Subcutaneous Epcoritamab Induces Lasting Responses in R/R LBCL

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In the phase 1/2 EPCORE NHL-1 trial (NCT03625037), treatment with subcutaneous epcoritamab-bysp (Epkinly) achieved deep and durable responses in patients with relapsed or refractory large B-cell lymphoma (LBCL). Further, patients who were complete responses had favorable long-term outcomes, according to updated data presented during the 2023 SOHO Annual Meeting.¹

At a median follow-up of 20 months (range, 0.3+ to 28.2), the T-cell–engaging bispecific antibody elicited an overall response rate (ORR) of 63% in the total LBCL population (n = 157), with a complete response (CR) rate of 39%, a partial response (PR) rate of 24%, and a stable disease (SD) rate of 3%; 24% of patients experienced disease progression.

Epcoritamab also induced high response rates across the populations analyzed. Specifically, in those with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL; n = 148), the ORR with the agent was 61%, including a CR rate of 39%. In those with primary mediastinal large B-cell lymphoma (PMBCL; n = 4), the ORR was 100%, with a 50% CR rate. The ORR was also 100% in patients with follicular lymphoma grade 3B (n = 5), with a CR rate of 60%.

In patients with DLBCL and HGBCL, the median duration of response (DOR) was 15.5 months (95% CI, 9.7-20.8), and in patients with LBCL who had prior exposure to CAR T-cell therapy, the median DOR had not yet been reached.

Notably, patients who achieved CRs with the agent experienced durable responses. The median duration of CR was 20.8 months (95% CI, 15.8-not reached [NR]) in evaluable patients with LBCL (n = 62) and in evaluable patients with DLBCL and HGBCL (n = 57). At 12 months, an estimated 77% and 76% of complete responders, respectively, remained in CR; at 15 months, these rates were 68% and 67%, respectively.

“Subcutaneous epcoritamab is a bispecific antibody with high single-agent activity in patients with relapsed or refractory LBCL. Longer follow-up reaffirms deep and durable CRs, which translate into favorable long-term outcomes with immediate overall survival not reached in complete responders,” said Yasmin H. Karimi, MD, in a presentation of the data. “Safety was manageable and consistent with previous reports, with no new safety signals observed.”

Developed utilizing the DuoBody platform, epcoritamab is a CD3xCD20 bispecific antibody that received accelerated approval from the FDA in May 2023 for use in adult patients with relapsed/refractory DLBCL not otherwise specified, including DLBCL arising from indolent lymphoma, and HGBCL, following at least 2 lines of systemic treatment.² The decision was supported by earlier EPCORE NHL-1 findings.

The trial enrolled patients with relapsed or refractory, CD20-positive mature B-cell neoplasms who previously received 2 or more lines of antineoplastic therapy, including at least 1 anti-CD20 monoclonal antibody.1 Patients were required to have measurable disease by PET/CT and an ECOG performance status of 0 to 2. Those who had prior exposure to CAR T-cell therapy were permitted.

In the dose-expansion phase of the trial, patients received subcutaneous epcoritamab via step-up dosing to the full recommended phase 2 dose of 48 mg. Treatment was continued until progressive disease or unacceptable toxicity.

The primary end point of the trial was ORR by independent review committee assessment, and key secondary end points comprised DOR, time to response, progression-free survival (PFS), overall survival (OS), CR rate, and safety/tolerability.

At the time of the data cutoff date of November 18, 2022, 157 patients with LBCL had been treated; this included 148 patients with DLBCL and HGBCL, 4 patients with PMBCL, and 5 patients with follicular lymphoma grade 3b.

In the overall LBCL population, the median age was 64 years (range, 20-83), with 18% of patients aged 75 years or older. Regarding ECOG performance status, 47% had a status of 0, 50% had a status of 1, and 3% had a status of 2. The median number of prior lines of therapy was 3, with a range of 2 to 11.

“This was a very challenging-to-treat population,” noted Karimi, who is a clinical assistant professor of Hematology, Internal Medicine, and Medical Oncology at the Hematology Clinic at the University of Michigan Comprehensive Cancer Center. Notably, 70% of patients had received 3 or more lines of therapy, 61% had primary refractory disease, 83% were refractory to their last therapy, and 75% were refractory to at least 2 consecutive lines of treatment. Thirty-nine percent of patients had previously received CAR T-cell therapy and 75% were refractory to the modality.

Additional data showed that the median OS was 18.5 months (95% CI, 11.7-NR) in the total LBCL population. In the subgroup of patients with DLBCL and HGBCL, the median OS was 18.5 months (95% CI, 11.3-NR). Notably, the median OS was not reached in those who achieved a CR. An estimated 95% of total complete responders remained alive at 12 months; this rate was 88% at 15 months.

In the patients with DLBCL and HGBCL who achieved CRs with epcoritamab, the median PFS was not yet reached. An estimated 87% of these patients remained free of disease progression at 12 months; at 15 months, 80% remained progression free.

At the time of date cutoff, 23% of patients were still receiving epcoritamab. The most common reason for discontinuation of the bispecific antibody was disease progression (56%), followed by toxicity (11%), allogeneic transplant (4%), patient withdrawal (3%), and other (2%).

The most common any-grade treatment-emergent adverse effects (TEAEs) were cytokine release syndrome (CRS; 51%), neutropenia (24%), pyrexia (24%), fatigue (23%), nausea (22%), and diarrhea (21%). Six percent of patients had immune effector cell–associated neurotoxicity syndrome (ICANS); 6% of these events were grade 1 or 2.

“CRS was predictable and primarily low grade,” Karimi said. “It occurred primarily after the first full dose in cycle 1 day 15, and median time to onset was around 20 hours after treatment.” Thirty-two percent of events were grade 1, 16% were grade 2, and 3% were grade 3. Tocilizumab (Actemra) was used to treat those who had grade 2 or 3 CRS events. All but 1 event resolved and the median time to resolution was 2 days (range, 1-27).

Fifteen patients experienced TEAEs that proved to be fatal. “Eight of these were events related to COVID-19,” Karimi noted. “There were 2 fatal events considered related to treatment; 1 was COVID-19 pneumonia and the other was ICANS in a patient with several confounding factors.”

Epcoritamab is currently under evaluation across different lines of therapy and in various combinations for DLBCL, Karimi concluded.

_References

_{1. Longer follow-up reaffirms subcutaneous epcoritamab induces deep and durable complete remissions in patients with relapsed/refractory large B-cell lymphoma: updated results from the pivotal EPCORE NHL-1 trial. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX. ABCL-500.}

_{2. 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 September 8, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b-cell}