Subcutaneous Epcoritamab in Combination with Rituximab + Lenalidomide (R²) for First-Line Treatment of Follicular Lymphoma: Initial Results from Phase 1/2 Trial

Background: Epcoritamab is a subcutaneously administered bispecific antibody that binds to CD3 on T cells and CD20 on B cells to kill malignant B cells. In the phase 1/2 EPCORE NHL-1 trial, single-agent epcoritamab produced deep responses in patients with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) and demonstrated a manageable safety profile. In the phase 1/2 EPCORE NHL-2 trial (NCT04663347), epcoritamab is being evaluated in combination with standard therapies in B-cell NHL. Despite some advances in first-line therapy, follicular lymphoma (FL) remains an incurable disease in most cases, and better treatment options are still needed. Due to the distinct mechanisms of action of each agent, the combination of epcoritamab with rituximab + lenalidomide (R²) may result in deeper and more durable responses compared to R² alone. Lenalidomide has immunomodulatory properties that may enhance epcoritamab activity. This epcoritamab combination has shown promising activity in patients with R/R FL in arm 2 of EPCORE NHL-2 (Falchi et al, ASCO 2022). Here we present initial data from arm 6 of EPCORE NHL-2, which is investigating the safety and efficacy of epcoritamab + R² as first-line therapy in patients with FL.

Methods: Adults with previously untreated CD20⁺ FL grade 1-3A who met GELF criteria for treatment were enrolled and received subcutaneous epcoritamab 48 mg + R² for 12 cycles of 28 d each. Epcoritamab was administered QW in cycles 1-2 and Q4W thereafter, for up to 2 y of treatment. Step-up epcoritamab dosing and corticosteroid prophylaxis were required during cycle 1 to mitigate CRS. Response to treatment was assessed by PET-CT per Lugano criteria.

Results: As of the data cutoff date of June 10, 2022, 41 treatment-naive patients with FL had received epcoritamab + R². The median age was 57 y (range, 39-78), and median time from initial diagnosis to first dose of epcoritamab was 12 wk (range, 2-352). The majority (85%) had grade 2 or 3A FL; 39% and 51% had stage III and IV disease, respectively. With a median follow-up of 4.4 mo (range, 0.7-7.5), treatment was ongoing in 36 (88%) patients; 5 (12%) discontinued treatment, 3 due to AEs and 2 due to disease progression. All patients experienced a treatment-emergent AE (TEAE), with 36 (88%) having events that were deemed related to epcoritamab. CRS (51%; 34% grade 1, 17% grade 2, no grade 3-4), neutropenia (41%; 17% grade 1-2, 24% grade 3-4), pyrexia (41%; all grade 1-2), injection-site reactions (37%; all grade 1-2), fatigue (29%; all grade 1-2), headache (29%; 27% grade 1-2, 2% grade 3-4), constipation (27%; all grade 1-2), and rash (27%; 20% grade 1-2, 7% grade 3-4) were the most common TEAEs. Most CRS events (in 41% of all patients) occurred after the first full dose of epcoritamab, all resolved (median time to resolution, 4 d; tocilizumab administered in 5 patients), and none led to treatment discontinuation. ICANS and clinical tumor lysis syndrome were not observed. One fatal TEAE was observed (COVID-19 pneumonia, considered not related to epcoritamab). Among efficacy-evaluable patients (n=29), the overall response rate was 90% (26/29), with 69% (20/29) having a complete metabolic response (CMR) as their best overall response. All CMRs and partial metabolic responses were ongoing at the time of data cutoff.

Conclusions: Subcutaneous epcoritamab + R² demonstrated a manageable safety profile, similar to that observed in the R/R setting, with no new safety signals, no ICANS events, and only low-grade CRS events, all of which resolved. This regimen showed encouraging efficacy, based on high response rates, when used as a first-line treatment for FL. These data support further clinical evaluation of epcoritamab + R² in previously untreated patients with FL.

Falchi:Roche: Consultancy, Research Funding; Genetech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Research Funding. Leslie:Eli Lily: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Jansssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celegene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Belada:Genmab: Research Funding. Kopeckova:Laboratoires Pierre Fabre: Current equity holder in private company; Novartis: Current equity holder in publicly-traded company, Honoraria; Viatris: Current equity holder in publicly-traded company; EISAI: Research Funding. Brody:BMS: Research Funding; Genentech: Research Funding; Seagen: Consultancy; Epizyme: Consultancy; ADC Therapeutics: Consultancy; Gilead/Kite: Research Funding; Merck: Research Funding; SeaGen, Roche, Genentech, Merck, ADC Therapeutics, Epizyme, Gilead, Kite, Astrazeneca: Research Funding. Canales:Amgen: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Kyowa: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy; Kite: Consultancy, Speakers Bureau; BMS: Consultancy; Beigene: Consultancy; La Paz University Hospital: Current Employment. Martín García-Sancho:Gilead/Kite: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Incyte: Consultancy, Other: Support for attending meetings and/or travel; Lilly: Consultancy, Other: Support for attending meetings and/or travel; Takeda: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; ADC Therapeutics America: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Miltenyi: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Kern: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Servier: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Eusa Pharma: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Clinigen: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Kyowa Kirin: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Roche: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Other: Support for attending meetings and/or travel. Nijland:Roche: Research Funding; Takeda: Research Funding; Genmab: Consultancy. Andersson:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Awan:Janssen: Consultancy; AbbVie: Consultancy; Merck: Consultancy; ADCT Therapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy; Incyte: Consultancy; Johnson and Johnson: Consultancy; MEI Pharma: Consultancy; Dava Oncology: Consultancy; Kite Pharma: Consultancy; Caribou Biosciences: Consultancy; Verastem: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Cardinal Health: Consultancy; Gilead Sciences: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Cellecter Bisosciences: Consultancy. Drott:Roche: Honoraria; Kyowa Kirin: Honoraria; Respiratorius AB: Membership on an entity's Board of Directors or advisory committees. Narkhede:Gilead: Research Funding; Roche: Research Funding; Genetech: Research Funding; Genmab: Research Funding; Gilead/Forty-seven: Research Funding; EUSA pharmaceuticals;: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen Inc.: Research Funding. Wahlin:Roche: Consultancy, Research Funding; Gilead Sciences: Research Funding. Rana:Genmab: Current Employment. Abbas:Genmab: Current Employment. Wang:Genmab: Current Employment. Dinh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Abrisqueta:AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Honoraria; Incyte: Consultancy.