Epcoritamab Approval Introduces Novel Later-line Treatment Option in R/R DLBCL

Approval of the first-in-class, subcutaneously administered T-cell–engaging bispecific antibody epcoritamab-bysp (Epkinly) provides an effective alternative to chemotherapy for patients with diffuse large B cell lymphoma (DLBCL) in the third-line setting, according to Tycel Phillips, MD.

On May 19, 2023, single-agent epcoritamab gained FDA approval for the treatment of patients with relapsed or refractory DLBCL and high-grade B-cell lymphoma who have received at least 2 prior lines of systemic therapy based on findings from the phase 2 EPCORE NHL-1 trial (NCT03625037).

Patients in the DLBCL cohort who received the agent (n = 157) achieved a deep, durable, and clinically meaningful overall response rate (ORR) of 63% (95% CI, 55%-71%), including a complete response (CR) rate of 39% (95% CI, 31%-47%). Notably, 51% of patients receiving the regimen experienced cytokine release syndrome (CRS), 6% displayed immune effector cell-associated neurotoxicity syndrome (ICANS), and 15% had serious infections. Adverse effects (AEs) were predominantly grade 1 or 2.¹

“Providing this option… is a big step in the right direction,” said Phillips, an associate professor in the Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, in Duarte, California. “Given the low rates of CRS and ICANS, [epcoritamab] can be safely given in a community setting, which should allow more patients to be exposed to these valuable treatments.”

In an interview with OncLive^®, Phillips discussed the significance of the FDA approval for epcoritamab in DLBCL, key data from the NHL-1 trial that support this approval, and how the approval of epcoritamab signals the expanding role of bispecific antibodies in DLBCL.

OncLive: What is the significance of the recent FDA approval of omidubicel in DLBCL?

Phillips: Given the lack of options with durable responses that we have for patients with relapsed or refractory DLBCL, this [approval] is very important, especially for individuals who are unable to make it to a center [that offers] CAR T-cell therapy or who are reluctant to travel. [Epcoritamab] also provides an option for those patients who may not have a durable response to CAR T [and can] hopefully recapture or improve upon the response they had to previous CAR T infusion. In a multitude of ways, [the approval of epcoritamab] provides patients either with options post-CAR T or an alternative to patients who are unfortunately unable to get CAR T-cell therapy.

How does epcoritamab address unmet needs in this patient population?

This [indication] is for DLBCL in the third line and beyond and in that setting, we have 3 CAR T products [approved; however,] those are limited to [administration in] approved CAR T centers. As this drug can be given outside of academic centers in private practice, epcoritamab does expand the reach of a T-cell–directed therapy to these patients. Given the ORR, the CR rate, and the durability of responses, this treatment provides a better alternative to some of the other agents that are approved in this setting such as lenalidomide [Revlimid], tafasitamab [Monjuvi] polatuzumab vedotin-piiq [Polivy], bendamustine [Bendeka], loncastuximab tesirine [Zynlonta], and selinexor [Xpovio].

What were the eligibility criteria for the EPCORE NHL-1 trial?

[EPCORE NHL-1] enrolled patients who had relapsed/refractory DLBCL who hadfailed 2 lines of therapy at the time of enrollment. Patients could have had prior exposure to CAR T, and there were several patients who had prior exposure to autologous stem cell transplant [ASCT]—21% of patients had prior ASCT and 39% of the patients had prior exposure to CAR T. [The study] enrolled patients with de novo DLBCL and transformed DLBCL, a few patients had hybrid B-cell lymphoma which is akin to double hit lymphoma, a few patients [had] primary mediastinal [disease], and some patients had grade 3B follicular [lymphoma].

What efficacy data from EPCORE NHL-1 supported this regulatory decision?

There was an ORR of 63%; [however,] that’s not necessarily the [best] indicator of response in DLBCL because you can’t live with this cancer. The CR rate is a more important barometer of how effective the treatment is [and] the CR for this treatment was 39%. In that heavily pretreated patient population, [this result] is impressive.

The time to response was fairly quick at 1.4 months, and the median time to CR was 2.7 months. At the last presentation [of these data], the median duration of response [DOR] was approximately 12 months and for patients in complete remission, the median DOR was not reached. The important thing is [that] patients who [achieved] CR appear [to] have a durable response. We’ll need longer follow up to see how that compares with what we see with the CAR T treatments, and see if there’s any plateau in patients who have a CR.

Were any notable safety data observed with epcoritamab? Given this toxicity profile, are there any patients you would hesitate to treat with this agent in clinical practice?

The safety profile was good for this treatment. With this line of treatment, the biggest concern is CRS and neurological events, such as ICANS. Most patients who discontinued treatment [did so because of] progressive disease and only 7% of patients discontinued treatment [because of] AEs. The major [AE observed was] CRS, which was seen in over 50% of the patients. Most of the CRS events were grade 1 to 2, and most of them were grade 1 at 31%, [followed by] grade 2 at 15%, and only 2.5% had grade 3 [CRS] or above.

Fever was noted but could also be [attributed to] CRS and there was [also] some neutropenia in patients. As far as neurological complications, only 10 patients in the entire study had ICANS, and only 1 [event] was higher than grade 1/2, which indicates that this treatment regimen is safe. As we are in the COVID-19 era [for the foreseeable future], these treatments need to be [evaluated] in the [context of] that [disease]. We’re going to run into related AEs with any other treatments we use for B-cell lymphomas, and this is no different.

What should be noted about the administration of this agent in clinical practice?

The approval of epcoritamab [is] a big step, [and provides] a bispecific antibody that we can use in routine clinical practice. The key thing [to note] with [epcoritamab is that] it is given as a step-up dose to reduce some of the AEs that we talked about, such as CRS and ICANS. The drug is given at a very low dose for the first subcutaneous injection, with the dose increasing as we move up [to] the final dose of 48 mg. Once the final dose is reached, the drug is given weekly for the first 3 cycles, [then] every other week for cycles 4 through 9, and then monthly until disease progression or intolerance.

How does the approval of epcoritamab bolster ongoing and future research on novel bispecific antibodies in this space?

Moving forward, other bispecifics will probably be approved in this setting. Some of them have a finite treatment period. The question will be whether we need to treat these patients indefinitely, or if we can stop treating some of these patients who [achieve a] CR and maintain that remission. Evaluating how this drug does with long-term follow-up, [and investigating] some of the other agents with a finite treatment [period] will be important and will dictate [whether] the field [proceeds] with these time-limited treatments, or [continues] treatment [until] progression or intolerance.

Patients who were CAR T-naïve had a higher ORR and CR rate than patients who were CAR T-exposed. This treatment may be a reasonable alternative for patients who cannot get access to CAR T. These are things that we have to keep in mind, and we’ll tease [them] out as we [gather] more information with [epcoritamab] and some of the other bispecific antibodies.

Please highlight any ongoing or future research in lymphoma at City of Hope?

At City of Hope, we have participated in quite a few studies with a multitude of bispecific antibodies and one trispecific antibody. We also have several CAR T products that are being explored with antigen targets other than the typical CD19 [marker]. The field itself is moving toward an immune-mediated approach to treatment for several different subtypes of lymphoma. City of Hope is at the forefront of exploring a lot of these treatments. The toxicity profile [of these bispecific antibodies is] much different than what we typically see with chemotherapy.

It’s an exciting time for our patients and for us as investigators to see how these treatments are making a difference.

Reference

FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. FDA. May 19, 2023. Accessed May 22, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b-cell