Epcoritamab Elicits 63.1% ORR in Relapsed/Refractory Large B-cell Lymphoma

Epcoritamab was found to produce an encouraging overall response rate (ORR) in patients with relapsed or refractory large B-cell lymphoma (LBCL) who previously received CAR T-cell therapy, according to topline data from the phase 1/2 EPCORE NHL-1 trial (NCT03625037).¹

The investigational subcutaneous bispecific antibody produced an ORR of 63.1%, as confirmed by an independent review committee (IRC), in a cohort of 157 patients with relapsed or refractory LBCL who received at least 2 prior lines of systemic therapy. Notably, 38.9% of these patients previously received treatment with a CAR T-cell therapy. This percentage was noted to have exceeded the prespecified threshold for efficacy per the trial protocol.

Moreover, the median duration of response with epcoritamab in these patients was 12 months.

Regarding safety, the most common toxicity experienced by those who received the agent was cytokine release syndrome (CRS), and this occurred in 49.7% of patients; 2.5% of these cases were grade 3 in severity.

Data from EPCORE NHL-1 will be submitted for presentation at a future medical conference, according to Genmab A/S.

“Together with our partner AbbVie, we will work with regulatory authorities to determine next steps and continue to evaluate epcoritamab in a variety of clinical trials as a potential treatment option for patients with various hematological malignancies,” Jan van de Winkel, PhD, chief executive officer of Genmab, stated in a press release. “We look forward to sharing the findings at a future medical meeting.”

The open-label, multicenter EPCORE NHL-1 trial was comprised of 2 parts: a phase 1 first-in-human, dose-escalation part, and a phase 2 expansion part. The dose-escalation portion of the research included patients with relapsed, progressive, or refractory CD20-positive mature B-cell non-Hodgkin lymphoma who were aged 18 years or older.²

Specifically, the trial included those with de-novo or transformed diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, primary mediastinal LBCL, follicular lymphoma, mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL).

To be eligible for enrollment, patients needed to have previously received an anti-CD20 monoclonal antibody–containing regimen, have measurable disease, an ECOG performance status ranging from 0 to 2, and acceptable renal and hepatic function. They could not be eligible to receive all available standard options, and they could not have had central nervous system lymphoma or CAR T-cell therapy within 30 days prior to receiving their first dose of epcoritamab. They also could not have chronic or ongoing infections or require immunosuppressive therapy.

In the phase 1 portion of the trial, patients received subcutaneous epcoritamab using a step-up approach, which comprised predefined priming or intermediate doses given over the course of 2 weeks, followed by full doses ranging from 0.0128 mg to 60 mg by cohort.

Participants were given the priming dose of the bispecific antibody subcutaneously on day 1 of cycle 1 and an intermediate dose, introduced at the 1.5 mg full dose level, to bridge the gap between the priming dose and the full dose, on day 8 of cycle 1. The agent was given in 28-day treatment cycles until progressive disease or intolerable toxicity. The specific schedule included weekly dosing in cycles 1 and 2 and every 2 weeks in cycles 3 through 6.

To further mitigate CRS severity, investigators administered prophylactic treatment with corticosteroids, antipyretics, and antihistamines 30 minutes to 120 minutes prior to the first 4 injections of epcoritamab, as needed, in cycle 2. During cycle 1, patients were hospitalized for at least 72 hours following the first and second administration of the agent, and for 24 hours after the third and fourth administrations.

The primary end points of the dose-escalation portion of the research were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the bispecific antibody.

A total of 73 patients were enrolled, and 68 patients received epcoritamab at full doses of 24 mg or less (n = 53), 48 mg (n = 12), or 60 mg (n = 3). Of these patients, 68% had DLBCL, 18% had follicular lymphoma, 6% had MCL, and 4% had high-grade B-cell lymphoma. The last 3 patients had primary mediastinal LBCL, SLL, and MZL.

Ninety-four percent of patients had an ECOG performance status of 0 or 1, and all participants were refractory to or had relapsed following treatment with anti-CD20 monoclonal antibodies. Ninety-nine percent of patients previously received chemotherapy. The median number of prior lines of treatment received was 3, and 85% of patients were refractory to their last line of systemic treatment. Nine percent of patients previously received CAR T-cell therapy.

Notably, among those with DLBCL, the median number of prior lines of systemic therapy received was 3, 15% previously underwent autologous stem cell transplant, and 11% received prior CAR T-cell therapy. Those with follicular lymphoma received a median of 5 lines of prior systemic treatment.

No dose-limiting toxicities were observed with epcoritamab. At a data cutoff of January 31, 2021, the MTD had not yet been reached, and 48 mg was identified as the RP2D for the agent. The most common treatment-emergent adverse effects reported with epcoritamab included pyrexia (69%), which was primarily linked with CRS (59%), and injection site reactions (47%), which included tenderness, warmth, erythema, itching, and pain.

In the phase 2 dose-expansion portion of the research, investigators set out to further explore the safety and efficacy of epcoritamab in 3 cohorts of patients with different types of relapsed or refractory B-cell non-Hodgkin lymphomas who had limited therapeutic options available.

The primary end point of this phase of the research was ORR per IRC assessment. Key secondary end points included DOR, complete response (CR) rate, duration of CR, progression-free survival, and time to response per Lugano criteria. Other end points included overall survival, time to next therapy, and rate of minimal residual disease negativity.

In March 2022, the FDA granted an orphan drug designation to epcoritamab for use in patients with follicular lymphoma.3 Epcoritamab is under exploration as a single agent in patients with relapsed or refractory DLBCL, as part of an open-label, randomized, phase 3 trial (NCT04628494).⁴ The agent is also being explored in a phase 1b/2 trial (NCT04663347), which is being done in patients with DLBCL and follicular lymphoma,⁵and a phase 1/2 trial (NCT04542824), which is being done in Japanese patients with relapsed or refractory non-Hodgkin lymphoma.⁶

References

1. Genmab and AbbVie announce topline results for epcoritamab (DuoBody-CD3xCD20) from phase 1/2 trial in patients with relapsed/refractory large B-cell lymphoma (LBCL). News release. Genmab A/S; April 13, 2022. Accessed April 14, 2022. https://bit.ly/3M4dYwm
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
3. 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 April 14, 2022. https://bit.ly/3Ku3O7u
4. A phase 3 trial of epcoritamab in R/R DLBCL. ClinicalTrials.gov. Updated November 10, 2021. Accessed April 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04628494
5. Safety and efficacy trial of epcoritamab combination in subjects with B-cell non-Hodgkin lymphoma (B-NHL) (EPCORE NHL-2). ClinicalTrials.gov. Updated April 14, 2022. Accessed April 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04663347
6. Trial of safety and efficacy of epcoritamab in Japanese subjects with R/R B-NHL. ClinicalTrials.gov. Updated January 11, 2022. Accessed April 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04542824