* Authors on the Steering Committee contributed equally to the oversight of the study, including study design and maintaining the quality of study conduct. CONTRIBUTORS Owen O'Connor, Barbara Pro, Tim Illidge and Lorenz Trumper formed the ECHELON-2 steering committee and contributed equally to the oversight of the study, including study design and maintaining the quality of study conduct.

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PURPOSE Epcoritamab is a subcutaneously administered CD3xCD20 T-cell–engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20+ B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. PATIENTS AND METHODS In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037 ), adults with relapsed or refractory CD20+ large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. RESULTS As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20‐83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell–associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. CONCLUSION Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.

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Introduction: Relapsed/refractory (R/R) follicular lymphoma (FL) remains a difficult-to-treat condition, with limited treatment options. New, tolerable treatments with unique mechanisms of action are needed, especially for high-risk patients whose disease progresses within 24 months of diagnosis (POD24). The epigenetic regulator EZH2 catalyzes the histone 3 lysine 27 trimethylation (H3K27m3) gene suppressive mark, which is essential for BCL6-driven germinal center (GC) formation. Conversely, a reduction in EZH2 catalytic activity is required for centroblast differentiation and initiation of the GC exit program. Activating mutations (MT) in EZH2, present in ~20% of FL patients, and enhanced H3K27me3 prevent GC exit, resulting in GC hyperplasia and lymphomagenesis. Tazemetostat, an investigational, selective, oral EZH2 inhibitor, has demonstrated durable, single-agent, antitumor activity in R/R FL patients with MT or wild-type (WT) EZH2. Herein, we report newly emerging interim efficacy and safety data from the MT and WT cohorts and the POD24 subgroup. Methods: This open-label, multicenter, phase 2 study (NCT01897571) evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL (Grade 1-3b). Key inclusion criteria included age ≥18 years, Eastern Cooperative Oncology Group performance status of 0-2, ≥2 prior treatment regimens, and measurable disease per 2007 IWG-NHL criteria. The primary endpoint was objective response rate (complete response + partial response). Secondary endpoints included progression-free survival and safety. The POD24 subgroup was composed of patients experiencing disease progression or relapse within 24 months of diagnosis or the start of frontline treatment with immunochemotherapy. Results: As of June 7, 2019, interim data were available for 99 patients (MT EZH2, n=45 [POD24, n=17; 38%]; WT EZH2, n=54 [POD24, n=30; 56%]). Of the 33 patients in the MT cohort with an objective response, 15 (45%) had a response at ≥6 months, 7 (21%) at ≥12 months, and 4 (12%) at ≥16 months. Of the 18 patients in the WT cohort with an objective response, 15 (83%) had a response at ≥6 months, 9 (50%) at ≥12 months, and 6 (33%) at ≥16 months. Data from the MT cohort continue to mature, with 11 (24%) patients enrolled in the past year and 17 (38%) patients still on treatment. Updated data from the fully enrolled MT cohort, and sub-group analyses from both WT and MT cohort, will be presented. Interim efficacy data from the response-evaluable population and POD24 subgroup of the MT and WT cohorts are presented in Table 1. These results demonstrate the potent, antitumor activity of tazemetostat regardless of the prognostic category of patients. Treatment-related Grade ≥3 adverse events (AEs) were reported in 17% of all patients and 15% of patients in the POD24 subgroup. The most frequently reported AEs were similar across the total population and the POD24 subgroup and included thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%), and fatigue (1%). Five percent of all patients discontinued treatment, and 9% had dose reductions due to treatment-related AEs. No treatment-related Grade 5 AE and deaths were reported. Conclusion: Tazemetostat was generally well tolerated, with a low incidence of treatment-related AEs. Tazemetostat demonstrated clinically meaningful, durable, single-agent activity across a spectrum of patients with FL, including the POD24 subgroup, and pronounced responses in patients with EZH2 activating mutations. Disclosures Morschhauser: BMS: Honoraria; Roche/Genentech: Consultancy; Servier: Consultancy; Janssen: Honoraria; Celgene: Honoraria; Gilead: Consultancy. Tilly:servier: Honoraria; merck: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy. Phillips:Bayer: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding. Ribrag:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses . Campbell:Janssen: Honoraria, Research Funding, Speakers Bureau. Jurczak:Servier: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Takeda: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Roche: Research Funding; Morphosys: Research Funding; TG Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gilead: Research Funding; AstraZeneca/Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. McKay:Epizyme: Consultancy, Honoraria. Opat:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria. Radford:GSK: Equity Ownership; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Whalen:Epizyme: Employment, Equity Ownership. Rajarethinam:Epizyme: Employment, Equity Ownership. Navia:Epizyme: Employment, Equity Ownership. Adib:Epizyme: Employment, Equity Ownership. Salles:Amgen: Honoraria, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Epizyme: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events.