Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, showed antitumor activity as monotherapy in patients with relapsed or refractory (R/R) follicular lymphoma (FL) who received ≥2 prior lines of therapy. In clinical studies in patients with R/R FL, lenalidomide and rituximab (R²) demonstrated an objective response rate (ORR) of 73%–78% and median progression-free survival (PFS) of 36–39 months. This global, multicenter phase 1b/3 study is designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + R² in patients with R/R FL after ≥1 prior therapy. We report an updated interim analysis of the phase 1b safety run-in where we assess the clinical activity and pharmacokinetics (PK) of TAZ when administered with R² in patients with R/R FL. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily) in 28-day cycles with standard-dose R² (NCT04224493). In addition to PK and safety, preliminary efficacy analysis was performed on the response-evaluable population, including best overall response, PFS, and duration of response (DOR) per investigator assessment according to Lugano 2014 response criteria. Results: As of January 22, 2022, 43 patients were enrolled and receiving TAZ + R² (400 [n = 4], 600 [n = 18], and 800 mg [n = 21]). These patients had a median age of 67 years (range, 39–83) and received a median of 1 prior therapy (range, 1–4). Overall, 15/43 (34.9%) patients were refractory to rituximab, 10/39 (25.6%) had POD24, and 6/41 (14.6%) had mutant-type EZH2. Median duration of treatment exposure was 32.0 weeks (range, 4.1–68.1). Mean C_max and AUC_0–t of TAZ 800 mg + R² at steady state were similar to those found for TAZ as monotherapy. PK of TAZ was not altered by concomitant administration of daily oral lenalidomide 20 mg, and PK of lenalidomide was not altered by concomitant administration of TAZ. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the January 2022 data cutoff. Serious treatment-emergent adverse events (TEAEs) were observed in 14 (32.6%) patients. Grade 3–4 TEAEs were observed in 24 (55.8%) patients; the most common grade 3–4 TEAE was neutrophil count decrease (n = 13; 30.2%). Of 38 patients evaluable for tumor assessment, 19 (50.0%) had a complete response, 17 (44.7%) had a partial response, and 2 (5.3%) had stable disease. ORR was 94.7% (n = 36). With a median follow-up of 5.8 months, median PFS and DOR were not reached and appeared to be similar, regardless of mutation status. Conclusions: TAZ + R² combination demonstrates consistent and unaltered PK for TAZ and lenalidomide as well as a favorable safety profile and efficacy trend. 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. Clinical trial information: NCT04224493.