Background: Dysregulation of histone methyltransferase EZH2 plays critical roles in lymphomagenesis. Emerging evidence shows that EZH2 also contributes to tumor immune evasion. SHR2554 is an oral, small-molecule inhibitor exhibiting potent selectivity for EZH2. We initiated a first-in-human study to assess SHR2554 across a broad spectrum of lymphoid neoplasms that had relapsed or was refractory to standard systemic therapies, including B-cell lymphomas, T-cell lymphomas, and classical Hodgkin lymphoma (cHL). Methods: This multicenter, phase 1 study was composed of 3 parts: dose escalation phase according to mTPI-2 design, dose expansion phase, and clinical expansion phase in selected tumor subtypes. Dose was escalated at 50, 100, 200, and 400 mg BID, and then de-escalated at 300 and 350 mg based on the observed toxicities. Two dose levels (300 and 350 mg) were expanded. Subsequently, follicular lymphoma (FL), peripheral T-cell lymphoma (PTCL), and cHL were selected for clinical expansion at RP2D. Primary endpoints were to assess the safety and determine the MTD and RP2D. Key secondary endpoint included clinical activity at RP2D in different subtypes. Results: As of Sep 10, 2021, 113 heavily pretreated pts were enrolled, with 53 (46.9%) having received ≥3 lines of prior systemic therapies. In dose escalation phase, DLTs occurred in 2 of 3 pts at 400 mg and 1 of 6 pts at 350 mg; thus, 350 mg BID was the MTD. Combined with the safety, tolerability, PK/PD, and preliminary efficacy findings observed in dose escalation and expansion phases, RP2D was determined to be 350 mg BID. As of cutoff date, 41 FL, 22 PTCL, and 21 cHL pts who received SHR2445 at 350 mg BID completed at least one post-baseline efficacy assessment. ORR in FL was 58.5% (95% CI 42.1-73.7); majority of responses (66.7%) were still ongoing, and the estimated median DoR was 9.3 mos (95% CI 5.6-NR). EZH2^mut FL pts showed a slightly higher ORR than EZH2^WT FL pts (62.5% vs 55.2%). EZH2 mutations were not detected in pts with PTCL or cHL. ORR in PTCL was 63.6% (95% CI 40.7-82.8); majority of responses (71.4%) were still ongoing, and the estimated median DoR was 7.4 mos (95% CI 2.9-NR). All cHL pts had received prior chemotherapy and anti-PD-1/PD-L1 antibodies. Shrinkage in target lesions was shown in 76.2% of cHL pts; ORR was 19.0% (95% CI 5.4-41.9); majority of responses (75.0%) were still ongoing, and the median DoR had not been reached yet. Grade ≥3 treatment-related AEs occurred in 38 of the 113 pts (33.6%), with the most common being decreased platelet count (17.7%), decreased neutrophil count (8.8%), decreased white blood cell count (8.0%), and anemia (6.2%). Conclusions: SHR2554 showed a manageable safety profile and promising anti-tumor activity in pts with r/r lymphomas, supporting further explorations in FL, PTCL, and cHL. Clinical trial information: NCT03603951.