Epcoritamab Plus R-DHAX/C Demonstrates High Response Rates and Manageable Safety in DLBCL

Epcoritamab plus R-DHAX/C (rituximab [Rituxan], dexamethasone, cytarabine, and oxaliplatin/carboplatin) displayed encouraging responses in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are eligible for autologous stem cell transplant (ASCT), according to preliminary results from arm 4 of the phase 1b/2 EPCORE NHL-2 trial (NCT04663347), which were presented at the 2022 EHA Congress.

The overall response rate (ORR) in this arm was 88%, with 65% achieving complete metabolic response (CMR; n = 17). Specifically, 100% of patients who received transplant responded (n = 14), with 86% achieving CMR (n = 12). Additionally, 75% of patients who did not receive transplant responded (n = 9), with 42% achieving CMR (n = 5).

“We have a second attempt to cure these patients when we offer second-line chemotherapy plus ASCT,” said lead study author Raul Córdoba, MD, PhD, coordinator of the Lymphoma Unit at University Hospital Fundación Jiménez Díaz. “We need to improve the efficacy data of the strategy that we are using in order to proceed to ASCT, using platinum-based regimens such as R-DHAX/C.”

The current standard of care for relapsed/refractory DLBCL is salvage chemoimmunotherapy, such as R-DHAX/C followed by consolidation with high-dose therapy (HDT) and ASCT. However, responses to salvage therapy are often poor, which leaves patients ineligible for ASCT or with a poor prognosis after receiving ASCT.

Epcoritamab is a bispecific antibody administered subcutaneously that simultaneously binds to CD20 on B cells and CD3 on T cells, inducing T-cell–mediated killing of CD20-positive malignant B cells. This mechanism of action, which is distinct from salvage chemoimmunotherapy with R-DHAX/C, makes the agent an optimal combination partner. In the dose-escalation part of the phase 1/2 EPCORE NHL-1 trial (NCT03625037), epcoritamab monotherapy showed meaningful antitumor activity and manageable toxicity in patients with heavily pretreated B-cell non-Hodgkin lymphoma (NHL).

The EPCORE NHL-2 trial is an open-label, multicenter trial investigating the antitumor activity and safety of epcoritamab plus standard-of-care R-DHAX/C in patients with high-risk B-cell NHL. Specifically, arm 4 evaluated epcoritamab plus R-DHAX/C in adult patients with relapsed/refractory DLBCL who were eligible for HDT and ASCT.

Eligible patients included those with relapsed/refractory, de novo or histologically transformed CD20-positive DLBCL, including T-cell/histocyte­–rich DLBCL, double-hit or triple-hit DLBCL, and grade 3B follicular lymphoma. Patients also needed to be eligible for R-DHAX/C and HDT and ASCT (HDT-ASCT), with an EGOG performance status of 0 to 2. Additional eligibility criteria included adequate organ function and disease measurable by magnetic resonance imaging or computed tomography (CT).

The median age of patients enrolled in the trial was 58 years (range, 28-75 years). Of these patients, 72% had received 1 prior line of therapy (n = 21), 21% had received 2 prior lines (n = 6), 7% had received 3 prior lines (n = 2), and 10% had received previous CAR T-cell therapy (n = 3). In total, 66% of patients had primary refractory disease (n = 19), and 48% relapsed within 6 months after therapy (n = 14). A total of 59% of patients (n = 17) were refractory to their last line of therapy.

The median time from the end of a patient’s previous line of therapy to their first dose of epcoritamab plus R-DHAX/C was 6 months (range, 1-49).

A total of 29 patients received the combination every week for 3, 21-day cycles.

Rituximab was administered intravenously (IV) at a dose of 375 mg/m² every 3 weeks, dexamethasone at 40 mg/d IV or orally on days 1 through 4, cytarabine at 2 g/m² IV repeated after 12 hours every 3 weeks, carboplatin at an area under the curve of 5 mg/mL x min (Calvert formula) or oxaliplatin at 100 mg/m² IV every 3 weeks. Patients who had postponed HDT-ASCT could continue with 28-day cycles of epcoritamab monotherapy weekly in cycle 4, every 2 weeks in cycles 5 through 9, and every 4 weeks thereafter until progressive disease (PD) or unacceptable toxicity. Responses were assessed by positron emission tomography-CT using Lugano 2014 criteria. Step-up subcutaneous epcoritamab dosing and corticosteroid prophylaxis were required in cycle 1 to mitigate cytokine release syndrome (CRS).

At a data cutoff of March 25, 2022, and a median follow-up of 5.8 months (range, 1.5-11.4), 52% of patients received transplant after epcoritamab treatment (n = 15). Of the 48% of patients who did not receive transplant (n = 14), 21% received ongoing treatment (n = 6), 21% discontinued treatment due to PD, and 7% discontinued treatment due to adverse effects (AEs; n = 2).

Additional results indicated that of the 14 patients who received ASCT, 14% (n = 2) achieved partial metabolic response (PMR). A total of 12 patients postponed or canceled HDT-ASCT and continued epcoritamab monotherapy. Of these patients, 33% achieved PMR (n = 4). Of the entire evaluable population (n = 26), 23% achieved PMR (n = 6). A total of 2 patients who did not receive ASCT experienced PD compared with no patients who received ASCT.

Epcoritamab plus R-DHAX/C had a manageable safety profile, and no new safety data were observed. All CRS events were low grade and resolved with standard management. There was 1 grade 2 immune effector cell–associated neurotoxicity syndrome (ICANS) event that resolved.

The most common treatment-emergent AEs (TRAEs) of any grade were thrombocytopenia (65%), neutropenia (44%), nausea (38%), CRS (38%), and anemia (38%). AEs of special interest included grade 1 or 2 CRS, which resolved in a median time of 2 days, and grade 2 ICANS, which occurred in 1 patient who had received prior CAR T-cell therapy. In total, 2 patients had TEAEs that led to epcoritamab discontinuation: 1 with grade 2 ICANS and 1 with Guillain-Barré syndrome. No clinical tumor lysis syndrome was reported. No fatal TEAEs were observed. AEs were graded by the Common Terminology Criteria for Adverse Events version 5.0 criteria.

In total, 38% of all patients experienced CRS (n = 11), with 28% experiencing grade 1 CRS (n = 8) and 10% experiencing grade 2 CRS (n = 3).

“We have seen very encouraging high response rates, so we can increase the number of patients who can proceed to ASCT and offer a [therapy with] curative intention,” Córdoba concluded.

These findings support further investigation of epcoritamab plus R-DHAX/C in transplant-eligible patients with relapsed/refractory DLBCL.

Reference

Córdoba R, Falchi L, Phillips T, et al. Preliminary phase 1/2 results of subcutaneous epcoritamab + R-DHAX/C in patients with relapsed or refractory diffuse large B-cell lymphoma eligible for autologous stem cell transplant. Presented at: EHA 2022 Hybrid Congress; June 9-12, 2022; Vienna, Austria. Abstract P1215