Elucidating Bispecific Impact in Diffuse Large B-Cell Lymphoma

In a conversation with CancerNetwork®, Jeff P. Sharman, MD, medical director of hematology research for US Oncology and Sarah Cannon Research Institute (SCRI), discussed the state of bispecific use among patients with diffuse large B-cell lymphoma (DLBCL). First, he highlighted relevant clinical trials evaluating bispecific agents in these large cell lymphoma groups.

The first trial, the phase 3 STARGLO trial (NCT04408638), he explained was limited in its US-based participation, which was instrumental in a negative ODAC meeting at which time the registration intent was voted againstat a vote of 8-to-1 for glofitamab-gxbm (Columvi).^1,2 The second, the phase 3 EPCORE DLBCL-1 (NCT04628494) assessing epcoritamab-bysp (Epkinly), is awaiting an efficacy readout despite a news release attesting to its positive data.^3,4 The final trial, the phase 3 SUNMO trial (NCT05171647) evaluated mosunetuzumab-axgb (Lunsumio) plus polatuzumab vedotin-piiq (Polivy) in the relapsed/refractory large B-cell lymphoma against rituximab (Rituxan), gemcitabine, and oxaliplatin (R-GemOx), a trial he explained is open-ended regarding whether the data will translate to approval.⁵

Next, he highlighted key clinical characteristics predictive of response with bispecifics, as well as his thoughts on a pathway to integration between these agents and antibody drug conjugates (ADC), specifically those with topoisomerase 1 payloads. Furthermore, he outlined strategies clinicians can employ to mitigate or manage treatment-emergent adverse effects (AEs), as well as challenges associated with universal administration of bispecifics in the outpatient at the onset of treatment. Finally, he addressed an inadequate implementation of immunotherapy options in this patient population, suggesting that oncology teams owe it to patients to offer these therapies so they don’t have to seek them out independently.

Which trials or ongoing research assessing bispecifics across DLBCL populations, particularly in the relapsed/refractory setting, do you believe have the potential to transform practice?

This is an interesting space, because there’s a handful of agents that are FDA approved, but many of them did so on the basis of single-arm studies, and they require their confirmation studies. In terms of agents most likely to go into relapsed large cell lymphoma, you have epcoritamab from both AbbVie and Genmab. Then you have 2 entrants with mosunetuzumab from Genentech and glofitamab from Roche. All of them have potential registration studies in relapsed large cell lymphoma.

The first one that we’ve seen data on was with glofitamab, and interestingly, there were differences in subgroups, and there was a relative under-participation of patients in the US. Glofitamab underwent an ODAC meeting at which time the registration intent was voted against that. The recommendation was not to approve glofitamab based on [the phase 3 STARGLO] study. Then epcoritamab is going to be, most likely, the next one that will be considered, and that’s based upon a study in which it’s compared with gemcitabine and oxaliplatin with rituximab. We haven’t seen the data on that yet, at least publicly, so we don’t know how the results of that are going to look, although I believe there’s been a press release on that, and it’s been reported as a positive study, so we’ll need to see the data.

Finally, mosunetuzumab in combination with polatuzumab, has also been [assessed] in relapsed large cell lymphoma. There’s another one where there will be questions as to whether it can be approved based upon the data, but those are the ones most likely to have impact in relapsed/refractory, large cell lymphoma.

What biomarkers or clinical characteristics may be predictive of response with bispecifics in this patient group?

I don’t know that we’ve seen a biomarker that is uniformly predictive of response. In fact, the response rates are quite good with these agents. The issue, to some degree, is one of sequencing. For patients who are eligible for CAR T-cell therapy, they frequently receive CAR T cells prior to bispecifics, and if a patient experiences treatment failure on a CAR T cell, then the likelihood of response for a bispecific is also seemingly lower. There’s going to be a lot of interest in defining whose patient’s immune system still has the ability to leverage the bispecific antibodies. I don’t know that there’s necessarily a blood test or even a tissue marker yet that’s been uniformly accepted as a predictive marker, but more the treatment environment.

The other thing is, of course, we have frontline studies where these agents are combined with CHOP-based chemotherapy, and I’m [quite] excited to see how those studies mature with time, because there’s, in my estimation, a high probability that those are going to be positive studies.

Do you see a clinical pathway for the next generation of ADCs—specifically those with topoisomerase 1 payloads—to integrate with bispecifics, or do you expect bispecifics to eventually render the ADC class redundant in the frontline DLBCL setting?

Antibody drug conjugates, particularly with polatuzumab, have impacted the field, although maybe not as much as had been hoped. We’ve seen how topoisomerase inhibitors have impacted many solid tumor malignancies, HER2 being a notable one. It certainly seems like there’s room for a topoisomerase inhibitor to be administered by way of antibody drug conjugate in lymphoma. However, at least at this point, there’s not a whole lot of assets that are far along in clinical development.

Given an emergent need for more patient-centric care, what strategies are being implemented to reduce treatment-related adverse effects with bispecific-containing regimens in DLBCL groups, and are there clinical markers or patient characteristics that may help inform safe dose reduction or discontinuation in responders to treatment?

That’s probably one of the biggest issues; the delivery of bispecifics is a challenge for many community oncology practices. Cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] can absolutely happen following these medications. In community practice centers where perhaps there’s no house staff on call, invariably, we’re trying to figure out what to do for these patients in the middle of the night and whether they can be safely kept as outpatients, or whether they need to be admitted to the hospital.

There’s [several] strategies to mitigate this. The context in which the drugs are given seems to matter a lot, so we see far fewer episodes of [CRS and ICANS] in the frontline setting when 2 cycles of CHOP are administered before the initiation of the bispecific and that suggests that somebody whose disease is better controlled may have less overall inflammatory response. We’ve also seen efforts [with] prophylactic dexamethasone or even prophylactic tocilizumab. These have been effective at reducing rates of cytokine release, though not eliminating them altogether. There’s a lot of effort trying to figure out how these can be safely administered in the outpatient setting without requiring inpatient monitoring, and those are some of the steps that are being used to advance those goals.

In your experience, what are the remaining hurdles preventing bispecific antibodies from being administered entirely in an outpatient setting from cycle 1, day 1?

The next generation of bispecific antibodies or perhaps even trispecific antibodies that are being developed, in some cases, have attenuated CD3 signaling, and that attenuation seems to mitigate [adverse] effects without necessarily dampening efficacy. We’re seeing these strategies in the next generation of bispecifics. The biggest problem for implementation right now is physician familiarity and physician comfort with using these medications, they can be incredibly effective and, in many circumstances, can prove to be [quite] useful agents for patients.

However, there is that comfort factor with management of CRS that individual providers have to become familiar with, and interestingly, the clinical use of tarlatamab in small cell lung cancer has actually had an interesting impact in hematologic malignancies, because a lot of physicians who may not otherwise encounter the [adverse] effects and toxicities of CRS management because they might not see as many hematologic patients are now confronting it in small cell lung cancer. That’s actually increasing some of the comfort for community providers to use these drugs as well.

How can we overcome challenges to access for bispecifics, particularly in community settings and resource-constrained regions?

Oftentimes hospitals are reluctant to put these drugs on formulary because the costs of the drugs outweigh the reimbursement for hospitalization of the patients for the conditions that they’re being admitted for. There’s room for closer partnership with drug manufacturers to perhaps provide starting dosages for patients so that they can be done in the hospital, because if they’re not on formulary, oftentimes we can’t get them in the hospital, then we’re stuck in the situation where maybe we have to give them in the clinic and observe the patient in the hospital and that’s clunky and cumbersome.

There’s room for closer alignment between the drug manufacturers and the hospitals that may be observing these patients. There’s also room for improvement and increasing our comfort with the mitigation strategies for how to administer these drugs and it’s worth noting that with every therapeutic drug class we’ve had in oncology, there’s always a learning curve. You could go back to [paclitaxel-related] infusion reactions or rituximab-related infusion reactions, or obinutuzumab-related infusion reactions, or any of the other drugs, where we’ve had to learn how to manage them, and we will learn to manage bispecifics. That process is already in place. It just never happens quite as quickly as we want.

How are sBLA approvals and label updates in the DLBCL space, such as epcoritamab’s revised recommendation for 24-hour hospitalization following administration of the first full 48 mg dose on cycle 1, day 15 in patients, impacting your day-to-day practice?

Different practices throughout the country have different levels of comfort with how patients are managed. Some practices are going to follow labels more closely than others, and the degree to which the labels can be relaxed and afford more opportunity for patients to be treated in the outpatient setting, those label modifications assist in the process of moving this towards a therapy that that can be more broadly distributed.

Is there anything else you would like to discuss that we might not have covered?

Immune checkpoint inhibitor therapies have had profound impacts on solid tumors, and yet we haven’t seen in at least most of the traditional non-Hodgkin’s lymphomas. We haven’t seen the incorporation of those agents. These are our immunotherapies, and like we had to learn how to deal with immune-related adverse [effects] for solid tumors, these are immune-related adverse [effects] by a different flavor, and we owe it to our patients to be able to bring the best therapies to them so that they don’t have to go seek them out independently.

References

1. May 20-21, 2025, meeting of the Oncologic Drugs Advisory Committee (ODAC) - day 1 FDA. Accessed April 2, 2026. https://tinyurl.com/28cema3t
2. 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
3. AbbVie announces topline results for epcoritamab (DuoBody® CD3xCD20) from phase 3 EPCORE® DLBCL-1 trial in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). News release. AbbVie. January 26, 2026. Accessed April 2, 2026. https://tinyurl.com/5y3vvhry
4. A phase 3 trial of epcoritamab vs investigator's choice chemotherapy in relapsed/​refractory (R/​R) diffuse large b-cell lymphoma (DLBCL) (EPCORE DLBCL-1). ClinicalTrials.gov. Updated March 3, 2026. Accessed April 2, 2026. https://tinyurl.com/44fudtjp
5. Budde LE, Zhang H, Kim WS, et al. Mosunetuzumab plus polatuzumab vedotin in transplant-ineligible refractory/relapsed large B-cell lymphoma: primary results of the phase III SUNMO trial. J Clin Oncol. 2025;43(36):3799-3811. doi:10.1200/JCO-25-01957