leaves us with things like tafasitamab/lenalidomide and/or R-GDP [rituximab (Rituxan), gemcitabine, dexamethasone, and carboplatin/cisplatin] or R-GemOx [rituximab, gemcitabine, and oxaliplatin] or some other chemotherapy.

NADEEM: One of the regimens that is very tolerable is pola-R [polatuzumab plus rituximab] and pola-BR [polatuzumab, bendamustine, and rituximab]. It would probably be a very reasonable thing for these patients with a moderate, slightly lower dose of bendamustine. I think they can have a good survival with that.

JACOBSON: You wouldn’t offer that to someone who had polatuzumab in their first line of therapy. But if it was for someone who got R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), and prednisone] or R-EPOCH [rituximab, etoposide phosphate, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride], that would be a reasonable approach.

NADEEM: I used pola-R when it was not even approved, [when] there were some phase 2 studies. The patient had progression on R-CHOP and was able to tolerate pola-R…lived for 3 years, and did not die from lymphoma.

DISCUSSION QUESTION

• In which scenarios might you prefer bispecific antibodies over traditional salvage chemotherapy?

JACOBSON: I think we’re talking about the glofitamab [Columvi]/GemOx and the polatuzumab/mosunetuzumab [Lunsumio] regimens. Are there situations where you can imagine referring patients? You’re not referring them for CAR T, but you’re going to refer them for 1 of these 2 regimens.

UNGER: Because both [bispecifics and CAR T-cell therapy are referrals], we’re sending the patient to the tertiary center of excellence in lymphoma and asking, “What do you recommend?” Patients come in and ask questions about one treatment vs another, but there are so many fine points to selecting one route vs another, notwithstanding the patient’s preference and inability to stay somewhere for a period…and so on.

JACOBSON: Recently, I was referred a 65-year-old man with cerebral palsy who had a reasonable quality of life and survival, despite his cerebral palsy. But in this setting, we have glofitamab/GemOx, where the progression-free survival curve plateaus in the 35% to 40% range.¹ Maybe we should give that a chance before we go straight to CAR T-cell therapy because assessing and managing neurologic toxicity in this patient would have been a challenge. We decided to go that route rather than go CAR T. That might be a type of patient where you have a motivated caregiver, and the patient’s willing to travel for it, but the toxicity of CAR makes it challenging for that patient.

KOCH: Have you encountered patients who were not CAR T eligible initially and were treated with bispecifics and then became CAR T eligible? You have to think about that, because you don’t want to use anti-CD19 drugs in a patient who could become CAR T eligible after second-line treatment.

JACOBSON: It’s happening more recently because these 2 regimens were added in the second line. Now that we have these available, some of my colleagues have given glofitamab/GemOx and got the patient to be much more medically fit. Patients who were sick from their disease became candidates for CAR T-cell therapy.

We’ll have to see how those patients do, because there is a theoretical concern that the bispecifics can lead to some T-cell exhaustion, and then you’re collecting tired T cells to make your CAR T cells. My feeling is that a drug like tafasitamab, which binds to the same portion of the CD19 molecule as the CAR T cells do, [doesn’t] make patients be CD19 negative.

For the half-life of tafasitamab, the CD19 is occupied. The CAR T cells will ignore it because they don’t see the target, so you need a washout period for tafasitamab before you can take someone to CAR T. Whether that’s 1 month or 3 months is not clear. For loncastuximab tesirine [Zynlonta], that doesn’t seem to happen. You could potentially use that as a bridge to get someone to CAR T as well, but it’s a data-free zone.

DISCUSSION QUESTIONS

• How does a patient’s response to and duration of first-line therapy influence your selection of second-line treatment?
• Please discuss how you adapt your approach based on primary refractory disease vs early vs late relapse patterns.

JACOBSON: Do you differentiate how you treat someone with primary refractory disease vs someone who relapses at 8 months?

KOCH: The guidelines that I tend to follow put those 2 types of patients in the same category.

NEWSOME: Sometimes it matters if someone got pola-R-CHP, and if it’s been 12 months since they’ve seen it, I might be more likely to reach back for that, especially if it’s bridging therapy. I’m going to rely on the tertiary center to guide me as to what they want us to use for bridging therapy. But if it’s been a year and they’re not a CAR T candidate—and when I use polatuzumab, I usually use pola-R [rather than] pola-BR—but in someone who hasn’t had polatuzumab in the up-front setting, then I usually just use pola-R. So it does matter what they got up front, especially with polatuzumab.

JACOBSON: If we’ve treated someone in the second line either with CAR T or with one of the bispecific regimens, or with pola-BR or tafasitamab/lenalidomide, and they’re relapsing, we talked about using some of the CD19-targeting therapies for someone we may want to eventually get to CD19 CAR T, but you also need to manage the disease in front of you.

One of the differences in my practice between the primary refractory disease and relapses at 8 months is that the patients who are primary refractory have very limited time to wait for some of these therapies. It’s harder to get them through that 1 or 2 months of getting their T cells collected and getting them to treatment than it is for someone who relapses at 8 months. Although you might want to avoid bendamustine ahead of collection for CAR T and you might want to avoid tafasitamab immediately ahead of CAR T, maybe the same is true for bispecifics. We all know that you have to treat the patient in front of you.

SINGH: Early relapse tells us that something is not OK. They have high risk, and if they are capable of getting the CAR T, I try to push to at least have an evaluation. They usually have a discussion with the lymphoma team before [we decide] what the bridge therapy could be.

DISCUSSION QUESTIONS

• Consider the LOTIS-2 trial (NCT03589469) data on loncastuximab for your patients with DLBCL:
  • Does the data address an unmet treatment need?

JACOBSON: Do you feel [loncastuximab] can meet an unmet need in relapsed/refractory DLBCL based on the data, and is there a patient population that you would prefer it for over some of the other drug options that we’ve talked about?

KOCH: This drug is an antibody-drug conjugate [ADC] like polatuzumab.

JACOBSON: Yes, but with a different chemotherapy payload.

KOCH: What’s to make us believe that this drug is superior to polatuzumab, which is used in first-line therapy? It has some benefit in third-line therapy with relatively limited data.

JACOBSON: A couple of things make it different from pola-tuzumab. Just because it’s an ADC doesn’t mean that it works the same way as another ADC or that they have similar mechanisms of resistance. We know CD19 is a more important target on the surface of large cell lymphoma than CD79B. That’s why CAR T cells were developed against CD19. Maybe there’s more target binding and therefore more endocytosis. The other is the mechanism of action. Polatuzumab has MMAE, which is a microtubule destabilizer. This has a PBD dimer, which works by a different mechanism. If a cancer cell has developed mechanisms of resistance to microtubule destabilizers, then this could be an effective drug. They don’t necessarily have to have the same mechanisms of resistance.

KOCH: Are there data that show that this drug works in patients whose disease is polatuzumab resistant?

JACOBSON: I’m not aware of anything specifically to say that. They could probably go back and look at how patients were treated in this study. I’m sure a number of them had received polatuzumab as first-, second-, or even third-line therapy because most of the patients were being treated in the fourth line in this study. But I don’t know the answer to that question specifically.

UNGER: I think it’s a little immature, and I would look for more data. But if I’m out of aces and this is the only thing available, I could see using it.

JACOBSON: Because of the favorable safety profile and the fact that the toxicity doesn’t overlap with other drugs we use, our thinking is to try to combine this drug with other drugs in large cell lymphoma, and even maybe move it up into an earlier line of therapy in those combinations. We’ve seen some data for loncastuximab in combination with rituximab that look very intriguing [LOTIS-5; NCT04384484].² There are going to be…some data for loncastuximab in combination with glofitamab as well [LOTIS-7; NCT04970901].

KOCH: It looks like it’s going to be interesting going forward.

NEWSOME: I think it has a role, especially if we’re using polatuzumab up front and patients are refractory to it, if they’re not CAR T or bispecific candidates, and then you try tafasitamab/lenalidomide, and they have progression. Or it’s something I would reach for as opposed to chemotherapy as a bridge. I’m willing to use it; I just haven’t been in a situation where it was indicated. I would consider it, especially in patients who have been through most of the first- and second-line and sometimes third-line therapy.

JACOBSON: Is anyone intrigued by the signal in double-hit lymphomas?³ Would that make you pick this over some of the other regimens for a relapsed double-hit lymphoma in the third or fourth line?

NADEEM: The number is too small to make a judgment that it’s going to work in double hit or triple hit, so I’m not sure.

KOCH: What is the argument to use this drug [instead] of a bispecific in third-line therapy?

JACOBSON: The argument there is for the patient who refuses to be referred to another center for the step-up dosing. There are some patients who may not be able to do that…. Can they go into the hospital for 3 days for the first dose? Can they go back and forth as frequently as they need to? What if they have to get readmitted for CRS [cytokine release syndrome] with dose 2 or dose 3?

The other thing is that there are some data to say in the real world that bispecifics for patients who have had at least a 6-month response to CAR T work very well, but bispecifics for patients who are primary refractory to CAR T or who have relapse within the first 6 months don’t work as well, and that may be because of similar mechanisms of resistance.⁴ Maybe you want to reach for it in those patients with early relapse or [who] are primary refractory to CAR T. You may want to reach for a different regimen than a bispecific.

NADEEM: When you do CAR T-cell therapy, and they don’t achieve a complete response, do they go to the third line right away based on partial responses or [wait for] the disease progression?

JACOBSON: With CAR T cells,…if you do a scan at 1 month and you see a partial response, about 40% of those partial responses will become a complete response by 3 months. Usually, I repeat a scan. There are a number of studies now trying to look at consolidation regimens for those patients to try to increase that 40% to 80%. Maybe it’s adding bispecifics or another drug. The problem is that you don’t want to overtreat the 40% of patients who are bound to have a complete response and give them some other toxicities. Those consolidation regimens have to be safe and well tolerated. If it’s a partial response, you should watch that patient but rescan within 6 to 8 weeks.

_{DISCLOSURES: Jacobson previously reported consultancy for AbbVie, ADC Therapeutics, Aleta Biotherapeutics, Appia Bio, AstraZeneca, Autolus, Bristol Myers Squibb/Celgene, Caribou Biosciences, Galapagos, Genmab, Genentech, Janssen, Kite/Gilead, Kyverna, Miltenyi, Novartis, Sana Biotechnology, and Synthekine; and research funding from Kite/Gilead. Singh previously reported employment with AstraZeneca and Rhythm Pharmaceuticals; and a consulting/advisory role with Cardinal Health.}

_REFERENCES

_{1. Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial. Lancet. 2024;404(10466):1940-1954. doi:10.1016/S0140-6736(24)01774-4}

_{2. Kwiatek M, Grosicki S, López Jiménez J, et al. Updated results of the safety run-in of the phase 3 LOTIS-5 trial: novel combination of loncastuximab tesirine with rituximab (Lonca-R) versus immunochemotherapy in patients with R/R DLBCL. Clin Lymphoma Myeloma Leuk. 2023;23(suppl 1):S439-S440. doi:10.1016/S2152-2650(23)01332-0}

_{3. Caimi PF, Ai WZ, Alderuccio JP, et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study. Haematologica. 2024;109(4):1184-1193. doi:10.3324/haematol.2023.283459}

_{4. Bansal R, De Menezes Silva Corraes A, Brunaldi L, et al. Real world outcome of patients with multiple myeloma who received bispecific antibodies after CAR-T therapy. J Clin Oncol. 2024;42(suppl 16):7520. doi:10.1200/JCO.2024.42.16_suppl.7520}