Epcoritamab Could Provide Active and Accessible Treatment Option for R/R LBCL

Chan Cheah, MBBS, FRACP, FRCPA, DMSc

The durable responses observed with the subcutaneous bispecific antibody epcoritamab (DuoBody- CD3xCD20) combined with the advantages of its off-the-shelf accessibility support its potential approval in patients with or refractory large B-cell lymphoma (LBCL), according to Chan Cheah, MBBS, FRACP, FRCPA, DMSc.

In November 2022, the FDA granted priority review to a biologics license application seeking approval of the agent in those who received 2 or more prior lines of systemic therapy.1 The application was supported by data from the phase 2 EPCORE NHL-1 trial (NCT03625037), in which patients in the LBCL cohort who received the agent (n = 157) achieved an overall response rate (ORR) of 63% (95% CI, 55%-71%), which included a complete response (CR) rate of 39% (95% CI, 31%-47%). The median duration of response (DOR) for patients who achieved a CR was not yet reached (NR).2

Under the Prescription Drug User Fee Act, the regulatory agency is expected to decide on this application by May 21, 2023.

“The approval of epcoritamab would provide another effective and well-tolerated agent for patients with relapsed and refractory LBCL,” said Cheah, who is a clinical hematologist, lymphoma lead and Fellowship Program Director at Sir Charles Gairdner Hospital. He is also a clinical professor in the Department of Internal Medicine at the University of Western Australia (WA) Medical School, and the founder of Blood Cancer Research WA, Perth, Australia.

In an interview with OncLive^®, Cheah discussed key safety and efficacy data from the EPCORE NHL-1 trial that may serve to support the approval of epcoritamab in patients with relapsed or refractory LBCL, and highlighted ongoing research efforts seeking to further move the needle forward in this disease.

OncLive: If epcoritamab is approved, which patients would benefit most? How would this decisionimprove outcomes for this population?

Cheah: [The approval of epcoritamab would be] important for patients because it’s highly active. The efficacy of the agent is seen across subgroups, including patients with adverse features such as double-hit lymphoma, or those who had experienced treatment failure following CAR T-cell therapy, which is a standard of care [SOC] in the third line for patients with LBCL. The advantage of off-the-shelf antibodies such as epcoritamab is that [they are] available on demand and do not require any kind of manufacturing period, [unlike] CAR T-cell therapy. That’s useful for patients, particularly those with rapidly progressing disease.

What patients would be included in the indication for epcoritamab?

My understanding is that the FDA approval [would] closely mirror the inclusion criteria for the [EPCORE] NHL-1 clinical trial. That [consists of] patients [who] have relapsed/refractory LBCL with greater or equal to 2 lines of prior systemic therapy, including one containing a CD20 monoclonal antibody. That certainly is a population which remains an unmet need.

What key efficacy data from the trial are being used to support this regulatory decision?

[EPCORE NHL-1] was a phase 2 trial [that included] 157 patients with LBCL. The median age of those patients was 64 years. The majority of these patients had diffuse large B-cell lymphoma, although a few had high-grade B-cell lymphoma, incorporating those with MYC and BCL2 translocations. A proportion of patients also had transformed lymphoma primarily from follicular lymphoma. There was a median of 3 prior lines of therapy, so this was a [relatively] heavily pretreated population. [About] 60% of patients were primary refractory, and 83% of patients were refractory to their last line of therapy. Thirty-nine percent of patients had prior CAR T-cell therapy exposure and [75%] of those patients were refractory to CAR T-cell therapy.

The efficacy seen in this study is somewhat more encouraging because of those high-risk features. The ORR in the study was 63%. Among those 157 patients, the CR rate was 39%, with a further 24% of patients achieving a partial response [PR]. Of course, the best outcomes in terms of durability of responses with immunotherapies, such as bispecific antibodies and CAR T-cell [agents], seems to be particularly observed in the subset of patients who achieved a CR. We have seen data with other agents [showing] that patients who attain a CR tend to have durable responses. Although the data on [this trial] are somewhat less mature, we are seeing durable CRs in that subset of patients, as well.

What did the trial reveal about the safety profile of this agent?

Like other CD20 and CD3 bispecific antibodies, the most common adverse effect [AE] seen is cytokine release syndrome [CRS]. We see [CRS] with a range of immunotherapies where the primary mode of action is T-cell–mediated cell [death]. Of course, we see it with CD19[-targeted] CAR T-cell therapies and with other CD20 bispecific antibodies. In this study, CRS of any grade was seen in about half of patients, although in virtually all cases this was grade 1 or 2. In fact, 48% of events were grade 1, which means [patients had] fever only without hypertension or hypoxia.

The timing of CRS in [patients treated with] epcoritamab is slightly different to that observed [with] other bispecific antibodies [like] glofitamab [RG6026]. Most CRS events occur within cycle 1. This agent is administered weekly with a priming and intermediate dose [given] prior to a first full dose, which is given on day 15 of cycle 1. With [this drug], most CRS events occur following day 15 of cycle 1, or the first full dose. In contrast, we see more CRS with glofitamab following that initial 2.5-mg dose on day 1 of cycle 1. [This speaks] to the agents’ slightly different pharmacokinetics in terms of where their biological activity hits.

The CRS is predictable and manageable. [About] 15% of patients required [treatment with the] IL-6 antibody tocilizumab [Actemra], which is a standard treatment for CRS. CRS resolved in virtually all patients within a median of 2 days. Only 1 patient needed to discontinue therapy because of CRS.

What are some key considerations when deciding which patients should receive the agent? What has been learned from other bispecific antibodies in the space?

I’ve certainly treated patients with rapidly progressive lymphoma within the context of clinical trials. As these agents are used more broadly outside of a clinical trial setting, and we [begin] treating patients at greater extremes of age or with more tenuous organ function, it remains to be seen whether new problems with tolerability emerge. [However], I suspect that’s not going to be the case. If you look at the real-world data that has been reported with [SOC] CAR T-cell therapy, which is mechanistically similar in many ways to T-cell engagers, the efficacy seen has been very similar to the registrational studies. I’ve certainly been comfortable using epcoritamab in elderly patients, those with less than normal renal function, and those with slight cytopenias.

Issues can arise when you have patients who will be less tolerant of CRS, particularly those who perhaps already have tenuous cardiac or respiratory function. [When] I think about the patients I’ve treated with bispecific antibodies who’ve had problems, it’s been those with preexisting cardiac disease with the tendency toward hypertension. This makes it quite challenging to manage them when they get treated with drugs like epcoritamab. When their blood pressure drops, it becomes very tricky [deciding] when to call, for instance, grade 2 CRS. If someone is starting off with a blood pressure of 90/40, that can be a little bit challenging.

Similarly, patients with significant preexisting pulmonary disease may theoretically be more challenging to treat because of the potential to develop hypoxia when starting on therapy. Hypoxia [is] a marker of severity for CRS. In clinical practice, it can sometimes become challenging to figure out what’s CRS and what [symptoms are] due to [a patient’s] underlying comorbidity. I think [those toxicities] are self-evident.

Because of how well tolerated [epcoritamab] is when you get patients through the first cycle, this will be a broadly applicable therapy and [will be] usable even for patients who [are] in their 80s. I can see this being used more broadly than CAR T-cell therapy, which is the obvious comparison.

What future research is planned for epcoritamab in LBCL?

Clearly, the field of LBCL is heading toward [the adoption of] these agents, and they appear to have the highest single-agent activity in patients with relapsed and refractory disease. We are seeing phase 3 studies based on the results from [EPCORE] NHL-1 starting to roll out. There is a frontline study in which patients are randomized between R-CHOP [ rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone] and R-CHOP plus epcoritamab. That study is opening soon. We’re also seeing studies in relapsed disease.

There are a variety of phase 2 studies exploring epcoritamab. For instance, [epcoritamab is being investigated] in second-line LBCL as a precursor to autologous stem-cell transplant [ASCT], or even a potential replacement for ASCT in patients with borderline fitness. As we [continue investigating] new agents like [epcoritamab], which are highly active and well tolerated, we’re finding new ways to incorporate them into earlier lines of therapy and hopefully improve the overall outlook for patients with LBCL. I’m excited to see where this agent can make inroads in earlier lines of therapy for this disease.

Would you like to highlight any ongoing research efforts in lymphoma being made at your institution?

We’ve got a couple of investigator-initiated studies running through the Australian Cooperative Cancer Group. We just started enrollment for a phase 2 study of R-CHOP plus pembrolizumab [Keytruda] in patients with primary mediastinal LBCL. We’ve got our first patient on that recently, and I’m really looking forward to seeing some more patients on that [trial]. We also have a phase 2 trial [GOlDiLOX; NCT05833763] of a different CD20/CD3 bispecific agent glofitamab in combination with pirtobrutinib [Jaypirca] in patients with relapsed/refractory mantle cell lymphoma [MCL]. I think those are the 2 most active agents in relapsed MCL and getting to combine them in patients with BTK-refractory disease is particularly exciting for us.

We will also be [presenting] subset analysis data [from] the phase 1/2 BRUIN trial [NCT03740529] of pirtobrutinib for MCL [at future meetings]. [Specifically,] we’ll be sharing some of the data around the efficacy of pirtobrutinib in high-risk subgroups of patients with MCL, such as those with TP53 mutations, blastoid and pleomorphic histology, etc. [There are] quite a few things that we are working on and I’m excited about [all the efforts being made].

References

1. Genmab announces US Food and Drug Administration accepts for priority review biologics license application (BLA) for epcoritamab (DuoBody®-CD3xCD20) for the treatment of relapsed/refractory large B-cell lymphoma (LBCL). News release. Genmab. November 21, 2022. Accessed May 16, 2023. https://www.businesswire.com/news
2. 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: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract LB2364.