Journal of Clinical Oncology APRIL 20, 2023

Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial

Catherine Thieblemont, Tycel Phillips, Herve Ghesquieres, et al.

Bottom Line

In patients with heavily pretreated relapsed or refractory large B-cell lymphoma, subcutaneous epcoritamab demonstrated robust and durable efficacy with an overall response rate of 63.1% and a manageable safety profile.

Key Findings

1. Among 157 treated patients with relapsed/refractory LBCL, the overall response rate (ORR) was 63.1% (95% CI, 55.0 to 70.6) [3.1.1].

2. The complete response (CR) rate was 38.9% (95% CI, 31.2 to 46.9).

3. At a median follow-up of 10.7 months, the median duration of response was 12.0 months overall, and not reached for patients achieving a complete response.

4. Cytokine release syndrome (CRS) occurred in 49.7% of patients; the vast majority were low-grade events (47.1% grade 1 or 2), with only 2.5% of patients experiencing grade 3 CRS.

5. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 6.4% of patients, with one fatal event.

Study Design

Design

Phase 1/2 Trial

Open-Label

Sample

157

Patients

Duration

10.7 mo

Median

Setting

Multicenter, global

Population Adults with relapsed or refractory CD20+ large B-cell lymphoma and at least two prior lines of systemic therapy (61.1% had primary refractory disease; 38.9% had prior CAR T-cell therapy exposure).

Intervention Subcutaneous epcoritamab in 28-day cycles (once-weekly step-up doses in weeks 1-3 of cycle 1, then full 48 mg doses once weekly through cycle 3, every 2 weeks in cycles 4-9, and every 4 weeks from cycle 10 onward) until disease progression or unacceptable toxicity.

Comparator None (Single-arm trial)

Outcome Overall response rate (ORR) as assessed by an independent review committee.

Study Limitations

• The single-arm, non-randomized study design precludes direct comparison with standard-of-care therapies or other novel CD19 or CD20 targeted agents.

• The relatively short median follow-up of 10.7 months at the time of primary analysis limits the evaluation of long-term overall survival and late relapse rates.

• A predominantly older and heavily pretreated patient cohort (median of 3 prior lines) was enrolled, leaving the drug's safety and efficacy in earlier lines of therapy unconfirmed.

Clinical Significance

The pivotal EPCORE NHL-1 trial established subcutaneous epcoritamab as a highly active, off-the-shelf T-cell engaging bispecific antibody for heavily pretreated, aggressive large B-cell lymphomas. Its high overall response rate (63.1%) and complete response rate (38.9%) in a difficult-to-treat population—including nearly 40% with prior CAR T-cell failure—coupled with manageable rates of high-grade CRS and ICANS, offered a vital alternative for patients ineligible for or relapsing after cellular therapies. This trial led to the accelerated FDA approval of epcoritamab for relapsed/refractory DLBCL in May 2023.

Historical Context

Prior to the advent of bispecific antibodies, treatment options for patients with relapsed/refractory large B-cell lymphoma failing two lines of therapy were largely restricted to CD19-directed CAR T-cell therapy. While curative for some, CAR T-cell therapy is limited by access, manufacturing time, and significant toxicities, and roughly half of treated patients eventually relapse. Epcoritamab emerged as an off-the-shelf alternative—a subcutaneously administered CD3xCD20 bispecific antibody designed to bring endogenous T-cells in proximity to CD20-expressing malignant B-cells. Subcutaneous delivery was strategically engineered to slow absorption and attenuate the peak cytokine spikes typical of intravenous T-cell engagers. The EPCORE NHL-1 study demonstrated that epcoritamab could achieve deep, durable remissions, marking a significant milestone in making bispecific antibody therapy accessible in the community oncology setting.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does a CD3xCD20 bispecific antibody like epcoritamab mediate tumor cell death, and why might subcutaneous administration offer a different toxicity profile compared to intravenous administration?

Key Response

Epcoritamab binds CD20 on B-cells and CD3 on T-cells, bringing them into close proximity to induce T-cell-mediated cytotoxicity independent of MHC restriction. Subcutaneous administration leads to slower absorption and lower peak plasma concentrations, mitigating the risk and severity of Cytokine Release Syndrome compared to the rapid spike seen with IV dosing.

Resident

In a patient receiving epcoritamab who develops fever, hypoxia, and hypotension on day 2 of cycle 1, what are the primary differential diagnoses, and how does the management of Cytokine Release Syndrome differ from standard sepsis management?

Key Response

The primary differential includes Cytokine Release Syndrome and infectious sepsis. While broad-spectrum antibiotics are necessary to rule out infection, CRS management relies on grading the severity and administering tocilizumab and/or corticosteroids. Epcoritamab utilizes a step-up dosing schedule specifically to mitigate severe CRS.

Fellow

Epcoritamab showed a 63.1 percent ORR in heavily pretreated R/R LBCL, including patients with prior CAR T-cell therapy. How do we sequence bispecific antibodies versus CAR T-cell therapy in the third-line setting, and what are the primary mechanisms of resistance to epcoritamab?

Key Response

Sequencing remains controversial, but CAR T is generally preferred earlier if the patient is fit due to its curative potential. Bispecifics like epcoritamab are excellent off-the-shelf options for patients ineligible for CAR T or progressing after it. Resistance mechanisms include CD20 loss or downregulation and T-cell exhaustion.

Attending

Given the advent of off-the-shelf bispecific antibodies like epcoritamab alongside established CAR-T therapies for R/R LBCL, how should institutional practices evolve regarding outpatient administration logistics and community oncology partnerships?

Key Response

Epcoritamab's subcutaneous delivery and manageable toxicity profile allow for potential transition to community-based or outpatient administration. Attendings must establish clear step-up dosing protocols, robust toxicity monitoring networks with local ERs, and pathways for tocilizumab access to safely decentralize care away from tertiary CAR-T centers.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The EPCORE NHL-1 trial used a single-arm phase I/II dose-expansion design. What are the statistical limitations of relying on an historical control for an ORR primary endpoint in this specific heavily pretreated population, and how could a synthetic control arm improve causal inference?

Key Response

Single-arm designs suffer from selection bias and lack a direct comparator, making it difficult to differentiate the drug's true effect from prognostic confounders in highly selected fit patients who survived multiple lines of therapy. Using a well-matched synthetic control arm would provide a more robust counterfactual to estimate relative efficacy accurately.

Journal Editor

When reviewing the EPCORE NHL-1 manuscript, how does the inclusion of various LBCL histologic subtypes alongside de novo DLBCL affect the interpretation of the 63.1 percent ORR, and what subgroup analyses are mandatory to justify broad regulatory approval?

Key Response

LBCL is a heterogeneous group. A critical reviewer would scrutinize whether the high ORR is driven disproportionately by more indolent transformed histologies or if it holds robustly in high-risk groups like double-hit lymphoma or primary refractory disease. Mandating rigorous forest plots for these subgroups is essential.

Guideline Committee

Based on the phase I/II data from EPCORE NHL-1, how should NCCN and ESMO guidelines position epcoritamab in the algorithm for R/R DLBCL, and does the evidence quality support a category 1 recommendation for its use post-CAR T-cell therapy?

Key Response

Current NCCN guidelines include epcoritamab as a category 2A recommendation for R/R DLBCL after 2 or more lines of systemic therapy. Because the data stems from a single-arm Phase II expansion rather than a randomized Phase III trial, it does not meet criteria for a Category 1 recommendation, though the high unmet need justifies its inclusion as a preferred off-the-shelf option.

Clinical Landscape

Noteworthy Related Trials

2017

ZUMA-1 Trial

n = 111 · NEJM

Tested

Axicabtagene ciloleucel (anti-CD19 CAR-T)

Population

Patients with refractory large B-cell lymphoma

Comparator

Historical controls (single-arm study)

Endpoint

Objective response rate (ORR)

Key result: Axi-cel demonstrated an ORR of 82% and a complete response rate of 54%, with durable responses in refractory LBCL.

2020

TRANSCEND NHL 001 Trial

n = 269 · Lancet

Tested

Lisocabtagene maraleucel (anti-CD19 CAR-T)

Population

Patients with relapsed or refractory large B-cell lymphoma

Comparator

Single-arm study

Endpoint

Objective response rate (ORR) and adverse events

Key result: Liso-cel produced an ORR of 73% and a complete response rate of 53%, with a favorable safety profile regarding severe CRS and neurotoxicity.

2022

NP30179 Trial

n = 155 · NEJM

Tested

Glofitamab (CD20xCD3 bispecific antibody)

Population

Patients with relapsed or refractory large B-cell lymphoma

Comparator

Single-arm study

Endpoint

Complete response rate (CRR)

Key result: Glofitamab yielded a complete response rate of 39%, with responses being highly durable alongside manageable adverse events.

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