Epcoritamab Wins European and Japanese Approval for Select Types of R/R LBCL


Epcoritamab-bysp has been approved by the European Commission and Japan's Ministry of Health, Labour, and Welfare for the treatment of select patients with relapsed/refractory large B-cell lymphoma.

Jan van de Winkel, PhD

Jan van de Winkel, PhD

The European Commission (EC) has granted conditional marketing authorization to epcoritamab-bysp (Tepkinly) for use as a single agent in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) following 2 or more lines of systemic treatment.1 Additionally, Japan’s Ministry of Health, Labour, and Welfare has approved the agent (Epkinly) for adult patients with select types of relapsed or refractory LBCL, including DLBCL, high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3b (FL3B) after at least 2 prior lines of systemic therapy.2

The EC decision is based on findings from the phase 1/2 EPCORE NHL-1 trial (NCT03625037), in which epcoritamab elicited an overall response rate (ORR) of 62% in the cohort of patients with DLBCL (n = 139), which included a complete response (CR) rate of 39%. The median duration of response was 15.5 months (range, 9.7-not reached [NR]).1

“With Tepkinly, people in Europe living with relapsed or refractory DBLCL who are in need of additional treatment options now have a readily available, innovative therapeutic option for this aggressive cancer,” Jan van de Winkel, PhD, chief executive officer of Genmab A/S, stated in a press release.1 “Today’s approval underscores our commitment to bringing our bispecific antibody to more patients worldwide. We’re excited to continue working with our partner AbbVie to further explore epcoritamab as potential core therapy across B-cell malignancies.”

The Japanese approval is supported by findings from EPCORE NHL-1 and the phase 1/2 EPCORE NHL-3 trial (NCT04542824).2 In 157 patients with LBCL enrolled on EPCORE NHL-1, the ORR with the bispecific antibody was 63% (95% CI, 55.0%-70.6%), which included a CR rate of 39%.2 In the 36 Japanese patients with relapsed or refractory DLBCL enrolled on EPCORE NHL-3, the ORR achieved with epcoritamab was 56% (95% CI, 38.1%-72.1%), with a CR rate of 44%.

“Despite recent advances in the treatment of LBCL, the prognosis for patients with relapsed/refractory LBCL remains generally poor, and there is a need for additional treatment options for patients whose condition has worsened after multiple lines of treatment,” Koji Izutsu, MD, PhD, principal investigator of EPCORE NHL-3 and head of the Hematology Department at the National Cancer Center Hospital, stated in a press release. “In the EPCORE NHL-3 trial, subcutaneous epcoritamab monotherapy demonstrated responses in a considerable number of patients with relapsed/refractory DLBCL, indicating that this approval is of great significance.”

EPCORE NHL-1: Design, Objectives, LBCL Efficacy/Safety Data

Patients with relapsed or refractory, CD20-positive mature B-cell neoplasms who received 2 or more prior lines of antineoplastic therapy, including at least 1 anti-CD20 monoclonal antibody, were enrolled to the open-label, multicenter EPCORE NHL-1 trial.3 Other inclusion criteria comprised measurable disease by PET/CT and an ECOG performance status ranging from 0 to 2. Those who previously received CAR T-cell therapy were allowed to enroll.

Patients were excluded if they had primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening, or a known past or current malignancy other than inclusion diagnosis.

For the dose-expansion portion of the trial, subcutaneous epcoritamab was administered at 48 mg once weekly during cycles 1 to 3, then once every 2 weeks in cycles 4 to 9, and then once every 4 weeks in cycles 10 and beyond. During cycle 1, a step-up dose of 0.16 mg of the agent was given on day 1, followed by an intermediate dose of 0.8 mg on day 8, then the full 48-mg dose on day 15 and thereafter. Treatment continued until disease progression or unacceptable toxicity.

ORR by independent review committee assessment served as the primary end point of the trial. Secondary end points included CR rate, time to response, DOR, progression-free survival (PFS), overall survival (OS), and safety.

At the time of the data cutoff date of November 18, 2022, a total of 157 patients with LBCL had been treated; this included 148 patients with DLBCL and HGBCL, 4 patients with PMBCL and 5 patients with FL3B.4

In the LBCL group, the median age was 64 years (range, 20-83), and 18% of patients were at least 75 years old. In terms of 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 received was 3 (range, 2-11).

Data presented during the 2023 SOHO Annual Meeting indicated that at a median follow-up of 20 months (range, 0.3+ to 28.2), epcoritamab elicited an ORR of 63% in the overall LBCL population (n = 157), which included a CR rate of 39%, a partial response (PR) rate of 24%, and a stable disease rate of 3%. Twenty-four percent of patients had progressive disease.

In those with DLBCL and high-grade B-cell lymphoma (n = 148), the ORR with the agent was 61% and the CR rate was 39%. Epcoritamab induced an ORR of 100% the groups of patients with PMBCL and FL3B; the CR rates in these groups were 50% and 60%, respectively.

Those who achieved a CR with the bispecific antibody had durable responses. In the 62 evaluable patients with LBCL and the 57 evaluable patients with DLBCL and HGBCL, the median duration of CR was 20.8 months (95% CI, 15.8-NR). Moreover, an estimated 77% and 76% of those who achieved CR remained in response at 12 months; these estimated rates were 68% and 67%, respectively, at 15 months.

In the total LBCL population, the median OS with epcoritamab was 18.5 months (95% CI, 11.7-NR); it was 18.5 months (95% CI, 11.3-NR) in those with DLBCL and HGBCL. In those who achieved a CR to treatment, the median OS was NR. Moreover, in those with DLBCL and HGBCL who experienced CRs, the median PFS was also NR.

Regarding safety, the most frequently experienced treatment-emergent adverse effects (TEAEs) included cytokine release syndrome (51%), neutropenia (24%), pyrexia (24%), fatigue (23%), nausea (22%), and diarrhea (21%). Moreover, 6% of patients had immune effector cell–associated neurotoxicity syndrome. Fifteen patients had fatal TEAEs.

EPCORE NHL-3: Design, Objectives, Safety Findings

The open-label, multicenter trial enrolled Japanese patients with relapsed, progressive, or refractory B-cell lymphomas and those with B-cell lymphomas that have achieved a PR or CR following standard-of-care (SOC) treatment.5 Patients needed to be at least 20 years of age and have CD20 positivity.

The trial was comprised of dose-escalation and -expansion phases. Part 1 included those with DLBCL, HGBCL, PMLBCL, follicular lymphoma (FL), marginal zone lymphoma, and small lymphocytic lymphoma. Part 2 included 5 arms that evaluated epcoritamab: monotherapy in those with DLBCL or FL (arm 1); in combination with rituximab (Rituxan) and lenalidomide (Revlimid) in those with relapsed or refractory FL (arm 2); in combination with rituximab and cyclophosphamide plus doxorubicin, vincristine, and prednisone in those with previously untreated DLBCL (arm 3); in combination with gemcitabine and oxaliplatin in those with relapsed or refractory DLBCL (arm 4); and as maintenance in those with FL and CR or PR after first- or second-line SOC treatment (arm 5).

The primary outcome measures of part 1 of the trial were to examine AEs and dose-limiting toxicities (DLTs). For part 2, investigators evaluated ORR in arm 1, DLT incidence in arms 2 to 4, and AEs in arms 2 to 5.

In the study, 56% of patients had primary refractory disease and the majority (81%) were refractory to the last therapy they received.2 Patients had received a median of 3 prior lines of therapy, with a range of 2 to 8. Notably, 44% of patients received 2 prior therapies, 25% received 3 prior therapies, and 31% received at least 4 prior therapies. Additionally, 19% of patients previously underwent autologous stem cell transplant. No patients had prior exposure to CAR T-cell therapy.

Safety data showed that in the 36 evaluable patients, all experienced AEs related to treatment. The most common toxicities reported in more than 15% of patients included CRS (83.3%), injection site reactions (58.3%), neutropenia (30.6%), lymphopenia (19.4%), reduced appetite (19.4%), thrombocytopenia (19.4%), and rash (19.4%).

Also Approved in the United States

In May 2023, the FDA approved epcoritamab for the treatment of adult patients with relapsed/refractory DLBCL not otherwise specified, including DLBCL arising from indolent lymphoma, and HGBCL, following at least 2 prior lines of systemic treatment.6,7 The decision was based on earlier EPCORE NHL-1 data.


  1. Genmab announces European Commission approval of Tepkinly (epcoritamab) for adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). News release. Genmab A/S. September 25, 2023. Accessed September 25, 2023. https://ir.genmab.com/news-releases/news-release-details/genmab-announces-european-commission-approval-tepkinlyr
  2. Epkinly (epcoritamab) approved by Japan Ministry of Health, Labour and Welfare as the first bispecific antibody to treat adult patients with certain types of relapsed or refractory (R/R) large B-cell lymphoma (LBCL). News release. Genmab A/S. September 25, 2023. Accessed September 25, 2023. https://ir.genmab.com/news-releases/news-release-details/epkinlytm-epcoritamab-approved-japan-ministry-health-labour-and
  3. Thieblemont C, Phillips T, Ghesquieres H, et al. 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. J Clin Oncol. 2023;41(12):2238-2247. doi:10.1200/JCO.22.01725
  4. 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.
  5. 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 25, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b-cell
  6. Trial of the safety and efficacy of epcoritamab in Japanese subjects with R/R B-NHL (EPCORE NHL-3). ClinicalTrials.gov. Updated August 8, 2023. Accessed September 25, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04542824
  7. EPKINLY (epcoritamab-bysp) approved by US FDA as the first and only bispecific antibody to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). News release. AbbVie. May 19, 2023. Accessed September 25, 2023. https://news.abbvie.com/article_display.cfm?article_id=12584
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