FDA Approval Summary: Epcoritamab with Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma

Abstract

In November 2025, the U.S. FDA granted traditional approval to epcoritamab-bysp in combination with lenalidomide and rituximab (R²) for adults with relapsed or refractory follicular lymphoma (FL). Approval was based on EPCORE FL-1, a randomized, open-label trial evaluating fixed durations of epcoritamab in combination with R² versus R² alone in patients with relapsed or refractory FL. Efficacy was based on the dual primary endpoints of progression-free survival (PFS) and overall response rate (ORR), as assessed by an independent review committee (IRC). By intention-to-treat analysis (N=488), PFS was statistically significantly longer in the epcoritamab plus R² arm, with a hazard ratio (HR) of 0.21 (95% CI: 0.13, 0.33) and p<0.0001 on first interim analysis. The median PFS was not reached (95% CI: 22, NR) in the epcoritamab plus R² arm and was 11.2 months (95% CI: 10.5, NR) in the R² arm. ORR per IRC was significantly higher in the epcoritamab plus R² arm, based on prespecified analysis of the first 232 patients assessed (96% vs. 81% with R²; p<0.0001). This article summarizes key aspects of the regulatory review, including endpoint selection, randomized dose optimization, and a potential single-trial approach to support both accelerated and subsequent traditional approval.

Introduction

The treatment landscape for patients with relapsed or refractory (R/R) follicular lymphoma (FL) has rapidly evolved with development of targeted therapies. Since 2021, the U.S. FDA has approved eight chemotherapy-free regimens for patients with R/R FL. These include CD19-directed chimeric antigen receptor (CAR)-T cell therapies, bispecific antibodies, a Bruton tyrosine kinase inhibitor (zanubrutinib with obinutuzumab), and regimens built on a lenalidomide and rituximab (R²) backbone.

Epcoritamab-bysp, a CD3 × CD20 bispecific T-cell engager, received accelerated approval (AA) in June 2024 for adults with R/R FL after two or more lines of systemic therapy. The AA was based on response rate and duration observed in a multicenter, single-arm trial (1, 2). As a condition of AA, a postmarketing confirmatory trial was required to verify the clinical benefit of epcoritamab. Based on the results of the confirmatory trial (EPCORE FL-1)(2, 3), in November 2025, FDA granted traditional approval to epcoritamab in combination with R² for adults with R/R FL and converted the third-line FL monotherapy indication to traditional approval. Herein, we summarize key considerations in the regulatory review of this application.

Clinical Trial Design

EPCORE FL-1 (Study M20–638; NCT05409066) is a randomized, open-label, global phase 3 trial evaluating the addition of epcoritamab to R² in patients with R/R FL after CD20-based chemoimmunotherapy (4). Eligible patients had stage II–IV classic FL with an indication for treatment and documented CD20 expression on the most recent biopsy. Key exclusion criteria included histologic transformation, prior allograft, absolute neutrophil count < 1.0 × 10⁹/L, platelet count < 70 × 10⁹/L (or < 50 × 10⁹/L in the setting of bone marrow infiltration or splenomegaly), known active infection, and inadequate organ function or performance status.

The design originally included a dose-finding portion with 1:1:1 randomization to epcoritamab with a 48 mg target dosage plus R², epcoritamab 24 mg plus R², or R² alone in 28-day cycles for up to 12 cycles. Randomization was stratified by disease history (progressive disease within 2 years of frontline therapy [POD24, yes/no] for 1 prior line; or time from last therapy to randomization [≥6 vs. <6 months] for >1 prior line) and region (U.S./Western Europe vs. rest of world). Based on data from a concurrent Phase 1b/2 trial (GCT3013–02; NCT04663347), 48 mg was identified as the recommended target dose of epcoritamab in combination with R². This led to closure of the 24 mg arm and transition to a 1:1 randomization (epcoritamab 48 mg plus R² vs. R² alone). After weekly step-up dosing in Cycle 1, epcoritamab 48 mg was administered subcutaneously on Days 1, 8, 15, and 22 of Cycles 2 and 3, then on Day 1 of Cycles 4 through 12. Both arms received lenalidomide 20 mg once daily on Days 1 to 21 for 12 cycles and rituximab (375 mg/m² intravenously on Days 1, 8, 15, and 22 of Cycle 1, then on Day 1 of Cycles 2 to 5) (2).

Initially, the primary endpoint was progression-free survival (PFS) by independent review committee (IRC) assessment using Lugano criteria (5). However, a protocol amendment in 2024 established dual primary endpoints of IRC-assessed overall response rate (ORR) and PFS based on Lugano criteria. The aim of this approach was to use a first interim analysis (IA1) of ORR to support AA, followed by traditional approval based on mature PFS results from the same trial (a “single trial” approach) (6). IA1 of ORR was conducted on the first 232 patients randomized to receive epcoritamab 48 mg plus R² or R² alone, while PFS was evaluated in all randomized patients (N=488). The key secondary endpoints in a prespecified hierarchical order were complete response (CR) rate per IRC, overall survival (OS), and minimal residual disease (MRD) negative status.

Results

A total of 488 patients with R/R FL were randomized to receive epcoritamab 48 mg plus R² (N=243) or R² alone (N=245) and comprise the intention-to-treat (ITT) efficacy population. Baseline characteristics were generally balanced between arms. In the overall population, the median age was 61 (range: 24–89) years, with 40% being age 65 or older; 72% were White, 24% Asian, and 2% were Black; and 24% were from the U.S. (4.5%) or Western Europe. Patients had a median of 1 (range: 1–7) prior line of systemic therapy, with 59% having 1, 24% having 2, and 17% having 3 or more prior lines. Few patients had prior CAR-T cell therapy (0.4%) or hematopoietic stem cell transplantation (8%). Forty-two percent had refractory disease to prior CD20-directed therapy, and 41% had disease progression within 2 years of frontline therapy.

Efficacy

Table 1 summarizes the results of the first prespecified interim analysis of EPCORE FL-1. This analysis demonstrated superiority of the epcoritamab 48 mg plus R² arm over R² alone in IRC-assessed ORR and PFS. In the first 232 patients randomized, there was a statistically significant improvement in ORR in the epcoritamab arm (96% vs. 81% with R²; p <0.0001). In the full ITT population (N=488), with a median duration of follow-up of 10.4 months, the trial demonstrated a statistically significant improvement in PFS in the epcoritamab arm with a hazard ratio (HR) of 0.21 (95% CI: 0.13, 0.33; p < 0.0001) (Fig. 1A). This interim, primary PFS analysis was performed at 54% information fraction (IF) (98 of the prespecified 181 total number of PFS events observed). The IRC-assessed CR rate was also statistically significantly higher in the epcoritamab arm (74% vs. 43%, respectively; p < 0.0001).

Table 1.

IRC-assessed efficacy results on first interim analysis

Outcome	Epcoritamab 48 mg + R2	R2
ORR Analysis Set	(N=116)	(N=116)
ORR a , n (%)	111 (96)	94 (81)
(95% CI)	(90, 99)	(73, 88)
P-valueb	< 0.0001
CR rate, n (%)	94 (81)	55 (47)
(95% CI)	(73, 88)	(38, 57)
ITT Population	(N=243)	(N=245)
PFS
Number of events, n (%)c	23 (9)	75 (31)
Progressive disease	19 (83)	63 (84)
Death	4 (17)	12 (16)
Median (95% CI), monthsd	NR (21.9, NR)	11.2 (10.5, NR)
Hazard ratiod (95% CI)	0.21 (0.13, 0.33)
P-valuee	< 0.0001
ORR, n (%)	216 (89)	181 (74)
(95% CI)	(84, 93)	(68, 79)
CR rate, n (%)	181 (74)	106 (43)
(95% CI)	(69, 80)	(37, 50)
P-valueb	< 0.0001

Abbreviations: R², lenalidomide and rituximab; CI, confidence interval; CR, complete response; ITT, intention-to-treat; ORR, overall response rate, NR, not reached; PFS, progression-free survival.

^aBased on Lugano criteria.

^bP-value (one-sided) is from a Cochran-Mantel-Haenszel test stratified by disease history and region.

^cRepresents 54% information fraction and median study follow-up of 10.4 months.

^dBased on Cox proportional hazards model stratified by disease history and region.

^eLog-rank p-value (one-sided) stratified by disease history and region.

^fKaplan-Meier estimate.

Source: FDA analysis

Figure 1.

Kaplan-Meier plots of progression-free and overall survival. (A) PFS per IRC on first interim analysis, representing 54% information fraction. (B) PFS per IRC on second interim analysis. (C) Overall survival at the time of PFS second interim analysis. Abbreviations: PFS, progression-free survival; IRC, independent review committee. Source: FDA analysis.

Results of the prespecified second interim analysis (IA2) are summarized in Table 2. With a median follow-up of 14.8 months in the ITT population, 141 PFS events had occurred, representing 78% of the total planned events. In a descriptive analysis, the results continued to indicate an improvement in PFS with epcoritamab plus R² arm compared to R² alone (Table 2 and Fig. 1B).

Table 2.

Efficacy results on second interim analysis (ITT population)

Outcome	Epcoritamab 48 mg + R2 (N=243)	R2 (N=245)
PFS per IRC
Number of events, n (%)a	35 (14)	106 (43)
Progressive disease	29 (83)	91 (86)
Death	6 (17)	15 (14)
Median (95% CI), monthsb	NR (NR, NR)	11.7 (11.1, 15.1)
HRc (95% CI)	0.21 (0.14, 0.31)
1-year PFS ratec (95% CI)	86 (81, 90)	49 (41, 56)
Overall survival
Number of events, n (%)	10 (4)	25 (10)
Median (95% CI), monthsb	NR (NR, NR)	NR (NR, NR)
HRc (95% CI)	0.38 (0.18, 0.80)d

Abbreviations: CI, confidence interval; IRC, Independent Review Committee; NR, not reached; OS, overall survival, PFS, progression free survival.

^aRepresents 78% information fraction and a median follow-up of 14.8 months.

^bKaplan-Meier estimate.

^cBased on Cox proportional hazards model stratified by disease history and region.

^dThe results are not significant, as the P-value did not cross the prespecified O'Brien-Fleming efficacy boundary (< 0.0001).

Source: FDA analysis

OS, which was prespecified to be tested at IA2, did not cross the efficacy bound (Table 2 and Fig. 1C). The survival data were immature, representing a median duration of follow-up of 14.8 months and an IF of 24% (35 of the prespecified 146 OS events). However, the OS data favored the epcoritamab arm and did not cross the pre-specified boundary for harm. As OS did not cross the prespecified efficacy boundary, MRD status was not formally tested.

Safety

In EPCORE FL-1, safety was based on 243 recipients of epcoritamab 48 mg plus R² and 238 recipients of R² alone. Select common adverse reactions (ARs) are summarized in Table 3 and detailed in the U.S. prescribing information (USPI) (2). In both arms combined, 85% of patients received thromboembolism prophylaxis, which included aspirin in the majority.

Table 3.

Select adverse reactions with higher rates in recipients of epcoritamab plus R² compared to R² alone

Adverse reaction by categorya		Epcoritamab 48 mg + R2 (N = 243)		R2 (N = 245)
		All Grades, %	Grade 3–4, %	All Grades, %	Grade 3–4, %
Adverse reactions (≥15% any grade and ≥5% higher in epcoritamab arm), excluding laboratory terms
Skin	Rash	46	11	34	6
Infections	Upper respiratory tract infection	33	3.3	18	0.4
	Pneumonia	24	16	8	4.6
	COVID-19	23	5	13	1.3
General	Fatigue	31	4.9	24	21
	Injection site reaction	27	0	0.4	0
	Fever	23	0.4	11	1.3
Immune disorders	CRS	24b	0	0.8	0
Gastrointestinal	Constipation	26	0.8	21	0
Nervous system	Neurological changes	15	1.2	8	1.3
New or worsening laboratory abnormalities (≥30% all grade and ≥10% higher in epcoritamab arm) c
Hematologicd	Neutrophils decreased	86	67	75	41
	Lymphocytes decreased	86	62	56	15
	Hemoglobin decreased	66	7	52	4.7
	Platelets decreased	50	10	37	7
Chemistry	ALT increased	58	7	36	0.9
	Phosphate decreased	49	–	28	–
	Sodium decreased	43	4.1	23	2.6
	Potassium decreased	41	9	20	4.7
	AST increased	40	2.9	29	0.9

^aIncludes grouped terms. Refer to prescribing information for definitions. An adverse reaction is an adverse event for which there is a reasonable possibility of a causal relationship to the drug.

^bCRS rate is based on 131 patients who received epcoritamab at the recommended dosage schedule.

^cDenominator varies, based on the number of patients with a baseline value and at least one post-treatment value

^dGrade 4 incidences: In epcoritamab plus R² arm, neutrophils decreased 41%, lymphocytes decreased 13%, platelets decreased 4.1%; in R² arm, neutrophils decreased 20%, lymphocytes decreased 3.0%, platelets decreased 3.4%.

Source: FDA summary and epcoritamab U.S. prescribing information

The epcoritamab plus R² arm had higher rates of serious ARs (51% vs. 27% with R² alone), including higher rates of serious infections (28% vs. 14%, respectively) driven largely by pneumonia and COVID-19. Although most patients (82%) in the epcoritamab arm had treatment interruptions due to ARs and 22% had lenalidomide dose reduction, the mean relative dose intensity of lenalidomide was similar between arms, suggesting that addition of epcoritamab did not appreciably compromise R² delivery. ARs occurring at least 10% more frequently in the epcoritamab arm, excluding laboratory abnormalities, included cytokine release syndrome (CRS), rash, respiratory infections, injection site reactions, fever, and opportunistic infections. In the epcoritamab arm, opportunistic infections (any grade: 16% vs. 3.8% with R²) included cytomegalovirus infection (6.6%), herpesvirus (6.6%), systemic fungal infections (2.1%), and other opportunistic viral infections (2.1%). The epcoritamab USPI advises Pneumocystis jirovecii pneumonia prophylaxis throughout treatment and consideration of herpesvirus prophylaxis.

In the epcoritamab arm, the most common new or worsening Grade 3 or 4 laboratory abnormalities were cytopenias (Table 3). Rates of Grade 4 neutrophil and lymphocyte decreases were numerically higher in recipients of epcoritamab plus R² (41% and 13%, respectively) than R² alone (20% and 3.0%, respectively). Despite higher rates of leukopenia and infections in the epcoritamab arm, the observed rate of fatal ARs was not increased (1.6% vs. 2.9% with R² alone; updated analysis).

The USPI for epcoritamab includes Boxed Warnings for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), each briefly summarized below. Of the 243 patients who received epcoritamab 48 mg plus R², all received step-up dosing to mitigate CRS, and 131 received the approved step-up dosing schedule detailed in the following section. CRS occurred in 24% of those 131 patients, including Grade 1 CRS in 19%, Grade 2 in 5%, no Grade 3 or higher CRS, and serious CRS in 12%. Most CRS events (88%) occurred during Cycle 1 (5% of patients after the 0.16 mg dose, 3.8% after the 0.8 mg dose, 2.3% after the 3 mg dose, and 18% after the first 48 mg dose). The median time to onset was 41 hours after the first 48 mg dose and 78 hours after the most recent dose (2). Concurrent neurologic ARs occurred in 1.5% of patients with CRS.

Premedications are necessary to reduce the risk of CRS. Patients with FL should be assessed for whether hospitalization or outpatient monitoring for the first 48 mg dose is appropriate based on comorbidities or other situational factors. Patients monitored in the outpatient setting after the first 48 mg dose should remain in proximity to a healthcare facility capable of managing CRS (2).

In EPCORE FL-1, 15% of patients in the epcoritamab arm developed neurologic changes including mental status changes and cognitive disorders; one case of ICANS (0.8%, Grade 1) was reported among patients who received the recommended step-up dosing schedule.

Clinical Pharmacology

The recommended epcoritamab dosage in combination with R² consists of a 3 step-up dosing schedule of 0.16, 0.8, and 3 mg administered weekly by subcutaneous injection, followed by a target dose of 48 mg administered weekly through Cycle 3, then once every 4 weeks from Cycle 4 through Cycle 12 (28-day cycles), in the absence of disease progression or unacceptable toxicity.

Two different step-up dosing schedules were evaluated in the pivotal study EPCORE FL-1. Compared with the 2-step up dosing schedule (0.16/0.8/48 mg), the 3-step up dosing schedule (0.16/0.8/3/48 mg) was associated with a substantially reduced incidence of CRS: from 46% (Grade 2: 9.8%) to 24% (Grade 2: 5.3%) with no Grade 3 or higher CRS. Serious CRS occurred in 26% vs. 12% of patients, respectively. The 3-step up dosing schedule is not expected to impact efficacy, as the first full epcoritamab dose is delayed by only one week.

The dosing schedules evaluated in EPCORE FL-1 were informed by the dose-finding study GCT3013–02 (NCT04663347), which evaluated two target doses of epcoritamab (24 mg and 48 mg) in combination with R² in patients with R/R FL who received at least one prior regimen containing an anti-CD20 monoclonal antibody. The study also evaluated two schedules for the 48 mg dose: 48 mg given weekly in Cycles 1–3, every 2 weeks in Cycles 4–9, then every 4 weeks thereafter vs. weekly on Cycles 1–2, then every 4 weeks from Cycle 3. An interim efficacy and safety analysis indicated that epcoritamab 48 mg had a higher CR rate than 24 mg (92% vs. 77%) with similar rates of Grade 3 or higher ARs. This study also demonstrated that epcoritamab administered weekly for 3 cycles had a higher CR rate than weekly dosing for 2 cycles (92% vs. 83%), and the efficacy was maintained during once every 4 weeks dosing. Therefore, the recommended target dose of epcoritamab in combination with R² was identified as 48 mg administered weekly in the initial 3 cycles (Cycles 1 to 3) and then every 4 weeks in Cycles 4 to 12. This dosing schedule was subsequently implemented in EPCORE FL-1.

No differences in the exposure (area under the plasma concentration-time curve [AUC] and average plasma concentration [C_avg]) of epcoritamab were observed when given as monotherapy or in combination with R². Exposure-response (E-R) analyses were conducted using the data (N = 438) from the two target doses of epcoritamab, 24 mg and 48 mg, plus R² in EPCORE FL-1 and Study GCT3013–02. E-R analysis for efficacy did not indicate notable differences in IRC-assessed ORR or CR rate between the two doses and suggested an association between the higher dose and longer durability of response. The E-R analysis for safety did not identify any new safety concerns with the 3 step-up dosing schedule (0.16/0.8/3/48 mg).

Regulatory Insights

EPCORE FL-1 provides substantial evidence of efficacy and demonstrates the clinical benefit of epcoritamab in combination with R² in patients with R/R FL. The safety profile was consistent with the established toxicity profiles of epcoritamab and the R² regimen. Overall, the results supported a favorable benefit-risk determination and traditional approval. The FDA’s benefit-risk determination is summarized in Table 4. Because EPCORE FL-1 was the postmarketing confirmatory trial for the third-line FL monotherapy indication approved in 2024, these data also supported conversion of that AA to traditional approval. Key considerations in the regulatory review of epcoritamab for R/R FL are next summarized.

Table 4.

Benefit-risk assessment of epcoritamab plus R² in patients with relapsed or refractory follicular lymphoma

Dimension	Evidence and Uncertainties	Conclusions
Analysis of Condition	• FL remains generally incurable, and relapse is nearly universal	• More effective but tolerable treatment options are needed for R/R FL.
Efficacy	• Efficacy was demonstrated in EPCORE FL-1, a phase 3 study that randomized 488 patients with R/R FL to receive a fixed duration of either epcoritamab 48 mg + R2 or R2 alone. On first interim analysis, the dual primary endpoints of IRC-assessed ORR and PFS were met, demonstrating the superiority of epcoritamab to R2. In the full ITT population,  - PFS HR was 0.21 (95% CI: 0.13, 0.33; p<0.0001), with a median study follow-up of 10.4 months. Median PFS was not reached (95% CI: 22, NR) in the epcoritamab + R2 arm vs. 11.2 months (95% CI: 10.5, NR) in the R2 arm.  - CR rate per IRC was 74% vs. 43%, respectively (p<0.0001). • On second interim analysis, PFS results were consistent. OS data favored the epcoritamab arm (HR 0.38; 95% CI, 0.18, 0.80) but are immature.	• The results confirm the clinical benefit of the addition of epcoritamab to R2. • Efficacy of epcoritamab + R2 is not well defined in patients with extensively pretreated FL or failure of CAR-T cell therapy.
Risks	• ARs that occurred ≥10% more frequently in the epcoritamab arm included CRS, rash, respiratory infections, injection site reactions, fever, and opportunistic infections. • The epcoritamab arm had higher rates of Grade 4 neutrophil (41%) and lymphocyte (13%) decreases and higher rates of serious ARs, including serious infections (28%) driven by respiratory illnesses. • In the 131 patients who received the recommended dosage schedule, CRS occurred in 25% (all Grade 1–2), and ICANS occurred in 0.8%.	• The risks of epcoritamab + R2 are acceptable in the intended R/R FL population. No new safety signals were identified. • The USPI includes warnings and precautions for CRS, ICANS, infections, and cytopenias. For risk mitigation, the USPI includes guidelines for hospitalization, pre- and post-epcoritamab medications, dose modifications, and infection prophylaxis.
Benefit/Risk	• EPCORE FL-1 provides substantial evidence of efficacy, with acceptable safety, in the intended population.	• Epcoritamab + R2 has an overall favorable benefit/risk in patients with R/R FL, supporting traditional approval. • The results verify the clinical benefit for the epcoritamab monotherapy indication, previously under accelerated approval, for the third- or later-line treatment of FL.

Source: FDA analysis

As a condition of AA, confirmatory trials are usually required to verify and describe the drug’s anticipated clinical benefit. As with EPCORE FL-1, these trials are often conducted in an earlier disease setting and may involve monotherapy or combination regimens. The epcoritamab development plan in FL exemplifies the timely verification of clinical benefit, with less than 1.5 years elapsing between AA and traditional approval. FDA’s Oncology Center of Excellence has underscored the importance of expeditiously confirming or refuting clinical benefit following AA (7). For lymphoma therapies, AA is typically based on response rate and duration of response in single-arm trials. These endpoints are reasonably likely to predict clinical benefit, but do not necessarily indicate clinical benefit (6), and disconnects between response rate, PFS, and OS may arise (8). Typically, after conducting a single-arm trial(s) to support AA of an oncology drug, sponsors have conducted a randomized controlled trial (RCT) evaluating survival outcomes to verify clinical benefit (7). In 2023, FDA was granted statutory authority to require the confirmatory trial(s) to be underway at the time of AA (9). The determination of “underway” is based on several factors, including current trial enrollment, projections on accrual completion and trial readout, and whether there is sufficient assurance of the trial’s timely completion (9).

A newer approach to expediting confirmation of clinical benefit is the “single-trial” approach. With this strategy, a single RCT could be used to support both AA (e.g., initial assessment based on a response-based endpoint, supported by durability) and subsequent traditional approval (based on longer-term follow-up of PFS and OS to confirm clinical benefit). In this setting, the trial could involve a family of statistical endpoints. This strategy is potentially more efficient than conducting two separate trials and addresses the expectation that a confirmatory trial be underway at the time of AA. This epcoritamab application represents the first lymphoma application that implemented a “single-trial” approach. This application was also reviewed under the Summary Review program, which maximizes efficiency by relying on sponsor-submitted data to support approval of a supplemental application without independent FDA verification of all data analyses.

Throughout the development of epcoritamab plus R², FDA and the sponsor had several meetings to discuss the overall registrational approach, including acceptable endpoints. Initially, PFS by IRC was the primary endpoint for EPCORE FL-1 with the intent of supporting traditional approval. The sponsor subsequently amended the EPCORE FL-1 protocol to include dual primary endpoints of ORR and PFS, with the intent of potentially supporting AA at the time of IA1.

At the time of IA1, the PFS IF was 54%. FDA generally discourages efficacy claims based on an interim analysis of PFS from immature data, such as data with less than 75% IF, as such analyses may not provide a sufficiently robust assessment and may overestimate the treatment effect. However, the PFS results at IA1, which demonstrated a substantially reduced risk of disease progression or death, were robust based on sensitivity and supplementary analyses, were consistent across subgroups including geographic region, and were supported by the observed ORR and CR rates. Furthermore, updated PFS results based on more mature data (i.e., an IF >75%), submitted during the review cycle, showed a consistent treatment benefit. Based on the totality of evidence and the robustness of the efficacy results at IA1, this application was ultimately granted traditional approval.

There are several notable limitations of the EPCORE FL-1 efficacy data, included under-representation of racial minorities, and underrepresentation of patients who were heavily pre-treated with only 17% of patients having received 3 or more prior lines of therapy. Therefore, the efficacy of epcoritamab plus R² in patients with extensively pretreated FL is uncertain, as is efficacy in patients with R/R disease after CAR-T cell therapy, since only one patient in the epcoritamab arm had prior CAR-T cell therapy. The optimal sequencing of CAR-T cell therapy relative to bispecific T-cell engagers, including epcoritamab, has not yet been established. Additionally, though favoring the epcoritamab arm, the OS data are immature; longer-term follow-up is prespecified in the analysis plan.

OS is considered an important endpoint that informs both the efficacy and the safety profile of the treatment. During the investigational new drug (IND) stage of EPCORE FL-1, FDA recommended incorporation of OS monitoring for harm to assess for interim evidence of increased mortality that could warrant early trial termination for safety concerns. This is distinct from an OS futility analysis, which evaluates whether the trial is likely to demonstrate an eventual survival benefit. The OS results at both IA1 and IA2 did not cross the pre-specified OS harm boundaries (HR of 1.43 and HR of 1.29, respectively). These boundaries were selected based on extensive simulation studies to ensure that, across a range of plausible OS HRs, the probability of observing an HR that exceeds these boundaries would be sufficiently high at the planned information fractions. Additionally, at the time of IA2, the OS HR was less than 1, with numerically fewer deaths in the epcoritamab arm. Based on the totality of clinically meaningful evidence of effectiveness, observed at both the interim and updated analyses, with no signal of OS harm, the review team determined that the data were adequately robust to support traditional approval.

Adequate dose optimization is another strength of the EPCORE FL-1 data. Dose optimization continues to be of utmost importance when evaluating add-on therapies. Project Optimus is an Oncology Center of Excellence initiative aimed to reform the dose optimization and dose selection paradigm in oncology drug development, with the ultimate goal of conducting dose optimization as early and efficiently as possible to bring new therapies to patients (10, 11). The epcoritamab dosages evaluated during dose optimization studies provided information to support the recommended dosage. As part of the dose-finding study, the evaluation of two different 48 mg dosages, in combination with R², highlighted that weekly epcoritamab doses for 3 cycles were associated with better responses than weekly epcoritamab doses for 2 cycles. Additionally, a lower intensity of every 4 weeks as early as 3 cycles after weekly dosing maintained responses without exposing patients to additional unnecessary doses or added toxicity. Additionally, the evaluation of two dosages (48 mg vs. 24 mg) in a randomized trial, with the option to close one dosage arm, and less frequent administration after Cycle 3 compared to monotherapy, provided sufficient data to support the approved dosage.

Conclusion

The approval of epcoritamab plus R² provides expanded treatment options for patients with R/R FL. The application exemplifies the timely confirmation of clinical benefit, the importance of randomized dose optimization, and the potential for a “single-trial” approach to streamline regulatory approval.