Subcutaneous Epcoritamab Demonstrates Early Activity, Favorable Tolerability in CLL

Subcutaneous epcoritamab demonstrated early activity and favorable tolerability in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and high-risk features, according to preliminary results from the EPCORE CLL-1 trial (NCT04623541), presented during the 2021 ASH Annual Meeting.¹

Of the 9 patients in the trial who were response-evaluable, 4 patients achieved responses with the agent; this included 1 complete response and 3 partial responses. Those who responded had high-risk disease, and 3 out of 4 responders harbored TP53 mutations.

“These first-reported clinical data for epcoritamab in patients with relapsed/refractory CLL showed no dose-limiting toxicities [DLTs] at doses up to 48 mg, manageable safety profile and no unexpected safety findings, no patients discontinued due to cytokine release syndrome [CRS] and no cases of immune effector cell–associated neurotoxicity syndrome [ICANS] or tumor lysis syndrome were observed,” presenting author Arnon P. Kater, MD, PhD, of the University of Amsterdam, Cancer Center Amsterdam, and colleagues, wrote in a poster on the data. “The expansion part of this study in patients with relapsed/refractory CLL and Richter syndrome will open later this year.”

As more BTK and BCL-2 inhibitors have become available, the treatment of patients with relapsed/refractory CLL has significantly improved. However, novel effective therapies are still needed for patients with this disease, as many will relapse.

Autologous T-cell–based therapies, like CAR T-cell therapy, have been shown to have low efficacy and this is thought to be because of disease-induced T-cell dysfunction. This dysfunction and high levels of circulating tumor cells have made it difficult to predict the safety and efficacy of T-cell reduction therapies in this disease. Although in vitro data suggest potential high efficacy with bispecific T-cell engagers, clinical data are limited.

A fully humanized bispecific antibody, epcoritamab produces strong activation and cytotoxic activity of CD4-positive and CD8-positive T cells that target and eliminate CD20-expressing cells. Previously, data from a first-in-human trial (NCT04358458) indicated that epcoritamab monotherapy had antitumor activity and manageable safety in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Specifically, the most frequent treatment-emergent adverse effects (TEAEs) reported with the bispecific antibody included pyrexia (69%), CRS (59%), and injection-site reaction (47%). At the 2021 ASH Annual Meeting, investigators shared the first results from the dose-escalation portion of EPCORE CLL-1.

The open-label, multicenter trial enrolled patients who had a diagnosis of CLL with evidence of CD20 expression, an ECOG performance status of 0 to 2, and acceptable laboratory parameters. Patients had to have received treatment with 2 or more prior lines of systemic therapy, including treatment with, or intolerance to, a BTK inhibitor. Patients also had to have measurable disease with 5 x 109/L B lymphocytes or measurable lymphadenopathy, and/or organomegaly.

Epcoritamab was administered in 4-week cycles until disease progression or intolerable toxicity. In the phase 1b, dose-escalation portion of the trial, patients received 24 mg of epcoritamab followed by 48 mg. The phase 2 expansion portion of the research is comprised of 2 arms who are receiving the agent at the recommended phase 2 dose of 48 mg. Cohort 1 of these patients had relapsed/refractory CLL.

The primary objective of the phase 1b of the trial was safety and tolerability in terms of DLTs, and a key secondary objective was antitumor activity. The primary objective for the phase 2 portion of the trial was antitumor activity.

At a data cutoff of October 1, 2021, 11 patients were enrolled to the trial. The median age of study participants was 63 years (range, 50-77) and the majority were male (91%). The median time from initial diagnosis was 157 months (range, 57-234). Fifty-five percent of patients had an ECOG status of 0, and 45% had a status of 1. Regarding disease stage, 27% were Rai high risk, 18% were Rai intermediate risk, 9% were Binet A, 9% were Binet B, and 36% were Binet C.

Patients received a median of 6 prior lines of therapy (range, 2-9) and all had previously been treated with a BTK inhibitor. Eighty-two percent of patients received prior ibrutinib (Imbruvica), 64% received prior venetoclax (Venclexta), and 18% received prior CAR T-cell therapy.

Most patients (64%) harbored TP53 mutations, 18% had an IGHV mutation, 18% had an SF3B1 mutation, and 18% had a NOTCH1 mutation, and 9% had a BIRC3 mutation. Moreover, 45% had del (11q), 73% had del(13q), 64% had del(17p), and 27% had Trisomy 12.

With a median follow-up of 5.4 months (range, 0.3-8.9) among all patients, 36% (n = 4) remained on treatment. Sixty-four percent of patients discontinued treatment with the agent due to progressive disease (45%), death (9%), or another reason (9%). The median duration of treatment was 2.1 months (range, 0.03-6.9) and the median number of cycles initiated was 3 (range, 1-8).

Regarding safety, no DLTs were reported at either the 24-mg or the 48-mg dose. Any-grade TEAEs reported in 15% or more of patients included CRS (73%), fatigue (36%), injection-site reaction (36%), nausea (27%), abdominal pain (18%), alanine aminotransferase increase (ALT; 18%), constipation (18%), cough (18%), diarrhea (18%), dyspnea (18%), erythema (18%), hypotension (18%), hyponatremia (18%), hypophosphatemia (18%), peripheral edema (18%), and pyrexia (18%). Grade 3 TEAEs included nausea (9%), abdominal pain (9%), and ALT increase (9%).

The most common hematologic TEAEs were thrombocytopenia (grade 3, 9%; grade 4, 36%;, any grade 45%), anemia (grade 3, 27%; any grade, 27%), and neutropenia (grade 3, 9%; grade 4, 18%; any grade, 27%).

Of the 73% patients who experienced CRS, 18% had a grade 1 event and 55% had a grade 2 event. The median time to onset was 9 days (range, 2-23). CRS events occurred early in treatment and resolved. Twenty-seven percent of patients experienced CRS that required a dose delay. However, no patients discontinued epcoritamab because of this toxicity. Notably, no cases of ICANS or tumor lysis syndrome were observed with the agent.

Further clinical investigation of epcoritamab in CLL and Richter syndrome is ongoing.

Reference

1. Kater AP, Christensen JH, Bentzen HH, et al. Subcutaneous epcoritamab in patients with relapsed/refractory chronic lymphocytic leukemia: preliminary results from the Epcore CLL-1 trial. Blood. 2021;138(suppl 1):2627. doi:10.1182/blood-2021-146563