ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR SHR2554 IN RELAPSED OR REFRACTORY (R/R) PERIPHERAL T‐CELL LYMPHOMA (PTCL): UPDATED OUTCOMES FROM THE FIRST‐IN‐HUMAN PHASE 1 STUDY

Abstract

Introduction: Inhibition of histone methyltransferase EZH2 represents a rational therapeutic strategy for lymphomas. SHR2554 is an oral small-molecule inhibitor exhibiting potent selectivity for EZH2. The multicenter, 2-part, phase 1 study was initiated to assess SHR2554 in patients (pts) with r/r lymphomas (NCT03603951). In part I, 350 mg BID was established as the recommended phase 2 dose (RP2D) based on the findings in the dose-escalation and expansion phases; subsequently, pts with selected lymphoma subtypes were recruited in the clinical expansion phase to receive SHR2554 at RP2D (Y Song et al. Lancet Haematol, 2022). Here we report the updated results of part I focusing on PTCL pts at RP2D. The prognosis of PTCL is extremely poor due to low response to chemotherapy regimens and limited treatment options thereafter, highlighting an urgent, unmet medical need. Methods: Pts with histologically confirmed PTCL that had relapsed or were refractory to ≥1 line of prior systemic therapy were eligible for inclusion in part I of this study. Efficacy and safety were assessed in PTCL pts who received at least one dose of SHR2554 at 350 mg BID. Results: Totally, 28 pts were included in this analysis: median age, 56 y (range 30–70); ECOG PS 1, 64.3% (18/28); median lines of prior systemic therapies, 2 (range 1–14). At data cutoff on 31 August 2022, the median follow-up duration was 11.9 mo (range 0.9–23.9). 17 pts achieved complete or partial response, resulting in a confirmed objective response rate (ORR) of 60.7% (95% CI 40.6–78.5). Responses were still ongoing in 58.8% (10/17) of the responders; estimated median duration of response (DoR) was 12.3 mo (95% CI 7.4–NR). 16 (57.1%) pts had disease progression or died; median progression-free survival (PFS) was 11.1 mo (95% CI 5.3–22.0). 4 (14.3%) deaths occurred; 1-y overall survival rate was 92.2% (95% CI 72.1–98.0). Of the 28 pts, 17 were diagnosed with angioimmunoblastic T-cell lymphoma (AITL), and 11 had PTCL not otherwise specified (PTCL-NOS). AITL pts showed better outcomes than PTCL-NOS pts: ORR, 76.5% versus 36.4%; median DoR, 20.3 versus 3.3 mo; median PFS, 22.1 versus 5.0 mo (Table). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 14 of the 28 pts (50.0%), with the most common being decreased platelet count (32.1%), decreased white blood cell count (14.3%), decreased neutrophil count (14.3%), and anemia (14.3%). One (3.6%) pt discontinued treatment due to TRAE (interstitial lung disease). No treatment-related deaths were reported. Conclusions: This extended follow-up analysis further provides evidence of potent anti-tumor activity, durable response, and acceptable safety of SHR2554 in pts with r/r PTCL. The research was funded by: The study was sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd. Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract Y. Shen Employment or leadership position: Jiangsu Hengrui Pharmaceuticals J. Shen Employment or leadership position: Jiangsu Hengrui Pharmaceuticals Z. Xiao Employment or leadership position: Jiangsu Hengrui Pharmaceuticals