Bispecific T-Cell Engagers Emerge as Later-Line Therapies for DLBCL

Mehdi H. Hamadani, MD

Professor of Internal Medicine

Division of Hematology & Oncology

Medical College of Wisconsin

Milwaukee, WI

TARGETED ONCOLOGY: What bispecific T-cell engagers are available for use in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL)?

MEDHI H. HAMADANI, MD: There are 2 bispecific agents recently approved in DLBCL. Epcoritamab-bysp [Epkinly] received approval in May [2023] and glofitamab-gxbm [Columvi] received approval [in June].^1,2 Epcoritamab is a CD20-binding bispecific agent. Simply put, epcoritamab binds to CD20 on the lymphoma cells and on the other end, it binds to CD3 on the T cells and brings the cytotoxic T cell close to the cancer cell to exert cell-mediated cytotoxicity. Epcoritamab binds to CD20 at a portion that is distinct from where rituximab [Rituxan] or obinutuzumab [Gazyva] binds; it's a distinct binding site.

These drugs are remarkably active. The loncastuximab tesirine [Zynlonta], tafasitamab [Monjuvi], or polatuzumab vedotin [Polivy] trials were run during a time period when CAR [chimeric antigen receptor] T-cell therapy failure was a problem. [The advantage of bispecific drugs is that these trials] are very recent.

Epcoritamab received accelerated FDA approval based on the EPCORE NHL-1 study [NCT03625037]. Epcoritamab is very feasible to give in the outpatient setting. It's a subcutaneous infusion. In our program [at Froedtert Hospital], we give the first 2 doses as outpatient, [and] the third is the full dose because it has step-up dosing.³ The third dose we give in the hospital, and from that point onward, if the patient doesn't develop CRS [cytokine release syndrome] or immune effector cell-associated neurotoxicity syndrome, everything is outpatient from that point onwards. It's definitely feasible in community settings, if you develop SOPs [standard operating procedures] for that, but the dosing schedule is cumbersome. It's weekly dosing long term. You come weekly for 3 months, then you come every other week for 6 more months, and then monthly; it gets easier after that.

What is the efficacy and safety of epcoritamab in heavily pretreated patients with DLBCL?

The rate of severe CRS is low, less than 3%.⁴ I would acknowledge that even grade 1 or grade 2 CRS is [a concern]. You need to have SOPs in place to manage it. You need to have access to tocilizumab [Actemra] day-in, day-out and you need to have expertise to administer it when it is needed.

But if you have that expertise, look at the activity profile of epcoritamab.… Whether you give it in the third line, fourth line, or fifth line, the [overall] response rates were above 60% and CR [complete response] rates are consistent. These are studies that had a lot of patients with CAR T cell failure [n = 61].⁴ It's [not the same as patients receiving] loncastuximab, [where there were] 13 patients with prior CAR T-cell therapy or tafasitamab for 20 patients with prior CAR T cells.^5,6 There are almost 100 patients, [including 61 with] prior CAR, and the drug works in that setting. The CR rates are about 40% [overall]. The CAR T-cell­ refractory patients maybe do less well than [all] CAR T-cell exposed patients, but this is a very relevant player in the CAR T-cell failure setting. A lot of CAR T cell failure management is going to happen in the community setting. If your choice of off-the-shelf tafasitamab or loncastuximab didn't work, then maybe epcoritamab would be an option.

What data support the use of glofitamab in this setting?

[Glofitamab] is a similar but very different drug, the newest approval. It’s a drug [I] have a lot of institutional experience with. Unlike epcoritamab, glofitamab is intravenous. It binds to 2 CD20 molecules for 1 CD3 molecule, so biologically it's very different. The benefit of [glofitamab] is a benefit shared with loncastuximab. It's a fixed-duration therapy; you treat for a year and then you stop the treatment.

This trial [NP30179; NCT03075696] also had 150 patients with DLBCL or similar histologies and a good chunk of patients with prior CAR T-cell therapy; 50 patients…so we're not talking about small sample size anymore.⁷ If you look at the activity, the [overall] response rates were above 50%, and these are across all dose levels. It was a phase 1 dose escalation trial. The response rates were much better at approved phase 2 doses. The responses are durable. These are patients who are [treated in the] third line and beyond. Glofitamab is a fixed duration therapy; these are patients with CAR T cell failure or are relapsed/refractory patients and you're stopping treatment on them. One question that people asked was: How do these patients actually do?

At the last American Society of Hematology meeting, Martin Hutchings, MD, PhD, had a very elegant analysis. They did a landmark analysis and looked at patients who stopped glofitamab therapy at a year and were in CR. Are the CRs durable? That's an important question to ask. Do bispecific [T-cell engagers] have any hope of curing these patients? It's too early to say, but...if you follow these patients—a lot of these patients didn't have adequate follow up—but these responses are sticking around. One year after stopping glofitamab, more than 70% of the patients were still in CR.⁸ Are these patients theoretically cured? No, but we are starting to ask this very provocative question: Is CAR T-cell therapy the only curative therapy for relapsed/refractory patients? Maybe not. Bispecifics may become huge players in that setting.

_References:

_{1. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. News release. FDA. May 19, 2023. Accessed September 18, 2023. https://tinyurl.com/2s47xp26}

_{2. FDA grants accelerated approval to glofitamab-gxbm for selected relapsed or refractory large B-cell lymphomas. News release. FDA. June 15, 2023. Accessed September 18, 2023. https://tinyurl.com/5a3xdxms}

_{3. Epkinly. Prescribing information. Genmab A/S, 2023. Accessed September 18, 2023. https://tinyurl.com/4n6bv3cd}

_{4. Thieblemont C, Phillips T, Ghesquieres H, et al. Primary results of subcutaneous epcoritamab dose expansion in patients with relapsed or refractory large b-cell lymphoma: a phase 2 study. Presented at 27th Congress of the European Hematology Association; June 9-12, 2022; Vienna, Austria. LBA2364.}

_{5. 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}

_{6. Qualls D, Buege MJ, Dao P, et al. Tafasitamab and lenalidomide in relapsed/refractory large B cell lymphoma (R/R LBCL): Real world outcomes in a multicenter retrospective study. Blood. 2022;140(suppl_1):787-789. doi:10.1182/blood-2022-167620}

_{7. 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}

_{8. Hutchings M, Carlo-Stella C, Morschhauser F, et al. Relapse is uncommon in patients with large B-cell lymphoma who are in complete remission at the end of fixed-course glofitamab treatment. Blood. 2022;140(suppl_1): doi:10.1182/blood-2022-157554}