A phase 1/2 study to evaluate the safety and efficacy of XNW5004, a selective EZH2 inhibitor, in subjects with relapsed/refractory non-Hodgkin lymphoma.

7012 Background: Prognosis of relapsed/refractory (R/R) non-Hodgkin Lymphoma (NHL) which has progressed on standard therapy remains poor. EZH2 is a methyltransferase playing crucial roles in gene regulation and epigenetic modifications. Gain-of-function mutations/overexpression of EZH2 has been found in NHL and correlates with disease progression. XNW5004 is a small molecule, highly selective inhibitor of EZH2. Here, we report the safety and efficacy of XNW5004 in subjects with R/R NHL from a phase 1/2 study. Methods: Subjects with histologically confirmed, R/R NHL who has received ≥ 2 lines of systemic therapies were eligible to enroll in this multicenter, open label, dose escalation and dose expansion study in China. Standard 3+3 design with accelerated titration was used for dose escalation in 6 doses of XNW5004 from 100mg to 2000mg, PO, BID. 800mg BID and 1200mg BID were selected for dose expansion in subjects with follicular lymphoma (FL) and peripheral T cell lymphoma (PTCL). Results: As of Dec 18, 2024, 120 subjects were enrolled (escalation:19, expansion: 101) including 51 FL and 58 PTCL. Median follow-up was 17.4 months (mos). 87.4% of the subjects had an Ann Arbor Stage of III-IV at baseline. The median lines of prior systemic therapy were 3. 93.8% of the FL subjects received anti-CD20 antibody, 68.8% were POD24 (progression of disease within 24 months of diagnosis). 91.7% of the PTCL subjects received HDAC inhibitor prior to enrollment. Any grade treatment-emergent adverse events (TEAEs) in ≥10% subjects included diarrhea, anemia, WBC count decreased, platelet count decreased, vomiting, nausea, and neutrophil count decreased. No DLT was observed. In dose escalation phase, ORR and DCR of the 16 evaluable subjects across doses was 56.3% and 87.5%, respectively. Median progression-free survival (mPFS) was 9.2 mos. Median duration of response (mDOR) and median overall survival (mOS) were not reached. In dose expansion phase, 1200mg BID was selected as RP2D. At 1200 mg BID, ORR in all FL, EZH2 wild type FL, and EZH2 mutant FL was 66.7%, 63.2%, and 70%, respectively. mPFS and mDOR in all FL was 10.8 mos and 7.4 mos, respectively. mOS was not reached. ORR in FL with POD24 was 56.5%. ORR in FL previously treated with CAR-T was 66.7%. ORR in FL previously received autologous stem cell transplantation was 100%. At 1200 mg BID, ORR in all PTCL, PTCL-NOS, and PTCL-AITL was 70.3%, 72%, and 68.2%, respectively. In all PTCL, mPFS was 15.7 mos and mDOR was 13.9 mos. mOS was not reached. Conclusions: XNW5004 has shown a well-tolerated safety profile and promising efficacy in different types of NHL. Pivotal studies of XNW5004 monotherapy in PTCL are ongoing. Clinical trial information: NCT06558513 .