Bispecific Agents Vs Loncastuximab as Third-Line Therapy for R/R DLBCL

Paolo Strati, MD

Assistant Professor

Department of Lymphoma/Myeloma

The University of Texas MD Anderson Cancer Center

Houston, TX

DISCUSSION QUESTIONS

• Now that there are several novel agents available in the relapsed/refractory [R/R] setting for diffuse large B-cell lymphoma [DLBCL], what is the optimal treatment selection and sequencing strategy for patients in the third-line setting?​
• What is your go-to third-line regimen for patients with R/R DLBCL?​
• Please share your thoughts on using bispecifics for the treatment of R/R DLBCL. ​
• Please share how you treat patients with bispecifics for R/R DLBCL; are they referred to an academic center? Will patients be treated in the community setting?

PAOLO STRATI, MD: Have any of you prescribed bispecifics, and how do you plan to collaborate and work with your local providers who prescribe bispecifics to your patients? Or do you have the ability to administer bispecifics at your site?

WILLIAM VELASQUEZ, MD: I referred [a patient]. It was for a third-line therapy and they appear to be getting it at the present time as we speak. So far, so good.

STRATI: How long did it take you from referral to [treatment]?

VELASQUEZ: This was short, about 4 weeks.

STRATI: Is the plan for the patient to come back to you after to 2 cycles?

VELASQUEZ: Let’s hope so. That’s the plan.

STRATI: I used to have a very specific pep talk that I used to give to my patients with R/R DLBCL before bispecific were approved. I used to say if they relapsed after CAR [chimeric antigen receptor] T-cell therapy, there’s no standard treatment with curative potential. The best treatment option should be a clinical trial. Outside of clinical trials, life expectancy used to be less than 6 months. Since epcoritamab-bysp [Epkinly] and glofitamab-gxbm [Columvi] have been approved, I’ve changed [what I tell patients]. It felt uncomfortable at the beginning, and it feels nice now.

My position is that even if lymphoma is coming back after CAR T-cell therapy, there is now a standard-of-care option that we should look into before looking into clinical trials, and that is bispecifics. Of course, the follow-up is still relatively short. Though 1 to 2 years [survival] for post-CAR T-cell relapse is probably reliable to estimate, at least [for those who] relapsed within the subsequent 5 years.^1,2 But the data are good; you see almost a plateau of 30% to 40% at 2 years.

In my opinion, it’s very promising, and I’ll be prescribing a lot of epcoritamab. We don’t have the ability to prescribe glofitamab in my institution, [though] we should be able to soon. It’s very manageable and I’m already working to refer back [to local oncologists]; most of my patients are not from Houston. I’m...making sure to identify providers in the community who will be able to continue treatment from cycle 3. I usually like to observe my patients the first 2 cycles and restage so that I have a better assessment of safety and efficacy before sending them back. But during those 2 cycles, I make sure to identify community oncologists who will be able to provide continuation of treatment locally.

SREENI CHITTOOR, MD: I’m going be the devil’s advocate. I want to see how you would address this. In reality…in spite of [the efficacy] seen with epcoritamab and the time-limited therapy with glofitamab, the issue in community practice is because of the cytokine release syndrome [CRS], even though they call this off the shelf, it’s not off the shelf for me. It’s definitely off the shelf in academic centers or major medical centers. But in community hospitals or for giving in our office, if there is an issue, the community hospitals are not able to address or deal with CRS. Then I’m going to ask myself, what would be the next best third-line therapy before I get around to bispecifics? Then I have to go back to loncastuximab tesirine [Zynlonta]. That’s a good antibody-drug conjugate. The data showed some of those patients had CAR T-cell therapy.³ Let us presume these patients [in the third line] did not have CAR T-cell therapy. I’m just trying to think of the third line. I’m just curious to know, am I being reasonable?

STRATI: Thank you for playing the devil’s advocate role. I’m going to make a few points. First of all, you brought up an important point, which is utilization of third line after CAR T-cell therapy or in somebody who never got CAR T-cell therapy before. When it comes to prescribing loncastuximab, tafasitamab [Monjuvi], or polatuzumab vedotin [Polivy] after CAR T-cell therapy, we have now multiple real-world retrospective studies all clearly showing that none of them work well.

I led the retrospective study for polatuzumab after CAR T-cell therapy. The median progression-free survival [PFS] after CAR T-cell therapy was in the order of weeks.⁴ There have been recently published data in Blood looking into tafasitamab plus lenalidomide [Revlimid] after CAR T-cell therapy saying there was a very short PFS.⁵ Even though for loncastuximab there has been some real-world experience…, we’re talking about a few months.⁶ If we use any of those 3 agents after CAR T-cell therapy, we have to keep in mind…only 30% to 40% of patients respond—10% to 20% have a complete response, and duration of response tends to be short. We should either think to consolidate with a stem cell transplant, either autologous if it hasn’t been given before, or allogeneic…or start to plan for the next line of therapy.

But bispecifics are different…bispecifics, despite previous CAR T-cell therapy exposure, seem to work quite well.^1,2 But, to your point, if CAR T-cell therapy was not given before, I agree. Polatuzumab, loncastuximab, and tafasitamab all may have very durable response. The issue is post CAR T-cell therapy relapse.

The other point that you made is also very important, and I completely agree with you. Any CRS is a problem in any hospital, and particularly in a community hospital. It doesn’t matter if it’s a grade 1 CRS. A grade 1 CRS for you is still a fever in an immunocompromised patient. You need to do workup, come to the hospital for the antibiotics, and you have to have tocilizumab [Actemra] available. It’s a major problem. The silver lining is that if we believe in the clinical trial data, usually there’s not a single case of CRS beyond day 1 of cycle 2, and definitely not beyond cycle 2…. But the real world may show different data. Maybe in the real world where the population will be less selected, [the toxicity may occur] beyond cycle 2. [There is a challenge] deciding when the ideal time is for patients to come back to the community. But if we believe in trial data, at this time, my suggestion is to keep the patient in the academic center for the first 2 cycles, then wait for referral back from cycle 3.

REFERENCES:

1. Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific t-cell-engaging antibody, in relapsed or refractory large b-cell lymphoma: dose expansion in a phase I/II trial. J Clin Oncol. 2023;41(12):2238-2247. doi:10.1200/JCO.22.01725

2. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large b-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913

3. Caimi PF, Ardeshna KM, Reid E, et al. The antiCD19 antibody drug immunoconjugate loncastuximab achieves responses in DLBCL relapsing after antiCD19 CAR-T Cell therapy. Clin Lymphoma Myeloma Leuk. 2022;22(5):e335-e339. doi:10.1016/j.clml.2021.11.005

4. Gouni S, Rosenthal AC, Crombie JL, et al. A multicenter retrospective study of polatuzumab vedotin in patients with large B-cell lymphoma after CAR T-cell therapy. Blood Adv. 2022;6(9):2757-2762. doi:10.1182/bloodadvances.2021006801

5. Qualls DA, Lambert N, Caimi PF, et al. Tafasitamab and lenalidomide in large B cell lymphoma: real-world outcomes in a multicenter retrospective study. Blood. Published online September 22, 2023. doi:10.1182/blood.2023021274

6. Iqbal M, Jagadeesh D, Chavez J, et al. Efficacy of CD19 directed therapies in patients with relapsed or refractory large b-cell lymphoma relapsing after CD19 directed chimeric antigen receptor T-cell therapy. Bone Marrow Transplant. Published online November 16, 2023. doi:10.1038/s41409-023-02148-4