Epcoritamab Shows Robust Antitumor Activity, Acceptable Safety in Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

Pipeline Report | <b>Pipeline Report: September 2021</b>

Epcoritamab had a manageable toxicity profile when subcutaneously administered to patients with relapsed/refractory B-cell non-Hodgkin lymphoma and was found to elicit encouraging responses in those who were heavily pretreated.

Epcoritamab had a manageable toxicity profile when subcutaneously administered to patients with relapsed/refractory B-cell non-Hodgkin lymphoma and was found to elicit encouraging responses in those who were heavily pretreated, according to findings from a phase 1/2 study (NCT03625037) published in the Lancet.1

Among those with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), epcoritamab elicited an overall response rate (ORR) of 13% (95% CI, 2%-38%) in those who received the agent at a dose ranging from 0.76 mg up to 12 mg. In those who received a dose ranging from 12 mg to 60 mg, the ORR was higher, at 68% (95% CI, 45%-86%). When the agent was given at 48 mg, the ORR climbed to 88% (95% CI, 47%-100%); when administered at a dose ranging from 48 mg to 60 mg, the ORR was highest, at 91% (95% CI, 59%-100%).

Ten evaluable patients with relapsed/refractory follicular lymphoma (FL) who received epcoritamab at a dose of 0.76 mg or higher experienced a high ORR of 90% (95% CI, 55%-100%). Among 5 evaluable patients who received the full doses of the agent ranging from 12 mg to 48 mg, the ORR was 80% (95% CI, 28%-99%).

Moreover, 2 of 4 evaluable patients with mantle cell lymphoma (MCL) responded to epcoritamab, when given at a dose ranging from 0.76 mg to 48 mg). In 3 patients with high-grade B-cell lymphoma, a partial response was achieved in 1 who received the full dose of 6 mg, 1 achieved stable disease with the 6-mg dose, and 1 experienced disease progression after receiving a 0.12-mg dose of the agent.

Notably, no dose-limiting toxicities (DLTs) were reported with the agent, the maximum tolerated dose had not yet been reached, and the full dose of 48 mg was identified as the recommended phase 2 dose. As such, the trial met its primary end point.

“Epcoritamab showed potent, single-agent, antitumor activity and an overall manageable safety profile,” Martin Hutchings, MD, PhD, lead study author and senior consultant in the Department of Hematology at the Copenhagen University Hospital, and colleagues, wrote. “Coupled with the mechanism of action and ease of administration of epcoritamab, these findings are highly encouraging for patients with relapsed or refractory B-cell non-Hodgkin lymphoma.”

Epcoritamab, a full-length IgG1 bispecific antibody, is derived from a humanized mouse anti-human CD3 monoclonal antibody and a human anti-CD20 monoclonal antibody. The agent was developed through the controlled antigen-binding fragment–arm exchange method that utilizes a technology platform referred to DuoBody and permits the retention of the native IgG1 structure and normal binding to the neonatal Fc receptor, which translates to a long half-life.

Preclinical data have demonstrated that epcoritamab has resulted in potent and selective T-cell–mediated cytotoxic activity against CD20-positive malignant B cells. Results from 2 in vivo studies indicated that when the agent was delivered subcutaneously to cynomolgus monkeys, the animals experienced a similar degree of prolonged B-cell depletion as they had with the intravenous formulation.

Notably, because the subcutaneous administration led to delayed and lower peak cytokine levels vs the intravenous formulation, it is hypothesized that this route of delivery may reduce the risk of cytokine release syndrome (CRS).

The first-in-human phase 1/2 dose-escalation and -expansion trial was launched to further examine subcutaneous epcoritamab in patients with relapsed/refractory non-Hodgkin lymphoma.

To be eligible for enrollment to the dose-escalation portion of the research, patients needed to be at least 18 years of age and have relapsed, progressive, or refractory CD20-positive mature B-cell non-Hodgkin lymphoma, which could include de novo or transformed DLBCL, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, FL, MCL, small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL).

Moreover, patients needed to have previously received an anti-CD20 monoclonal antibody–containing regimen, have measurable disease, an ECOG performance status of 0 to 2, and acceptable renal and hepatic function. They could not have been eligible to receive all standard options.

In the phase 1 dose-escalation portion of the research, subcutaneous epcoritamab was given to patients using a step-up approach. Predefined priming or intermediate doses were delivered over the course of 2 weeks, and this was followed by full doses that ranged from 0.0128 mg to 60.0 mg by cohort. Investigators utilized this strategy to mitigate the severity of CRS.

Participants were given the priming dose of the agent on day 1 of cycle 1 and an intermediate dose on day 8 of cycle 1; the latter was introduced at the 1.5-mg full dose level to bridge the gap between the priming dose and the full dose. Moreover, epcoritamab was given at 1 mL in 28-day treatment cycles until progressive disease or intolerable toxicity per the following schedule: 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.

Notably, prior to the first 4 injections of the agent, prophylactic treatment with corticosteroids, antipyretics, and antihistamines were given to patients; these treatments were also given on an as-needed basis during cycle 2 to further mitigate the severity of CRS. Patients were also hospitalized for at least 72 hours following the first and second dose of the agent during cycle 1.

Patients were also permitted to receive concomitant medications or treatments like supportive care in the form of saline infusion, systemic glucocorticosteroids, antihistamine, antipyretic

medications, vasopressin or vasopressors, low- or high-flow oxygen or positive-pressure ventilation support, or intravenous tocilizumab (Actemra) to manage CRS.

The primary end points of the dose-escalation portion of the trial were to identify the maximum-tolerated dose of epcoritamab and the recommended phase 2 dose of the agent.

A total of 73 patients were enrolled to the dose-escalation portion of the trial and 68 patients were given epcoritamab at full doses of 24 mg or less (n = 53), 48 mg (n = 12), or 60 mg (n = 3). Among the patients who received treatment, 68% had DLBCL, 18% had FL, 6% had MCL, and 4% had high-grade B-cell lymphoma. One patient each had primary mediastinal B-cell lymphoma, SLL, and MZL.

Ninety-four percent of patients had an ECOG performance status of 0 or 1, and all patients were refractory to, or had relapsed following treatment with an anti-CD20 monoclonal antibody. Moreover, 99% of patients had prior chemotherapy. The median prior lines of treatment received was 3, and 85% of these patients were reported to be refractory to the last line of systemic therapy they had received. Nine percent of patients had prior CAR T-cell therapy.

At the data cutoff date of January 31, 2021, 22% of the patients who received epcoritamab were still on treatment. Most patients (68%) discontinued the agent because of disease progression. None of the patients discontinued treatment because of treatment-related toxicities, but 1 patient did so due to an unrelated fatal adverse effect (AE), which was COVID-19–related pneumonia.

Regarding safety, the most frequent treatment-emergent toxicities reported with the agent included pyrexia (69%), which was largely linked with CRS (59%), as well as injection site reactions (47%), which included tenderness, warmth, erythema, itching, and pain. The majority (91%) of pyrexia cases were grade 1 or 2 and all but 1 injection site reaction were grade 1 (97%).

Sixty-eight percent of patients experienced serious AEs, the most common of which were pyrexia and pneumonia. Twenty-eight percent of patients experienced a serious AE of pyrexia that was determined to be related to the treatment.

Additionally, CRS was reported in all of the different dosing groups, but all cases were grade 1 or 2 in severity and were determined to be manageable. The median time to onset of the first CRS effect following the first priming dose of epcoritamab was 1.4 days (range, 0.9-3.1). After the full dose of the agent was given, the median time to onset was 1.8 days (range, 0.8-3.1). Incidence nor severity of this effect did not increase with higher doses of the agent.

The median time to resolution of the longest CRS event was 1.0 day (range, 0.5-2.0) with respect to cases that occurred following the first priming dose; for cases occurring after the first full dose of the agent, the median time to resolution was 2.2 days (range, 0.9-4.6).

The most frequent symptoms associated with CRS included pyrexia (59%), hypotension (24%), hypoxia (18%), tachycardia (15%), and chills (10%).

Four patients who received the agent at a dose of 24 mg or lower experienced neurological symptoms determined to possibly be related to the investigative agent and these included grade 1 partial seizure, grade 1 agraphia, grade 3 hypersomnia, and grade 3 confusion and depressed level of consciousness.

“Epcoritamab is currently being studied in a range of trials, including other phase 1/2 studies, as a single agent or in combination with other anti-lymphoma therapies across a range of B-cell non-Hodgkin lymphoma histologies, in the relapsed or refractory setting as well as in previously untreated patients,” the study authors concluded.

Reference

  1. 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