FDA Grants Orphan Drug Designation to Epcoritamab for Follicular Lymphoma

The FDA has granted an orphan drug designation to epcoritamab for use as a potential therapeutic option for patients with follicular lymphoma.

The FDA has granted an orphan drug designation to epcoritamab for use as a potential therapeutic option for patients with follicular lymphoma, according to an announcement from Genmab A/S.1

Developed using Genmab’s DuoBody-CD3 technology, which was designed to direct cytotoxic T cells to tumors to produce an immune response against malignant cells, epcoritamab simultaneously binds to CD3 on T cells and CD20 on B cells. The IgG1 bispecific antibody also prompts T-cell–mediated killing of lymphoma B cells.

The agent is under investigation in several clinical trials, including the phase 1/2 EPCORE NHL-1 trial (NCT03625037), which is being done in relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL); a phase 1b/2 trial (NCT04663347), which is being done in those with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma; and another phase 1/2 trial (NCT04542824), which is being done in Japanese patients with relapsed/refractory NHL.

“This orphan drug designation is an important milestone for epcoritamab,” Jan van de Winkel, PhD, chief executive officer at Genmab, stated in a press release. “With AbbVie, we remain committed to further developing epcoritamab in this patient population, as well as in patients diagnosed with other B-cell hematologic malignancies.”

The first-in-human, dose-escalation and -expansion EPCORE NHL-1 trial sought to examine subcutaneous epcoritamab in patients with relapsed/refractory NHL.2 The dose-escalation portion of the research enrolled those with relapsed, progressive, or refractory CD20-positive B-cell NHL, which could include de novo or transformed DLBCL, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL).

To be eligible for enrollment to this phase, patients needed to be at least 18 years of age, have received prior anti-CD20 monoclonal antibody–containing regimen, have measurable disease, an ECOG performance status of 0 to 2, and have acceptable renal and hepatic function. These patients could not be candidates to receive available standard therapies.

These patients were given subcutaneous epcoritamab as part of a step-up approach. Predefined priming or intermediate doses were given over 2 weeks, and this was followed by full doses that ranged from 0.0128 mg to 60.0 mg by cohort. This strategy was used as an effort to mitigate the severity of cytokine release syndrome (CRS) experienced with the agent.

Patients received a priming dose of epcoritamab on day 1 of cycle 1, and an intermediate dose on day 8 of cycle 1; the latter was given at the 1.5-mg full dose level to bridge the gap between the priming dose and the full dose. Beyond the priming dose, the agent was given at 1 mL in 28-day cycles until disease progression and intolerable toxicity. Patients received weekly doses in cycles 1 and 2 on days 1, 8, 15, and 22; every 2 weeks in cycles 3 through 6 on days 1 and 15; and every 4 weeks beginning at cycle 7, to be given on day 1.

Saline infusion, systemic glucocorticosteroids, antihistamine, antipyretic medications, vasopressin or vasopressors, low- or high-flow oxygen or positive-pressure ventilation support, or intravenous tocilizumab (Actemra) were permitted to help manage CRS.

The primary end points of this portion of the research were to determine the maximum-tolerated dose and the recommended phase 2 dose of the investigational agent.

Seventy-three patients were included in the dose-escalation portion of the trial; 68 patients received the agent at full doses of 24 mg or less (n = 53), 48 mg (n = 12), or 60 mg (n = 3). Of those who received treatment, most (68%) had DLBCL, 18% had follicular lymphoma, 6% had MCL, and 4% had high-grade B-cell lymphoma. One patient each had primary mediastinal B-cell lymphoma, SLL, and MZL.

The majority of patients (94%) had an ECOG performance status of 0 or 1, 100% of patients were refractory to or had relapsed following treatment with an anti-CD20 monoclonal antibody, 99% of patients previously received chemotherapy, and 9% received prior CAR T-cell therapy. Patients had received a median of 3 prior lines of treatment, and 85% were refractory to the last line of systemic therapy they had received.

At a January 31, 2021, data cutoff date, 22% of patients were still receiving the bispecific antibody. Sixty-eight percent of patients discontinued because of progressive disease, but no patients discontinued due to toxicities. One patient discontinued treatment because of an unrelated fatal adverse effect (AE), which was pneumonia that was associated with COVID-19.

When the agent was given at a dose of 0.76 mg or higher, it produced an overall response rate (ORR) of 90% (95% CI, 55%-100%) among the 10 evaluable patients with relapsed/refractory follicular lymphoma. In 5 patients who received the full doses of the agent ranging from 12 mg to 48 mg, the ORR was slightly lower, at 80% (95% CI, 28%-99%).

Among those with relapsed/refractory DLBCL who received epcoritamab at a dose ranging from 0.76 mg to 12 mg, the ORR with the agent was just 13% (95% CI, 2%-38%). In those who received the agent at doses ranging from 12 mg to 60 mg, the ORR was 68% (95% CI, 45%-86%). When administered at 48 mg, the ORR was 88% (95% CI, 47%-100%); the ORR was 91% (95% CI, 59%-100%) among those who received the agent at doses ranging from 48 mg to 60 mg

When epcoritamab was administered at a dose ranging from 0.76 to 48 mg, 2 of 4 evaluable patients with MCL responded to treatment. Among 3 patients with high-grade B-cell lymphoma, 1 patient who was given a full dose of 6 mg achieved a partial response, 1 patient who received the 6-mg dose had stable disease, and 1 patient who received the 0.12-mg dose had disease progression.

The most common treatment-emergent AEs reported with the agent included pyrexia (69%), with was mostly associated with CRS (59%), and injection site reactions (47%). Ninety-one percent of the patients who experienced pyrexia had grade 1 or 2 events, and 97% of injection site reactions were grade 1 in severity.

CRS was reported in all the dosing groups examined, but all events were either grade 1 or 2 in severity. The most common symptoms linked with CRS were pyrexia (59%), hypotension (24%), hypoxia (18%), tachycardia (15%), and chills (10%).


  1. Genmab announces US Food and Drug Administration granted orphan drug designation to epcoritamab (DuoBody®-CD3xCD20) in follicular lymphoma. News release. Genmab A/S; March 8, 2022. Accessed March 8, 2022. https://bit.ly/3Ku3O7u
  2. Hutchings M, Mous R, Clausen MR, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021;398(10306):1157-1169. doi:10.1016/S0140-6736(21)00889-8