First‐line treatment with epcoritamab in combination with bendamustine plus rituximab induces sustained remissions beyond 3 years in patients with follicular lymphoma

Abstract

First‐line (1L) bendamustine plus rituximab (BR) leads to high response rates in follicular lymphoma (FL), but maintaining durable remissions remains challenging. We report the 3‐year follow‐up from arm 3 of the phase 1b/2 EPCORE NHL‐2 trial (NCT04663347) of epcoritamab, a subcutaneously administered CD3×CD20 bispecific antibody, combined with BR in patients with newly diagnosed FL. Twenty‐five patients received epcoritamab plus BR, followed by epcoritamab monotherapy for up to 2 years. At a median follow‐up of 41.3 months, the best overall response and CR rates were both 96%. The median time to CR was 1.5 (range 1–6) months. At 3 years, 87% of responders maintained CR. High CR rates were observed across subgroups, including 100% of patients with bulky disease (≥7 cm), 93% with Follicular Lymphoma International Prognostic Index score ≥3, and 100% with bone marrow involvement. The three‐year progression‐free survival and overall survival rates were 83% and 96%, respectively. Three patients progressed within 24 months of initiating treatment. Long‐term data were consistent with prior reports and the known safety profiles of the individual agents, with no high‐grade cytokine release syndrome or immune effector cell‐associated neurotoxicity syndrome events. Infections occurred in 92% of patients; COVID‐19 was the most common (84%). Overall, 1L FL treatment with epcoritamab plus BR resulted in deep, durable responses beyond 3 years with a consistent safety profile. These results compare favorably with BR alone, although they require confirmation in further studies, and highlight the versatility of epcoritamab in combination with various standards of care and in improving outcomes in FL.

INTRODUCTION

Follicular lymphoma (FL) accounts for approximately 20% of non‐Hodgkin lymphomas (NHLs) and has the second‐highest incidence among lymphoma subtypes overall. ¹ , ² Chemoimmunotherapy (CIT) regimens such as bendamustine plus rituximab (BR) are common treatment options globally for patients with previously untreated FL ³ , ⁴ , ⁵ , ⁶ and demonstrate favorable efficacy and safety profiles compared with another common first‐line (1L) treatment for FL, rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). ⁷ , ⁸ Specifically, treatment with BR in the 1L setting has been shown to produce higher overall response rates (ORRs), complete response (CR) rates, and 3‐year progression‐free survival (PFS) rates compared with R‐CHOP. ⁹ , ¹⁰ , ¹¹ Rituximab plus lenalidomide (R²) is a promising chemotherapy‐free 1L treatment with a safety profile that differs from that of CIT regimens. ¹² However, treatment of indolent lymphomas such as FL with CIT or R² is not curative, and relapsing patients have, overall, progressively shorter remissions with subsequent therapies; most patients eventually require several treatment regimens. ⁷ A subset of patients also experience disease progression within 24 months (POD24) after 1L therapy and have a poor long‐term prognosis. ¹³ , ¹⁴ For example, 12% of 1L patients in the phase 3 RELEVANCE trial experienced POD24, with no difference between the R² and CIT groups. ¹⁵ Therefore, despite advances in therapy, there is still a need for novel treatment combinations that provide deeper and more durable responses in FL.

Epcoritamab is a subcutaneously (SC) administered CD3×CD20 bispecific antibody (BsAb) that is approved as monotherapy for relapsed or refractory FL after ≥2 lines of systemic treatment and in combination with R² after ≥1 line of systemic treatment. ¹⁶ , ¹⁷ Recent reports have demonstrated that epcoritamab plus R² induces deep, durable remissions with an 88% CR rate in 1L FL and an 83% CR rate in relapsed or refractory FL. ¹⁷ , ¹⁸ Epcoritamab induces T‐cell–mediated killing of CD20⁺ B cells and indirectly promotes natural killer (NK) cell activation. ¹⁹ , ²⁰ , ²¹ Rituximab functions through NK‐cell–mediated antibody‐dependent cellular cytotoxicity of tumor cells, ²² and prior studies have shown that, despite both binding to CD20, neither epcoritamab nor rituximab negatively affects the tumor‐killing function of the other agent when combined at clinical concentrations. ²⁰ , ²³ Instead, epcoritamab enhances rituximab‐mediated cytotoxicity and demonstrates mechanistic potentiation of cytotoxicity, ²¹ highlighting the combination of epcoritamab with BR as an attractive potential treatment option in FL. Here, we report updated, long‐term efficacy and safety results of epcoritamab in combination with BR in patients with previously untreated FL from the EPCORE NHL‐2 trial.

MATERIALS AND METHODS

Study design and treatment

EPCORE NHL‐2 (NCT04663347) is a phase 1b/2, open‐label, multicenter, multicohort dose‐escalation (Part 1) and dose‐expansion (Part 2) clinical trial investigating the safety and efficacy of epcoritamab (alone or in combination with standard therapies) in patients with B‐cell NHL. In arm 3, patients with no prior systemic FL treatment received epcoritamab plus BR for six 28‐day cycles (cycles [C] 1–6), followed by epcoritamab monotherapy for up to 2 years. Epcoritamab was administered SC once weekly (QW) as a two step‐up dose regimen in C1, comprising one 0.16 mg priming dose (C1, day [D] 1) and one 0.8 mg intermediate dose (C1D8), followed by full 48 mg doses QW in C1–3, every 2 weeks in C4–9, and every 4 weeks (Q4W) from C10 through the 2‐year maximum treatment duration. Bendamustine 90 mg/m² was administered on D1–2 and rituximab 375 mg/m² was administered on D1 of C1–6 (Supporting Information S1: Figure S1).

Patients received premedication with antihistamines (diphenhydramine 50 mg or equivalent) and antipyretics (acetaminophen 650–1000 mg or equivalent) prior to each epcoritamab administration in C1, and daily cytokine release syndrome (CRS) prophylaxis with corticosteroids (prednisolone 100 mg orally or oral/intravenous corticosteroid equivalent) for 4 days prior to each dose of epcoritamab in C1 and during repriming.

As supportive treatment, patients received prophylaxis for Pneumocystis jirovecii initially per the investigator's discretion, which was later mandated when corticosteroids were administered for 4 or more consecutive days. Prophylaxis against herpes was required if there was a history of recurrent herpes infections, neutropenia, and/or low CD4⁺ cell counts (<200 cells/μL). Immunoglobulin (Ig) and growth factors could be administered per the investigator's discretion, but in the event of recurrent grade 3 or higher neutropenia, growth factors were mandated.

The study was approved by the institutional review board or central ethics committee at each participating institution, and was conducted according to the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation E6 consolidated guideline for Good Clinical Practice, and applicable regulatory requirements. All patients provided written informed consent.

Patients

Key inclusion criteria for arm 3 of the EPCORE NHL‐2 trial were previously untreated FL grade 1–3A, CD20⁺ FL at representative (previous or current) tumor biopsy, measurable disease (defined as ≥1 measurable nodal lesion [long axis >1.5 cm and short axis >1.0 cm] or ≥1 measurable extra‐nodal lesion [long axis >1.0 cm] on computed tomography [CT] or magnetic resonance imaging [MRI]), Eastern Cooperative Oncology Group performance status score of 0–2, and a need for treatment due to symptoms and/or disease burden as defined by Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. ²⁴ Key exclusion criteria included grade 3B FL or histologically confirmed transformation to aggressive lymphoma, clinically significant cardiovascular disease, prior lymphoma therapy, or central nervous system involvement of lymphoma.

Endpoints and assessments

The primary endpoint was investigator‐assessed ORR, defined as the percentage of patients achieving CR or partial response per Lugano criteria. ²⁵ To evaluate for pseudoprogression, indeterminate response was assessed by LYRIC (Lymphoma Response to Immunomodulatory Therapy Criteria). ²⁶ Tumor response was evaluated by positron emission tomography (PET)‐CT (or CT/MRI and fluorodeoxyglucose PET when PET‐CT was not available) at Weeks 6, 12, 18, 24, 36, and 48, and every 24 weeks thereafter until disease progression. Key secondary endpoints included CR rate, time to tumor response (TTR), time to CR (TTCR), duration of CR (DOCR), PFS, and overall survival (OS).

Safety/tolerability assessments of treatment‐emergent adverse events (TEAEs) were performed from the first dose of the drug until either 60 days after the last dose or the date of patient withdrawal of consent, the start of a new systemic anticancer therapy, or death—whichever occurred first (up to ~3 years). Adverse events (AEs) were coded using Medical Dictionary for Regulatory Activities version 27 and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All TEAEs, including serious AEs, were assessed from the day of the first treatment dose until 60 days after the last dose of epcoritamab, or until the start of new anti‐lymphoma therapy if this occurred earlier. Serious AEs considered by the investigator as related to epcoritamab were reported after the safety follow‐up visit (>60 days after the last dose). CRS and immune effector cell‐associated neurotoxicity syndrome (ICANS) were graded using American Society for Transplantation and Cellular Therapy consensus grading criteria, ²⁷ and clinical tumor lysis syndrome (TLS) was graded according to Cairo–Bishop criteria. ²⁸ Second primary malignancies were reported on an ongoing basis.

Longitudinal assessments of peripheral NK cells, CD4⁺ T cells, and CD8⁺ T cells were performed by flow cytometry (cells/µL) using the A438 TBNK panel (IQVIA Laboratories). Ig levels were assessed by individual investigators using standard assays on the first day of every cycle, at the end of treatment, during the safety follow‐up, and after treatment follow‐up.

Statistical analysis

All analyses were descriptive and based on the full analysis set, which included all patients who received ≥1 dose of study treatment. ORR was summarized, with the corresponding 95% confidence intervals calculated using the Clopper–Pearson method. Time‐to‐event endpoints were analyzed using Kaplan–Meier methods, and patients without an event were censored at the date of last disease assessment/contact. For the OS analysis, patients for whom death was not reported were censored at the latest date they were known to be alive. Safety analyses were conducted in the safety population, which also included all patients who received ≥1 dose of study treatment.

RESULTS

Patients and treatment exposure

In total, 25 patients were enrolled between March 2021 and November 2021 to receive epcoritamab plus BR for 6 cycles, followed by epcoritamab monotherapy maintenance for up to 2 years. Baseline characteristics are presented in Table 1. Fourteen patients (56%) were male, the median age was 56 years (range 32–80 years), 56% had a Follicular Lymphoma International Prognostic Index (FLIPI) ²⁹ score of 3–5, and 28% had bulky disease (≥7 cm) (Table 1). All patients met at least 1 GELF criterion. The median (interquartile range) time from initial diagnosis to first dose was 7.1 (4–45) weeks; 15 patients (60%) had high beta‐2 microglobulin levels, 10 patients (40%) had elevated lactate dehydrogenase levels, and 3 patients (12%) had received prior radiotherapy. Overall, 23 of the 25 patients had received COVID‐19 vaccination.

Table 1.

Baseline demographic and clinical characteristics.

Characteristics	Epcoritamab plus BR (N = 25)
Age at confirmed consent
Median, years (range)	56 (32–80)
<65 years, n (%)	18 (72)
Male at birth, n (%)	14 (56)
Race, n (%)
White	19 (76)
Black/African American	1 (4)
Not reported	5 (20)
ECOG PS, n (%)
0	19 (76)
1	6 (24)
2	0
Histologic grade, n (%)
1	2 (8)
2	14 (56)
3A	9 (36)
Ann Arbor stage, n (%)
III	10 (40)
IV	15 (60)
FLIPI score, n (%)
0–1	2 (8)
2	9 (36)
3–5	14 (56)
Bulky disease,a n (%)
<7 cm	18 (72)
≥7 cm	7 (28)
Bone marrow involvement, n (%)	12 (48)
LDH
Elevated	10 (40)
Normal	15 (60)
Beta‐2 microglobulin, n (%)
High	15 (60)
Normal	8 (32)
Missing	2 (8)
Median (range) time from initial diagnosis to first dose, weeks	7 (4–45)

Abbreviations: BR, bendamustine plus rituximab; ECOG PS, Eastern Cooperative Oncology Group performance status; FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase.

^a Per investigator, classified by the largest diameter of any lesion.

As of the data cutoff on April 9, 2025, the median follow‐up was 41.3 months. Eleven patients (44%) completed treatment per protocol and 14 (56%) did not complete the 2 years of trial treatment of epcoritamab. Nine patients (36%) discontinued treatment due to AEs (7 due to COVID‐19), 1 patient (4%) discontinued due to progressive disease (PD), 2 patients (8%) withdrew consent, 1 patient (4%) discontinued due to patient decision, and 1 patient (4%) with long‐term COVID‐19 and persistent CR discontinued due to medical decision. Patient disposition is shown in Figure 1.

Figure 1.

EPCORE NHL‐2 arm 3 patient disposition. Flowchart illustrating patient screening, enrollment, and disposition as of the data cutoff on April 9, 2025. ^a“Other” reasons for treatment discontinuation were patient decision, and medical decision in a patient with long‐term COVID‐19 and persistent CR. AE, adverse event; CR, complete response; PD, progressive disease.

During the combination therapy phase, the median duration of treatment was 6, 5, and 5 months for epcoritamab, rituximab, and bendamustine, respectively (Supporting Information S1: Table S1). Twenty‐four patients (96%) completed 6 cycles of rituximab, and 22 patients (88%) completed 6 cycles of bendamustine. The median relative dose intensities (RDIs) were 100%, 99%, and 99% for epcoritamab, rituximab, and bendamustine, respectively. During the epcoritamab monotherapy phase, the median duration of treatment was 14 months, with an RDI of 99% in C7–9 and 97% in C10 and beyond (Supporting Information S1: Table S1).

Twenty‐four patients (96%) received systemic antibacterials (including prophylaxis for P. jirovecii). Twenty‐two patients (88%) received antiviral agents as either prophylaxis or treatment of viral infection. Fifteen patients (60%) received granulocyte colony‐stimulating factor as either prophylaxis or treatment of neutropenia. Eight patients (32%) received Ig in the conventional setting as substitution or as infection prophylaxis.

Efficacy

ORRs and CR rates were both 96% (24/25 patients), with only 1 patient (4%) experiencing the best overall response of PD (Table 2 and Figure 2A). Notably, the CR rate and ORR at the end of epcoritamab plus BR treatment was 96%, which matches the best ORR. Responses were observed early, with a median TTR and TTCR of 1.5 months, corresponding with the first scheduled assessment (Table 2). The median DOCR was not reached (NR), and an estimated 87% of patients remained in CR at 3 years (Figure 2B). High CR rates (≥83%) were observed across patient subgroups, including 100% (7/7) of patients with bulky disease, 93% (13/14) of patients with a FLIPI score ≥3, and 100% (12/12) of patients with bone marrow involvement (Supporting Information S1: Figure S2). In total, 19 of 24 patients (79%) had CR at data cutoff.

Table 2.

Best ORRs and TTR.

	Epcoritamab plus BR (N = 25)
ORR, n (%)	24 (96)
95% CI	80–100
CR, n (%)	24 (96)
95% CI	80–100
PR, n (%)	0
PD, n (%)	1 (4)
TTR, months (range)	1.5 (1.1–2.6)
TTCR, months (range)	1.5 (1.1–5.6)

Abbreviations: BR, bendamustine plus rituximab; CI, confidence interval; CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; TTCR, time to complete response; TTR, time to response.

Figure 2.

Responses in patients who received 48 mg doses of epcoritamab plus BR ( N  = 25). (A) Swim lane plot detailing the treatment and response duration. Each bar represents an individual patient. The length of the bar indicates the time from the start of treatment. Symbols denote unique or changed responses relative to the prior assessment and the final response; intervening assessments with the same response are not shown. Per protocol, patients continued to receive scans if they discontinued treatment for reasons other than PD. One patient with PD by Lugano had PD IR3 by LYRIC that converted back into CR after the data cutoff. (B) Kaplan–Meier curve showing the DOCR for patients who achieved CR. The y‐axis represents the probability of maintaining CR and the x‐axis represents the time in months from the first documented CR. The numbers below the x‐axis denote the number of patients with available data at each assessment. Tick marks indicate censored patients. AE, adverse event; BR, bendamustine plus rituximab; CI, confidence interval; CR, complete response; DOCR, duration of complete response; EOT, end of treatment; IR, indeterminate response; LYRIC, Lymphoma Response to Immunomodulatory Therapy Criteria; NE, not estimable; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease.

Among the 24 patients with CR, 11 patients completed treatment per protocol, all of whom (100%) had CR at the end of treatment. Of these patients, 9 (82%) maintained their CR at data cutoff, with a median post‐treatment follow‐up of 18 months (Figure 2A).

Eleven patients discontinued treatment while in CR for reasons other than PD or death and had a response measurement after discontinuation (median treatment duration, 12.7 months); CR was maintained in 9 (82%) of these patients at data cutoff, with a median posttreatment follow‐up for DOCR of 24 months (Figure 2A).

Among all patients (N = 25), the median PFS and OS were both NR, with estimated 36‐month rates of 83% and 96%, respectively (Figure 3A,B). Three patients (12%) experienced POD24, and these were the only patients who received subsequent antilymphoma therapy during this study. One of these patients (4%) experienced PD on the first assessment in this study. In this patient, FL grade 3A was detected in an inguinal lymph node at baseline. At the time of disease progression, a liver biopsy was performed that showed CD30 pleomorphic B‐cell lymphoma—a mixed feature between Hodgkin lymphoma and diffuse large B‐cell lymphoma. The patient was then treated with R‐CHOP, and upon further progression, continued with brentuximab and rituximab with ifosfamide, carboplatin, and etoposide with autologous stem cell transplantation, with ongoing remission at the time of last follow‐up. Of the remaining 2 patients who had initially responded to treatment, 1 received 7 subsequent lines of therapy, including CIT and allogenic stem cell transplantation, and the other received rituximab monotherapy.

Figure 3.

Kaplan–Meier curves illustrating PFS (A) and OS (B) in patients treated with 48 mg doses of epcoritamab plus BR ( N  = 25). The dashed line shows the 36‐month estimate. The y‐axis represents the probability of survival (PFS or OS) and the x‐axis represents the time in months. Tick marks indicate censored patients. The numbers below the x‐axis denote the number of patients with available data at each assessment. BR, bendamustine plus rituximab; CI, confidence interval; NR, not reached; OS, overall survival; PFS, progression‐free survival.

Safety

All 25 patients treated with epcoritamab plus BR experienced ≥1 TEAE. The most common TEAEs were COVID‐19 (84%), CRS (68%), nausea (64%), injection‐site reaction (56%), fatigue (52%), neutropenia (52%), and serious infection (52%). Grade ≥3 TEAEs were reported in 23 patients (92%). The most common grade ≥3 TEAEs were serious infection (44%), including COVID‐19 (24%) and neutropenia (40%) (Table 3). Serious TEAEs were reported in 18 patients (72%). The incidence of grade ≥3 TEAEs and serious TEAEs was the highest during the first 24 weeks of treatment (epcoritamab plus BR), with rates improving during the epcoritamab monotherapy treatment period. This trend held true for both overall neutropenia and grade ≥3 neutropenia.

Table 3.

Summary of most frequent (>20%) TEAEs by worst toxicity grade in patients treated with 48 mg epcoritamab plus BR.

	Epcoritamab plus BR (N = 25)
Event, n (%)
Any TEAE	25 (100)
Grade ≥3 TEAE	23 (92)

Most common (>20%) TEAEs, n (%)	Any grade	Grade ≥ 3
COVID‐19a	21 (84)	6 (24)
CRSb	17 (68)	0
Nausea	16 (64)	0
Local injection‐site reactionc	14 (56)	0
Fatigue	13 (52)	1 (4)
Neutropeniad	13 (52)	10 (40)
Serious infectione	13 (52)	11 (44)
Constipation	12 (48)	0
Pyrexia	10 (40)	0
Anemiaf	9 (36)	2 (8)
Cough	9 (36)	0
Vomiting	7 (28)	1 (4)
Back pain	6 (24)	0
Decreased appetite	6 (24)	0
Diarrhea	6 (24)	0
Headache	6 (24)	0
Leukopeniag	6 (24)	3 (12)
Myalgia	6 (24)	0
Rash	6 (24)	0
Thrombocytopeniah	6 (24)	0

Note: Data shown are TEAEs and selected combined terms occurring for any‐grade TEAEs reported in ≥20% of patients.

Abbreviations: BR, bendamustine plus rituximab; CRS, cytokine‐release syndrome; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment‐emergent adverse event.

^a COVID‐19 includes COVID‐19 or COVID‐19 pneumonia.

^b CRS signs and symptoms included fever in 17 patients, hypotension in 4 patients, hypoxia in 1 patient, and other symptoms in 11 patients.

^c Local injection‐site reaction includes injection‐site reactions as MedDRA High Level Group Terms.

^d Neutropenia includes neutropenia or neutrophil count decreased.

^e Serious infections include serious TEAEs in the MedDRA System Organ Class of infections and infestations, including COVID‐19. Details of specific serious infections can be found in Supporting Information S1: Table S2.

^f Anemia includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell counts decreased, and serum ferritin decreased.

^g Leukopenia includes leukopenia and white blood cell count decreased.

^h Thrombocytopenia includes hematopoietic thrombocytopenia using Standardised MedDRA Queries narrow search.

Infection occurred in 23 patients (92%). There were 33 infection events (including 5 grade ≥3 events) during the combination treatment and 52 infection events (including 10 grade ≥3 events) during epcoritamab monotherapy. Details of serious infections by type are included in Supporting Information S1: Table S2, and infections by time period during the study period are included in Supporting Information S1: Table S3. With regard to Ig levels in these patients, an initial decline from baseline to C3D1 was observed, but they generally remained at a lower level through C26D1 (Figure 4A–C).

Figure 4.

Individual datapoint box‐and‐whisker plots for (A) IgG, (B) IgA, and (C) IgM levels (mg/dL) in patients over the course of treatment, from baseline through C26D1. The numbers below the x‐axis denote the number of patients with available data at each assessment. C, cycle; D, day; IgA, immunoglobulin A; IgG, immunoglobulin G; and IgM, immunoglobulin M.

During the combination treatment, 1 patient (4%) discontinued all treatment due to PD during C3. Twenty‐three patients (92%) completed 6 cycles of bendamustine; 1 patient (4%) discontinued bendamustine after C2 due to rash but completed treatment with rituximab and epcoritamab, and 1 patient (4%) discontinued bendamustine after 4 cycles due to rash but completed rituximab and 11 cycles of epcoritamab. This same patient ended treatment due to a fatal TEAE of COVID‐19 despite being treated for COVID‐19 and being previously vaccinated. In total, 9 patients (36%) discontinued epcoritamab due to TEAEs: 7 (28%) due to COVID‐19 (including the patient described above), 1 (4%) due to mesenteric panniculitis, and 1 (4%) due to recurring cytomegalovirus (CMV) reactivation events during treatment. One patient (4%) was diagnosed with progressive multifocal leukoencephalopathy (PML) by brain biopsy and was alive with neurologic sequelae at the time of data cutoff, almost 2 years after PML onset. ³⁰ There was 1 death (4%) in this study due to COVID‐19‐related respiratory failure.

CRS events were experienced by 17 patients (68%). All CRS events were low grade (grade 1 or 2); most occurred after the first full dose of epcoritamab and resolved in all patients (Supporting Information S1: Table S4). There were 5 patients (20%) with serious CRS events. The median time to first onset of CRS was 16 days (range 6–29) and the median time to resolution was 2 days (range 1–7). No ICANS or clinical TLS events were reported.

Four patients (16%) experienced a secondary primary malignancy: 2 basal cell carcinoma, 1 Bowen's disease, and 1 cutaneous T‐cell lymphoma.

Pharmacodynamics

Median B‐cell levels reached undetectable levels (≤ 10 B cells/μL in blood) by C1D15 and remained undetectable in subsequent cycles (Supporting Information S1: Figure S3A). There was a decrease in peripheral CD4⁺ T cells from baseline to C4. Peripheral CD8⁺ T cells predominantly remained close to baseline levels throughout the combination treatment, resulting in a reduction in the CD4:CD8 ratio from 1.5 at C1 to 0.5 at C3, with a transient increase to 1.1 at C4, followed by a reduction that was maintained out to C7 (Supporting Information S1: Figure S3B–D). Absolute total lymphocytes decreased from baseline to C1D15 and remained close to this lower level through C7, except for a moderate increase at C3 (Supporting Information S1: Figure S3E). There was a slight decrease in circulating NK‐cell levels from baseline to C1D15, with an increase above baseline from C2D8 to C3D1 and another decrease at C4D1, after which NK‐cell levels remained lower up to at least C7 (Supporting Information S1: Figure S3F).

DISCUSSION

In this study, epcoritamab plus BR as a treatment for patients with previously untreated FL led to deep and durable responses. With over 3 years of median follow‐up, ORRs and CR rates were high, with all but 1 patient achieving CR and an estimated 87% of patients maintaining CR at 3 years. The addition of epcoritamab to BR did not impact the dose intensity of BR, and the majority of patients were able to complete the planned number of BR cycles. While the timing of the study during the COVID‐19 pandemic clearly impacted the results of the trial, overall, the long‐term safety and tolerability data were generally consistent with those of prior reports.

The most common TEAEs in this study were hematologic and infectious in nature, aligning with the known profiles of bendamustine‐ and BsAb‐containing regimens. There was 1 death due to COVID‐19, and 7 patients discontinued due to AEs of COVID‐19. Other studies conducted around the same time as this trial also observed high rates of COVID‐19. ³¹ , ³² , ³³ However, the rate of COVID‐19 infection was lower (40%) in the NHL‐1 trial of epcoritamab monotherapy for the treatment of patients with relapsed or refractory FL, despite that trial having been conducted during a similar period as this study. While the sample size in this study is small and may be confounded by the COVID‐19 pandemic, the difference in infections observed between the NHL‐1 trial and this study suggests that the addition of BR has the potential to increase infection risk.

Opportunistic infections were also observed, including 1 case of PML, 1 P. jirovecii infection, and 2 cases of CMV reactivations, of which 1 was CMV colitis. The occurrence of these infections, and particularly viral reactivations, could be ascribed to the B‐cell–depleting mechanism of action of epcoritamab, together with the immunosuppressive activity of bendamustine. As expected for a CD20‐targeting agent, our analysis confirmed that Ig levels decreased from C1 to C3, and 8 patients overall were supplemented with intravenous Ig for prophylactic/preemptive use. Given that these observations are based on a small series of patients, additional data are needed to further understand the impact of epcoritamab plus BR on opportunistic infections.

Grade ≥3 TEAEs and serious TEAEs, including neutropenia and infections, primarily occurred within the epcoritamab plus BR treatment period, and rates decreased over time during the epcoritamab monotherapy treatment period. No ICANS or clinical TLS events were reported, and all CRS events were low grade, predictable, and resolved in all patients.

The efficacy results of this trial compare favorably with those of other studies of 1L CIT in patients with FL. In this cohort of patients with difficult‐to‐treat disease features (100% Ann Arbor stage III/IV, and over half with a FLIPI score of 3–5), the CR rate was 96% and the 3‐year PFS rate was 83%. In comparison, in a retrospective analysis of patients with FL treated with 1L BR at 18 US cancer centers, CR rates were 72% in patients with grade 1–2 FL and 66% in patients with grade 3A FL, with estimated 3‐year PFS rates of 75% and 65%, respectively. ³⁴ The results from our study are also similar to recent results from another arm of the EPCORE NHL‐2 trial investigating 1L treatment with epcoritamab plus R² in patients with grade 1–3A FL, which demonstrated a CR rate of 88% and a 3‐year PFS estimate of 83%. ¹⁸ Both the study presented here and the recent results with epcoritamab plus R² suggest the potential of these treatment regimens for 1L FL treatment. These findings support the benefit of incorporating epcoritamab as a potential new backbone that would be flexibly deployed with different agent combinations in frontline FL.

This study recruited a relatively high‐risk population, including 100% of patients with Ann Arbor stage III or IV disease and 56% with a FLIPI score of 3–5. Importantly, our data showed consistent efficacy regardless of these high‐risk baseline disease characteristics. Although our study had a small sample size, these data compared favorably with other larger studies that included high‐risk populations. For instance, a study of BR with 2 years of rituximab maintenance demonstrated a CR rate of 62%, with a 3‐year PFS rate of 77% in patients with Ann Arbor stage II–IV FL and high‐risk disease characterized by high tumor burden and/or FLIPI score, and only 56% of patients with a FLIPI score of 3–5 achieved CR. ³⁵ Similarly, a retrospective study of patients with grade 1–3A FL with high tumor burden treated in 17 Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea centers showed a CR rate of 85% and a 6‐year PFS rate of 79% in cases treated with BR with 2 years of rituximab maintenance. ¹⁰

Prior exposure to bendamustine‐containing regimens has been shown to negatively affect prognosis for patients receiving chimeric antigen receptor (CAR) T‐cell therapy. ³⁶ Furthermore, given that both CAR T‐cell and BsAb therapies are T‐cell–engaging, the potential for a negative impact of prior bendamustine treatment on BsAb therapy has been considered. ³⁷ The pharmacodynamic analyses in this study showed a progressive reduction in peripheral CD4⁺ T cells during the first 3 cycles, consistent with the mechanism of action of bendamustine, ³⁸ and no negative impact on CD8⁺ T‐cell counts during treatment. The robust and rapid B‐cell depletion observed in this study and the TTCR of 1.5 months (consistent with that of epcoritamab monotherapy in NHL‐1 [TTCR, 1.5 months ¹⁵ ]) suggest that adding epcoritamab to BR did not appear to impair T‐cell cytotoxicity; however, as our translational observation did not extend beyond C7 and functional assays were not performed, further studies would be informative. This is consistent with the findings from the NHL‐1 study. ¹⁵

As this was a nonrandomized, single‐arm study, there are limitations in drawing definitive conclusions on the comparative efficacy of the combination with BR alone or other therapies used in 1L for FL. As previously noted, the small sample size of this study may also limit the generalizability of these results, particularly for subgroup analyses. TEAE reporting criteria in this study ended 60 days after the final dose of epcoritamab; however, per protocol, investigators were asked to report any serious AEs considered to be related to epcoritamab, regardless of timing. Another limitation of this study is the lack of immunophenotyping data collected past C7, which affects our ability to draw conclusions on whether T‐cell counts normalize following bendamustine treatment and during the epcoritamab monotherapy treatment period.

Given these limitations, additional studies, possibly randomized, of this combination treatment can help to further elucidate its utility for the treatment of FL within the broader treatment landscape. More generally, this study, along with other recent studies, ¹⁸ provides evidence for the use of epcoritamab in combination with current 1L treatment options to increase the effectiveness and durability of treatment responses. Expanding the number of patients who respond to 1L FL treatment and extending the time to next treatment are particularly important in light of data that demonstrate that PFS becomes progressively shorter with each line of treatment. ⁷ , ³⁹ The SC route of administration of epcoritamab also offers a more convenient option compared with intravenous therapies for both 1L and later lines of treatment across patient types and practice settings.

In conclusion, treatment of high‐disease‐burden, treatment‐naïve patients with FL with epcoritamab plus BR demonstrated high CR rates and long‐term remissions with a median follow‐up of 41.3 months. Given the potential toxicity of treatment with bendamustine, physicians should carefully consider which patients are most likely to benefit from this combination. Additional studies evaluating 1L FL treatment regimens that include epcoritamab are currently underway, including chemotherapy‐free and doublet treatment approaches. This study, along with historical evidence, suggests that epcoritamab represents a key therapy to improve outcomes in B‐cell NHL.

AUTHOR CONTRIBUTIONS

Umberto Vitolo: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Lorenzo Falchi: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Per‐Ola Andersson: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Marcel Nijland: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Fritz Offner: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Sylvia Snauwaert: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Jacob H. Christensen: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Michael R. Clausen: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Alexander Fosså: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Pilar G. Prieto: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Eliza A. Hawkes: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Judit M. Jørgensen: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Yasmin H. Karimi: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Catharina Lewerin: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Joost S. P. Vermaat: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Björn E. Wahlin: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision. Poliana Patah: Methodology; data curation; writing—original draft; writing—review and editing; visualization. Christopher Morehouse: Formal analysis; validation; visualization; writing—original draft; writing—review and editing. Malene Risum: Methodology; validation; formal analysis; data curation; writing—original draft; writing—review and editing; project administration. Zhu Li: Formal analysis; validation; visualization; writing—original draft; writing—review and editing. Jennifer Marek: Methodology; data curation; writing—original draft; writing—review and editing; visualization. Joshua D. Brody: Investigation; resources; writing—original draft; writing—review and editing; visualization; supervision.

CONFLICT OF INTEREST STATEMENT

Umberto Vitolo, MD, has received honoraria from AbbVie, AstraZeneca, Gilead, Incyte, Merck Sharp & Dohme (MSD), Regeneron Pharmaceuticals Inc., and Sobi, and served on advisory committees for AbbVie, Genmab, Gilead, Incyte, MSD, and Regeneron Pharmaceuticals Inc. Lorenzo Falchi, MD, has received research funding from AbbVie, AstraZeneca, BeOne Medicines, Genentech, Genmab, Innate Pharma, and Roche; received consultancy fees and/or honoraria from AbbVie, AstraZeneca, Chugai, Genentech, Genmab, Kite, Merck, NOBO Medicine, Roche, and Sanofi; and served on advisory boards for AbbVie, ADC Therapeutics, Bristol Myers Squibb (BMS), Chugai, Genentech, Genmab, Johnson & Johnson, and Regeneron Pharmaceuticals Inc. Per‐Ola Andersson, MD, PhD, has received research funding from Gilead and honoraria from AbbVie, AstraZeneca, BeOne Medicines, Eli Lilly, Janssen, Sobi, and Takeda. Jacob Haaber Christensen, MD, PhD, has served on advisory boards for Jannsen and Takeda, and received research funding from Takeda. Michael Roost Clausen, MD, PhD, has served on advisory boards for AbbVie, AstraZeneca, Eli Lilly, Genmab, Janssen, MSD, and Roche, and received travel expenses from AbbVie, Genmab, Janssen, Pfizer, and Roche. Alexander Fosså, MD, PhD, has received honoraria from BMS, EUSA Pharma, Johnson & Johnson, Kite/Gilead, Kyowa Kirin, MSD, Roche, Sobi, and Takeda; received research support from Roche and Takeda (outside of the submitted work); and served as a consultant for Gilead, Kite, Sobi, and Takeda. Pilar Gomez Prieto, MD, has received honoraria from AstraZeneca and Incyte, and served on speakers bureaus for Eli Lilly and Kite. Eliza A. Hawkes, MBBS Hons, FRACP, DMedSc, has received research funding from AbbVie, AstraZeneca, BMS, Merck, Roche, and TG Therapeutics; received travel expenses from AbbVie, AstraZeneca, Genmab, and Janssen; served on a data safety monitoring or advisory boards for AbbVie, AstraZeneca, BeOne Medicines, Gilead, Janssen, MSD, Novartis, Regeneron Pharmaceuticals Inc., Roche, and Sobi; and served in unpaid leadership or fiduciary roles for the American Society of Hematology, Global Lymphoma Registry Alliance, and Women in Lymphoma. Judit Meszaros Jørgensen, MD, PhD, has served on advisory boards for AstraZeneca, AbbVie, BMS, Caribou Biosciences, Gilead/Kite, Incyte, Roche, and Sobi, and received travel expenses from AbbVie and AstraZeneca. Yasmin H. Karimi, MD, has received research funding from AbbVie, AstraZeneca, Lilly/Loxo, Merck, Roche/Genentech, and Xencor, and travel expenses, consultancy fees, and honoraria from AbbVie, ADC Therapeutics, AstraZeneca, Foresight Diagnostics, Incyte, Pfizer, and Roche/Genentech. Björn Engelbrekt Wahlin has served on advisory boards for and received research funding from Incyte, and received consultancy fees from AbbVie and AstraZeneca. Poliana Patah, MD, PhD, is currently employed by AbbVie and holds equity in the company. Christopher Morehouse, MS; Malene Risum, MD, PhD; Zhu Li, MS; and Jennifer Marek, BS, are currently employed by Genmab and hold equity in the company. Joshua D. Brody, MD, has served on advisory boards for and received research funding from Asgard, AstraZeneca, BMS, Corvus, Genentech/Roche, Genmab, Kite/Gilead, Merck, and Novartis. Marcel Nijland, MD, PhD; Fritz Offner, MD, PhD; Sylvia Snauwaert, MD, PhD; Catharina Lewerin, MD, PhD; and Joost S. P. Vermaat, MD, PhD, MSc, declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

FUNDING

This study was funded by Genmab A/S and AbbVie. Umberto Vitolo is also supported by FPRC ETS 5 x 1000 Ministero della Salute 2021 EMAGEN and the Italian Ministry of Health, Ricerca Corrente 2025‐2026. Lorenzo Falchi is also supported by a grant from Blood Cancer United and through the NIH/NCI Cancer Center Support Grant P30 CA008748.

Supporting information

Supporting File 1.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are openly available in clinicaltrials.gov at https://clinicaltrials.gov/study/NCT04663347, reference number NCT04663347. Deidentified individual patient data collected during the trial will not be available upon request for further analyses by external independent researchers. Aggregated clinical trial data from the trial are provided via publicly accessible study registries/databases as required by law. For more information, please contact clinicaltrials@genmab.com.