Epcoritamab for R/R B-Cell Non-Hodgkin Lymphoma Proves Safe, Effective

Further investigation of epcoritamab (DuoBody®-CD3xCD20) for the treatment of relapsed or refractory B-cell non-Hodgkin lymphoma is warranted after the agent proves safe with preliminary antitumor benefit, according to results of a phase 1/2 study published in The Lancet.¹

Over half of patients with relapsed or refractory B-cell non-Hodgkin lymphoma relapse after high-dose chemotherapy and autologous stem-cell transplantation (ASCT). Additionally, many patients are ineligible for ASCT due to factors such as comorbidities, age, or insufficient response to salvage chemotherapy. For patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma who relapse within 2 year after first-line therapy, the prognosis is poor, despite high response rates to chemotherapy.

Epcoritamab, which was created using the controlled antigen-binding fragment-arm exchange method, is a full-length IgG1 bispecific antibody that is derived from a humanized mouse anti-human CD3 monoclonal antibody and a human anti-CD20 monoclonal antibody. Preclinical studies have found that the agent may induce selective T-cell mediated cytotoxic activity against CD20-positive malignant B cells. 

"These initial trial results are encouraging, and their publication in The Lancet speaks to the strong interest from the clinical community in this important area of study," said Mohamed Zaki, MD, PhD vice president and head, global oncology development, AbbVie, one of epcoritamab’s co-developers, in a press release.² "We look forward to further study of epcoritamab in B-cell lymphomas and other hematologic malignancies, and our continued pursuit of potential new treatment options for patients."

The phase 1/2 EPCORE trial (NCT03625037) was designed to find the maximum-tolerated dose and safety of epcoritamab in patients with relapsed, progressive, or refractory B-cell lymphoma. The sequential assignment study, open-label study, has an estimated enrollment of 486 participants and an estimated study completion date of December 30, 2025. Primary end points include adverse events (AEs), tolerability, and clinical efficacy evaluation. Secondary end points include pharmacokinetic parameters, immunogenicity of the anti-drug antibody, and patient-reported outcomes.³

The analysis looked at 73 patients enrolled in the dose-escalation portion of the study between June 2018 and July 2020. Lymphoma types included diffuse large B-cell lymphoma (68%), follicular lymphoma (18%), mantle cell lymphoma (6%), and 3 had high-grade B-cell lymphoma (4%). Additionally, 1 patient had primary mediastinal large B-cell lymphoma, 1 patient had small lymphocytic lymphoma, and 1 patient had marginal zone lymphoma.1

Of the 73 patients enrolled, 68 were administered study therapy and included in the safety analysis set. Fifty-three patients were allocated to epcoritamab ≤24 mg, 12 were allocated to epcoritamab 48 mg, and 3 were allocated to epcoritamab 60 mg.

In the ≤ 24 mg arm, 44 patients discontinued treatment, 41 patients discontinued due to progressive disease and 3 due to the initiation of new treatment. Nine patients remained on study at the time of analysis.

In the 48 mg arm, 8 patients discontinued treatment. Reasons for discontinuation included progressive disease (5), investigator decision (1), adverse event (1), and death (1). Four patients were still on study treatment at the time of the analysis.

In the 60 mg arm, 1 patient discontinued treatment due to the initiation of new treatment. Two patients were still on study treatment at the time of the analysis.

The median age for the general population was 68 (range, 57-75) and 665 were male. ECOG performance status included 0 (51%), 1 (43%), 2 (4%), and 3 (1%). Ann Arbor stages included 1 (4%), 2 (18%), 3 (24%), and 4 (54%). Sixty-two percent had extranodal disease. The median time since diagnosis was 29.7 months (range, 13.7-66.8) and the median time since relapse or progression was 1.6 months (range, 1.1-2.3). The median number of previous lines of therapy was 3 (range, 2-4.5). Previous therapies included anti-CD20 monoclonal antibodies (100%), anthracyclines (91%), alkylating agents (99%), ASCT (15%), and chimeric antigen receptor (CAR) T cell therapy (9%). Eighty-five percent of patients were refractory to their last line of systemic therapy, 82% were refractory to alkylating agents, and 87% were refractory to their last anti-CD20 monoclonal antibody therapy.

The median age of the relapsed or refractory diffuse large B-cell lymphoma cohort (n = 46) was 68 (range, 55-74) and 65% were male. ECOG performance statuses included 0 (50%), 1 (46%), and 2 (4%) and Ann Arbor Stages included 1 (7%), 2 (11%), 3 (26%), and 4 (57%). Sixty-three percent of patients had extranodal disease. The median time since diagnosis was 25.4 months (range, 11-54.6) and the median time since relapse or progression was 1.5 months (range, 1.1-2.3 months. The median number of previous lines of therapy was 3 (range, 2-4). Previous therapies included anti-CD20 monoclonal antibodies (100%), anthracyclines (100%), Alkylating agents (100%), ASCT (15%), and CAR T cell therapy (11%). Eighty-nine percent of patients were refractory to their last line of systemic therapy, 87% were refractory to alkylating agents, and 89% were refractory to their last anti-CD20 monoclonal antibody.

The median age of the relapsed or refractory follicular lymphoma cohort (n = 12) was 73 (range, 63-76) and 67% were male. ECOG performance statuses included 0 (50%), 1 (33%), 2 (8%), and 3 (8%). Ann Arbor stages included 2 (33%), 3 (33%), and 4 (33%), Fifty percent of patients had extranodal disease. The median time since diagnosis was 61.5 months (range, 24.2-153.1) and median time since last relapse or progression was 1.6 months (range, 1.2-2.6). The median number of prior lines of therapy was 4.5 (range, 2.5-8). Previous therapies included anti-CD20 monoclonal antibodies (100%), anthracyclines (75%), alkylating agents (100%), and ASCT (8%). Eighty-three percent of patients were refectory to their last line of systemic therapy, 75% were refectory to alkylating agents, and 83% were refractory to their last anti-CD20 monoclonal antibody.

The overall response rate (ORR) of patients with relapsed or refractory diffuse large B-cell lymphoma who received 12-60 mg of epcoritamab (n = 22) was 68% (95 CI, 45-86). A complete response was seen in 45% of patients and a partial response in 23% of patients. Stable disease was seen in 23% of patients. The median time to response was 1.4 months (range, 1.2-2.6). The follow-up duration was 9.3 months (8.2-14.8).

In patients with relapsed or refractory diffuse large B-cell lymphoma who received 48 mg (n = 8), the ORR was 88% (95% CI, 47-100). A complete response was seen in 38% of patients, and a partial response in 50% of patients. The median time to response was 1.4 months (range, 1.3-2.6) with a median follow-up duration of 9.3 months (range, 8.2-14.8).

In patients with relapsed or refractory diffuse large B-cell lymphoma who received 60 mg (n = 3), the overall response rate was 100% (95% CI, 29-100). And all were complete responses. The median time to response was 1.3 months (range, 1.1-1.4) and the median follow-up duration was 9.2 months (range, 9.2-9.3).

In patients with relapsed or refractory follicular lymphoma who received 0.76-48 mg of the study agent (n = 10), the overall response rate was 90% (95% CI, 55-100). Complete responses were seen in 50% of patients and a partial response was seen in 40% of patients. Progressive disease was seen in 10% of patients. The median time to response was 1.9 months (range, 1.5-3.5) and the median follow-up duration was 13.6 months (range, 10.4-16.5).

No response was seen in the 1 patient with relapsed or refractory follicular lymphoma who received 58 mg of epcoritamab. The patient experienced progressive disease, and the follow-up duration was 6.6 months.

In patients with relapsed or refectory mantle cell lymphoma who received 0.76-48 mg (n = 4), the ORR was 50% (95% CI, 7-93). A complete response was seen in 25% of patients and a partial response in 25% of patients. Stable disease was seen in 25% of patients. The median time to response was 1.4 months (range, 1.3-1.5) and the median follow-up duration was 10.2 months (range, 7.6-10.5).

The patient with relapsed or refectory mantle cell lymphoma who received 48 mg of the agent experienced a partial response. The time to response was 1.3 months and the follow-up duration was 7.7 months. 

In terms of safety, common grade 1/2 AEs included pyrexia (63%), cytokine release syndrome (59%), injection site reaction (47%), fatigue (38%), and diarrhea (26%). Grade 3 AEs included pyrexia (6%), fatigue (6%), hypotension (6%), and anemia (13%). Grade 4 dyspnea was seen in 1% of patients.

Cytokine release syndrome was more common in patients in the 48 mg and 60 mg cohorts, occurring in 67% of patients in each arm compared with 57% of patients in the ≤ 24 mg arm. Neurological symptoms occurred in 8% of patients in the ≤ 24 mg arm. Grade 3 tumor lysis syndrome occurred in 8% of patients in 48 mg arm.

No dose limiting toxicities were observed and 48 mg was identified as the recommended phase 2 dose.

"The publication of these data in The Lancet, coupled with the presentation of the results at multiple medical congresses, demonstrate the importance of these early results and underscore the significant interest in the potential of next generation antibody therapeutic options for patients diagnosed with hematologic malignancies, whose current treatments may not be providing benefit," said Jan van de Winkel, PhD, chief executive officer of Genmab, one of epcoritamab’s co-developers in a press release. "Together with our partner, AbbVie, we are committed to evaluating the, safety and efficacy of epcoritamab in patients diagnosed with B-cell lymphomas and other hematologic malignancies."

_REFERENCES:

_{1.Hutching M, Mous R, Clausen M, 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.}

_{2.Clinical trial of investigational epcoritamab (DuoBody®-CD3xCD20) in patients with relapsed/refractory b-cell non-Hodgkin's lymphoma (B-NHL) published in the lancet. News release. AbbVie. September 9, 2021. Accessed November 15, 2021. https://bit.ly/3wRZ3Pw.}

_{3.GEN3013 trial in patients with relapsed, progressive or refractory B-cell lymphoma. ClinicalTrials.gov. Accessed November 15, 2021. https://bit.ly/3Hooey0.}