Fixed-Duration Epcoritamab + R² Drives Deep and Durable Responses in Patients with Relapsed or Refractory Follicular Lymphoma: 2-Year Follow-up from Arm 2 of the Epcore NHL-2 Trial

Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, has been approved as a single agent for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma and follicular lymphoma (FL) after ≥2 lines of systemic therapy based on results from the phase 1/2 EPCORE® NHL-1 trial (NCT03625037). For patients (pts) with R/R FL, rituximab + lenalidomide (R²) is an approved and widely accepted regimen based on results from the AUGMENT trial (overall response rate [ORR], 78%; complete response [CR] rate, 34%; estimated 2-y progression-free survival [PFS], 58%). There exists a clear need for improvement of outcomes, especially for pts with high-risk features, including disease progression within 24 mo of first-line chemoimmunotherapy (POD24) or primary/double-refractory disease, for whom there is no established standard of care. Previously, in arm 2 of the EPCORE NHL-2 trial (phase 1b/2; NCT04663347), fixed-duration epcoritamab + R² showed encouraging antitumor activity and a manageable safety profile in a large population of pts with R/R FL, including high-risk pts (Merryman et al, ASCO 2023). Here, we present long-term follow-up beyond 2 y and minimal residual disease (MRD) analysis for the first time.

Methods: Adults with R/R CD20⁺ FL received subcutaneous epcoritamab + R² for up to 12 cycles (Cs; 28 d each). Epcoritamab was administered with a 2-step (0.16 and 0.8 mg) step-up dosing (SUD) regimen in C1 and 48-mg full doses either QW in C1-3, Q2W in C4-9, and Q4W in C≥10 (arm 2a) or QW in C1-2 and Q4W in C≥3 (arm 2b) for up to 2 y. MRD analysis was performed on peripheral blood mononuclear cell samples collected at prespecified time points (clonoSEQ® assay, Adaptive Biotechnologies) and quantified as tumor clones detected per 1 x 10⁶ nucleated cells. The primary endpoint was ORR per Lugano criteria.

Results: As of May 15, 2024, 111 pts with R/R FL had received epcoritamab 48 mg + R². Median age was 65 y, 61% had stage IV disease, and 57% had only 1 line of prior treatment. Most pts had received alkylating agents (93%) and anthracyclines (64%); 3% had received prior CAR T. At a median follow-up of 25.3 mo (range, 2.4+ to 34.1), 17 pts (15%) were still on treatment, 41 (37%) completed treatment per protocol, and 53 (48%) discontinued treatment (progressive disease, n=18; AEs, n=22; pt withdrawal, n=7; death, n=1; COVID-19 control measure, n=1; and other reason, n=4 [investigator decision]).

The ORR was 96%, and CR rate was 87%. CR rates were similarly high regardless of high-risk features: primary refractory (n=39)/non-primary refractory (n=72), 90%/86%; double refractory (n=39)/non-double refractory (n=72), 82%/90%; POD24 (n=42)/non-POD24 (n=69), 79%/93%. Estimated 24-mo PFS and overall survival rates were 70% and 90%, respectively. At 24 mo, an estimated 69% of responders remained in response (duration of response; DOR), and an estimated 75% of complete responders remained in CR (duration of CR; DOCR). MRD status was assessed in 73 evaluable pts; of these, 64 (88%) became MRD negative.

With the majority of pts being enrolled and treated during the global COVID-19 pandemic, COVID-19 was reported in 57% of pts and led to epcoritamab discontinuation in 11% of pts; COVID-19 events included 5 grade (G) 5 treatment-emergent AEs (TEAEs; COVID-19, n=3; COVID-19 pneumonia, n=2). The other most common TEAEs were neutropenia (62%) and CRS (51%). CRS events with this 2-step SUD regimen were mostly low grade (38% G1, 12% G2, 2% G≥3) and primarily occurred following the first full dose on C1D15; all resolved, and none led to epcoritamab discontinuation. ICANS occurred in 1 pt (G1) and resolved.

Conclusions: With more than 2 y of follow-up, fixed-duration epcoritamab + R² continued to show deep and durable responses (CR rate, 87%; estimated 24-mo DOCR, 75%) in pts with R/R FL, irrespective of high-risk features. Considering limitations of cross-trial comparisons, these results (estimated 2-y PFS, 70%) compare favorably with those reported for R² alone in the AUGMENT trial (estimated 2-y PFS, 58%). The depth of responses was underscored by MRD negativity in 88% of evaluable pts. There were no new safety findings, and the safety profile remained consistent with previous reports. Epcoritamab + R² is being studied further in the ongoing, randomized, phase 3 EPCORE FL-1 trial (NCT05409066).

Falchi:Genentech, Roche, Genmab, Abbvie, Sanofi, EvolveImmune: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Roche, Genmab, AbbVie, Innate, BeiGene: Research Funding; AbbVie, Genentech, ADC Therapeutics, Seagen, Ipsen: Membership on an entity's Board of Directors or advisory committees; EvolveImmune: Consultancy; Roche: Consultancy, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Research Funding; Taylor Francis: Other: Journal Editor; Kaplan: Other: CME Presentation: Projects in Knowledge. Sureda Balari:EBMT: Other: President; GETH-TC: Other: President; GSK: Consultancy, Honoraria, Speakers Bureau; Takeda Pharmaceutical: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding, Speakers Bureau; Mundipharma: Consultancy; Alexion: Honoraria; Roche: Honoraria, Other: Travel Expenses; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees. Leppä:BeiGene, Genmab, Gilead, Incyte, Novartis, Orion, Roche: Membership on an entity's Board of Directors or advisory committees; Bayer, BMS, Genmab, Hutchmed, Novartis, Nordic Nanovector, Roche: Research Funding; Gilead, Incyte, Novartis: Honoraria. Vermaat:Secura Bio: Consultancy. Holte:SERB: Consultancy; Incyte: Consultancy; Pierre Fabre: Consultancy. Merryman:Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; DG Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Merck: Research Funding. Lugtenburg:Takeda, Servier: Research Funding; BMS, Roche, Takeda, Genmab, AbbVie, Incyte, Regeneron, Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Y-mAbs Therapeutics: Other: Consultancy Honoraria. Costa:AbbVie, AstraZeneca, BMS, Janssen: Consultancy, Speakers Bureau. Linton:AbbVie: Consultancy, Research Funding, Speakers Bureau; CellCentric: Research Funding; Janssen: Research Funding; Regeneron: Research Funding; Step Pharma: Research Funding; AstraZeneca: Research Funding; MSD: Research Funding; MorphoSys: Research Funding; Celgene: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding; Genmab: Consultancy, Other: Member of the Epcoritamab Global Council, Research Funding; Nurix: Research Funding; Viracta: Research Funding; ADC Therapeutics: Research Funding; Roche: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; BMS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau. Sunkersett:AbbVie: Current Employment. Morehouse:Genmab: Current Employment, Current equity holder in publicly-traded company. Steele:Genmab: Current Employment, Other: owns Genmab stock; Janssen: Other: owns Janssen stock; AbbVie: Other: owns AbbVie stock. Marek:Genmab: Current Employment. Wang:Genmab: Current Employment. Hoehn:Genmab: Current Employment, Current equity holder in publicly-traded company. Hutchings:BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Janssen/J&J: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Belada:Swixx: Consultancy; Pharmacyclis: Research Funding; Astra Zenecca: Research Funding; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; Regeneron: Research Funding; Gilead Sciences: Consultancy; AbbVie: Consultancy; Swixx BioPharma: Consultancy.