Phase I study of the bifunctional anti-PD-L1/TGF-bRII agent SHR-1701 combined with SHR2554, an EZH2 inhibitor, in patients with previously treated advanced lymphoma and solid tumors

2507 Background: Despite the remarkable successes of cancer immunotherapies, the majority of patients (pts) experience only partial response and most pts will progress. Enhancer of zeste homolog 2 (EZH2) as an epigenetic target for cancer therapy has been shown to enhanced antigen presentation and synergize with immunotherapy in preclinical studies. This study investigates the safety and efficacy of SHR-1701 (anti-PD-L1/TGF-βRII) plus SHR2554 (EZH2i) in pts with pretreated advanced lymphoma and solid tumors. Methods: This open-label, single-arm, phase 1 study enrolled pts with pretreated advanced lymphoma and solid tumors. Escalating doses of SHR2554 (300–350mg bid) plus fixed-dose SHR-1701 (30mg/kg q3w) were evaluated in the dose-escalation phase. SHR2554 at the recommended phase 2 dose (RP2D) plus SHR-1701 were administered in the dose-expansion phase. The primary end point was determination of the RP2D of SHR2554 plus SHR-1701. Secondary end points included safety and preliminary activity. Results: By January 6, 2023, 33 patients were enrolled (dose-escalation: n=7; dose-expansion, n=26). No dose-limiting toxicities were observed, and RP2D was established as SHR2554 350mg bid plus SHR-1701 30mg/kg q3w. Treatment-related adverse events (TRAEs) occurred in 13 of 32 patients (40.6%), mainly including platelet count decreased (21.9%), anemia (15.6%) and vomiting (15.6%). The most common Grade ≥3 TRAEs were anemia (3.1%) and fever (3.1%). In the efficacy-evaluable population (n = 26), objective response rate (ORR) was 57.7%, including 2 complete response (CR) achieved by patients with Metastatic Renal Cell Carcinoma and classical Hodgkin lymphoma (cHL). 16 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) after a median of 10 prior lines of therapy have been enrolled. 16 (100%) cHL pts had received prior anti-PD1/PD-L1 antibody therapy, and 15 ( 93.8%) prior epigenetic therapies, such as decitabine or chidamide. Out of 14 cHL-evaluable patients, ORR was 100% and the CR rate was 7.1%. Conclusions: SHR-1701 combined with SHR2554 showed acceptable safety profile and encouraging antitumor activity in immunotherapy-pretreated cHL, establishing the foundation for further exploration. Clinical trial information: NCT04407741 .