Tazemetostat in Combination with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Phase 1b Results of Symphony-1

Background: The preferred second-line treatment for patients with relapsed/refractory (R/R) follicular lymphoma (FL) is either lenalidomide in combination with rituximab (R²) or an anti-CD20 antibody in combination with chemotherapy/immunotherapy. Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with R/R FL whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or who have no satisfactory alternative treatment options. EZH2 modulates the B-cell tumor microenvironment, supporting combination approaches to treatment. SYMPHONY-1 (EZH-302; NCT04224493) is a phase 1b/3 study designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + lenalidomide and rituximab (R²) in patients with R/R FL after ≥1 prior therapy. We report the results after complete enrollment of the phase 1b safety run-in to assess safety and clinical activity of TAZ when administered with R², including data for subsets of patients by mutation status, rituximab-refractory disease, and progression of disease in 24 months (POD24).

Methods: Patients aged ≥18 years with histologically confirmed FL grade 1-3A who were previously treated with ≥1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy were enrolled. The phase 1b portion enrolled patients regardless of EZH2 mutation status. Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R². Protocol-mandated dose modifications included simultaneous dose interruption and/or reduction of TAZ and lenalidomide for grade 3 neutropenia and thrombocytopenia. Primary endpoints of the phase 1b portion were safety and determination of the RP3D. Secondary endpoints included pharmacokinetic (PK) parameters. Preliminary efficacy analysis was performed on the response-evaluable population, including best overall response, progression-free survival (PFS), and duration of response (DOR) per investigator assessment, according to Lugano 2014 response criteria.

Results: As of June 14, 2022, 44 patients were enrolled and receiving TAZ + R² (400 [n=6], 600 [n=19], and 800 mg [n=19]). Median age was 67 years, and 31.8% of patients had received >1 prior therapy. Overall, 35/42 patients (83.3%) had wild-type (WT) EZH2 FL. Patients with high-risk disease include 15 patients (34.1%) with rituximab-refractory disease and 12 patients (27.3%) with POD24 disease. Median duration of treatment exposure of tazemetostat was 9.1 months. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the data cutoff. The PK of TAZ at all dose levels was not altered by concomitant administration of daily oral lenalidomide 20 mg, and the PK of lenalidomide was not altered by concomitant administration of any of the TAZ doses. The RP3D of TAZ was determined to be 800 mg BID in combination with R². The most common grade 3-4 TEAE was neutropenia (n=15; 34.1%). The most frequent type of dose modification due to TEAEs for any study treatment was drug interruption (n=30; 68.2%). In the 800-mg cohort, the median dose intensity was 98%, 93%, and 100% for tazemetostat, lenalidomide, and rituximab, respectively. Of 41 patients evaluable for tumor assessment, 21 (51.2%) had a complete response, 19 (46.3%) had a partial response, and 1 (2.4%) had stable disease. The overall response rate (ORR) in the response-evaluable population was 97.6% (n=40). The ORRs in patients with WT EZH2 and MT EZH2 were 97% (n=32) and 100% (n=7), respectively. ORRs in patients with rituximab-refractory disease was 100% (n=14) and in patients with POD24 disease was 100% (n=11). With a median follow-up of 11.2 months, median PFS and median DOR were not reached and appeared to be similar, regardless of rituximab-refractory, POD24, or EZH2 mutation status.

Conclusions: TAZ + R² combination therapy demonstrates a consistent and manageable safety profile, with no new safety signals. The combination therapy maintained its efficacy, regardless of mutation status. Durable responses were seen in patients with high-risk disease, including those with rituximab-refractory and POD24 disease. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ RP3D 800 mg + R² in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

Batlevi:GLG Pharma: Consultancy; Juno/Celgene: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Autolus: Research Funding; Xynomic: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Bayer: Research Funding; Roche/Genentech: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy; ADC Therapeutics: Other: Provision of Services; Bristol-Myers Squibb: Other: Ownership / Equity Interests; Provision of Services; Dava Oncology: Other: Provision of Services. Salles:BMS/Celgene: Honoraria; Debiopharm/Velosbio/Ipsen: Honoraria; Beigene: Honoraria; Bayer: Honoraria; AbbVie: Honoraria; Epizyme: Honoraria; Genentech/Roche: Honoraria; Genmab: Honoraria; Incyte: Honoraria; Janssen: Honoraria; Kite/Gilead: Honoraria; Loxo: Honoraria; Milteniy: Honoraria; Morphosys: Honoraria; Novartis: Honoraria; Rapt: Honoraria; Regeneron: Honoraria; Takeda: Honoraria. Park:Gilead: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Research Funding; Teva: Consultancy; G1 Therapeutics: Consultancy; Seattle Genetics: Research Funding, Speakers Bureau; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees. Phillips:Gilead: Consultancy; Genmab: Consultancy; Bayer: Consultancy; Epizyme: Consultancy; Genentech: Consultancy, Research Funding; Xencor: Consultancy; AbbVie: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Eli Lilly: Consultancy; Pharmacyclics: Consultancy; Beigene: Consultancy; Incyte: Consultancy, Other: Travel Expenses ; AstraZeneca: Consultancy. Amengual:Appia Pharmaceuticals: Research Funding; AstraZeneca: Consultancy; Daiichi Sankyo: Consultancy. Andorsky:AstraZeneca: Other: Steering Committee; AbbVie: Consultancy. Campbell:Amgen: Consultancy, Research Funding; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene (BMS): Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Roche: Consultancy, Research Funding. McKay:Abbvie: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Celgene/BMS: Consultancy; Epizyme: Consultancy; Gilead/Kite: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Recordati Rare Diseases: Consultancy; Roche: Consultancy; Takeda: Consultancy. Leonard:Calithera: Consultancy; Constellation: Consultancy; Eisai: Consultancy; Epizyme: Consultancy; Roche/Genentech: Consultancy; Genmab: Consultancy; Gilead/Kite: Consultancy; Grail: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Lilly: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Mustang Bio: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Second Genome: Consultancy; Sutro: Consultancy; ADC Therapeutics: Consultancy; BMS/Celgene: Consultancy; Regeneron: Consultancy; Miltenyi: Consultancy; Bristol-Myers Squibb: Consultancy; Beigene: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; AbbVie: Consultancy. Sondhi:Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chen:Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Slatcher:Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Lin:Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Szanto:Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Abbadi:Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Morschhauser:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Allogene therapeutics: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees.

Tazemetostat, an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with R/R FL whose disease has mutant EZH2 and who have received 2 or more prior therapies or who have no satisfactory alternative treatment options. The current study is examining tazemetostat in combination with lenalidomide and rituximab in patients with R/R FL after one prior therapy.