Fixed-Duration Epcoritamab Plus Pola-R-CHP Demonstrates Durable Efficacy in First-Line DLBCL

Epcoritamab Plus Pola-R-CHP
in DLBCL | Image Credit: © Bipul
Kumar - stock.adobe.com

Fixed-duration epcoritamab-bysp (Epkinly) plus polatuzumab vedotin (Polivy), rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) elicited robust and durable responses when used in the frontline treatment of patients with diffuse large B-cell lymphoma (DLBCL), according to follow-up data from arm 3 of the phase 1b/2 EPCORE NHL-5 study (NCT05283720).1

The findings, which were presented at the 2025 European Hematology Association Congress, showed that at a median follow-up of 16.1 months (range, 0.3-23.9), the regimen elicited an 100% overall response rate (ORR) in evaluable patients (n = 35), which comprised a complete response (CR) rate of 97% and a partial response (PR) rate of 3%. Patients responded to treatment early, with a median time to response of 2.7 months (range, 1.3-3.3) and a median time to CR of 2.8 months (range, 1.3-10.9). Moreover, responses proved to be durable, with median duration of response and duration of CR both not reached (NR). The 2-year progression-free survival was also NR.

“These promising results compare favorably to other regimens in [the first line] and may provide higher cure rates for patients with first-line DLBCL than standard of care,” Daniel Alan Kerr, MD, of Tampa General Cancer Institute, in Tampa, Florida, said in a presentation of the data. “Further exploration of epcoritamab plus pola-R-CHP in first-line DLBCL is warranted.”

Examining Arm 3 of EPCORE NHL-5: Design, Dosing, and Objectives

The third arm of the EPCORE NHL-5 study enrolled patients with histologically confirmed CD20-positive DLBCL, including those with DLBCL not otherwise specified, such as de novo or histologically transformed from follicular lymphoma (FL) or marginal zone lymphoma (MZL); double-hit or triple-hit lymphoma, and grade 3B follicular lymphoma. Patients were required to be at least 18 years of age; have newly diagnosed, treatment-naive disease; an ECOG performance status no higher than 2; an International Prognostic Index (IPI) score ranging from 2 to 5, and a measurable disease.

Epcoritamab was administered via step-up dosing in cycle 1, at 0.16 mg on day 1, 0.8 mg on day 8, and the full dose of 24 mg or 48 mg on day 15. For cycles 2 through 4, the full dose was given on days 1, 8, and 15; for cycles 5 through 8, epcoritamab was given at the full dose on day 1. Each treatment cycle consisted of 21 days. Polatuzumab vedotin was given at a dose of 1.8 mg/kg on day 1, rituximab at a dose of 375 mg/m2 on day 1, cyclophosphamide at 750 mg/m2 on day 1, doxorubicin at 50 mg/m2, and prednisone at 100 mg on days 1 to 5.

The primary end point is dose-limiting toxicities (DLTs) of epcoritamab plus antineoplastic agents. Other key end points included ORR and CR rate by investigator assessment, time to response and time to CR, as well as safety. Exploratory end points included analyses of biomarkers and pharmacokinetics (PK).

Investigators also established that diphenhydramine, acetaminophen, and corticosteroids would be mandatory for cytokine release syndrome (CRS) prophylaxis and would be given with the first 4 doses of epcoritamab. Although the initial recommendation was 100 mg of prednisone for 4 days, the recommendation at the time of the presentation was 15 mg of dexamethasone for 4 days. Granulocyte colony-stimulating factor (G-CSF) or pegylated G-CSF was also mandatory.

The median patient age was 64 years (range, 24-76), with 49% of patients aged 65 years or older. Fifty-one percent of patients were female, and most had Ann Arbor stage IV disease (65%), DLBCL subtype (92%), de novo DLBCL type (94%), and bulky disease smaller than 6 cm (73%). About half (54%) had germinal center B-cell (GCB) origin. Regarding ECOG performance status, 57% of patients had a status of 0, 32% had a status of 1, and 11% had a status of 2. IPI scores were 0, 2, 3, and 4 to 5 for 6%, 19%, 47%, and 28% of patients, respectively. The majority of patients (84%) had extranodal disease at screening. The median time from initial diagnosis to the first dose of epcoritamab was 0.7 months (range, 0.3-4).

The data cutoff date for the presentation was October 1, 2024. At the time of cutoff, 86% of patients completed treatment with epcoritamab, and 14% had discontinued. The most common reason for discontinuation was adverse effects (AEs; 5%), followed by other (5%), and COVID-19 (3%). Eighty-six percent of patients had completed treatment with pola-R-CHP, and 14% had discontinued it.

The median duration of exposure to epcoritamab was 5.1 months (range, 0.03-6.5), and there was a median number of 8 cycles (range, 1-8) received. More than half of patients (65%) experienced a dose delay or interruption of treatment with epcoritamab because of an AE. Additionally, the median duration of exposure to pola-R-CHP was 3.7 months (range, 0.2-4.8) and the median number of cycles received was 6 (range, 1-6). Dose reductions or delay/interruptions of pola-R-CHP due to AEs occurred in 14% and 41% of patients, respectively.

Additional Efficacy Insights

Subgroup analyses revealed that the CR rates with the epcoritamab regimen in those younger than 65 years (n = 19) and 65 years or older (n = 16) were 100% (95% CI, 82.4%-100.0%) and 93.8% (95% CI, 69.8%-99.8%). In those with 0 to 1 extranodal sites (n = 14), the CR rate was 92.9% (95% CI, 66.1%-99.8%); in those with 2 or more sites (n = 21), the CR rate was 100% (95% CI, 83.9%-100.0%). In those with bulky disease smaller than 6 cm (n = 26), the CR rate was also 100% (95% CI, 86.8%-100.0%); in those with disease that was 6 cm or larger (n = 9), the CR rate was 88.9% (95% CI, 51.8%-99.7%).

When broken down by IPI score, those with a 2 (n = 7), 3 (n = 17), or 4 to 5 score (n = 9) experienced CR rates of 100% (95% CI, 59.0%-100.0), 94.1% (95% CI, 71.3%-99.9%), and 100% (95% CI, 66.4%-100.0%), respectively. When broken down by ECOG performance status, those with a status of 0 or 1 (n = 31) experienced a CR rate of 96.9% (95% CI, 83.8%-99.9%) and those with a status of 2 (n = 3) experienced a CR rate of 100% (95% CI, 29.2%-100.0%). Those with GCB (n = 18) had a CR rate of 94.4% (95% CI, 72.7%-99.9%), and those with activated B-cell/non-GCB/unclassified disease (n = 15) had a CR rate of 100% (95% CI, 78.2%-100.0%).

Notably, rapid and sustained minimal residual disease (MRD) negativity was also reported. The MRD-negativity rate at cycle 3 day 1 was 81% in all patients and 83% in those who achieved a CR.

Safety Spotlight and PK Insights

“AEs were manageable, and the safety profile was consistent with previous findings,” Kerr said.

Any-grade treatment-emergent AEs (TEAEs) were reported in 97% of patients and 92% were related to epcoritamab. Grade 3 or 4 TEAEs occurred in 76% of patients and 57% were associated with epcoritamab. Serious AEs were observed in 54% of patients and 46% were related to epcoritamab. Eight percent of patients experienced TEAEs that led to epcoritamab discontinuation; 3% were related to the drug. One TEAE was grade 5 and it was not determined to be linked with epcoritamab. Notably, no DLTs or instances of immune effector cell–associated neurotoxicity syndrome or clinical tumor lysis syndrome occurred.

The TEAEs that occurred in at least 20% of patients included neutropenia (grade 1/2, 0%; grade 3/4, 65%), CRS (51%; 0%), anemia (13%; 19%), nausea (30%; 0%), diarrhea (27%; 0%), COVID-19 (22%; 3%), asthenia (22%; 3%), constipation (22%; 0%), peripheral neuropathy (22%; 0%), and upper respiratory tract infection (22%; 0%).

Taking a closer look at CRS, which occurred in 51% of patients, this effect was grade 1 in 35% of patients and grade 2 in 16% of patients. The median time to onset of first event was 16 days (range, 3-39), and all cases resolved in a median of 2 days (range, 1-6). CRS prophylaxis included dexamethasone (30%), other corticosteroids (68%), and intravenous (IV) fluid (24%). Interventions for CRS included tocilizumab (Actemra; 19%), corticosteroids (8%), tocilizumab plus corticosteroids (3%), and IV fluid (5%).

“CRS timing was predictable and coincided with interleukin-6 [IL-6] peak,” Kerr added. The majority of effects occurred after the first full dose in cycle 1 day 15 and were primarily confined to the first treatment cycle. Predictable IL-6 cytokine elevation was observed 24 hours following the first full dose of treatment in cycle 1 day 16.

The PK profile of epcoritamab plus pola-R-CHP proved to be comparable to what has been observed with epcoritamab monotherapy in relapsed or refractory large B-cell lymphoma and follicular lymphoma following the first full dose at 48 mg. Moreover, investigators reported that CD8-positive T cells and effector memory subsets were increased with the combination, as well as Ki67-positive proliferating CD8-positive T cells.

“Epcoritamab plus pola-R-CHP treatment expands CD8-positive effector memory T cells with an increase in differentiation and functional marker expression,” Kerr concluded.

Reference

Kerr DA, Lavie D, Avigdor A, et al. Durable efficacy with fixed-duration epcoritamab + polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) for 1L DLBCL (EPCORE NHL-5). Presented at: 2025 European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract S247.