Phase 1 study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced solid tumors.

2503 Background: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a promising therapeutic strategy for multiple tumor types. SHR-1701 is a novel bifunctional anti-PD-L1/TGF-βRII agent. This dose escalation and expansion phase 1 study aimed to evaluated the safety and preliminary anti-tumor acitivity of SHR-1701 in refractory solid tumors. Methods: The dose escalation period was initiated by accelerated titration (1 mg/kg Q3W) and then switched to 3+3 scheme (3, 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W). The dose expanded at doses of 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W. The primary objectives were to determine the safety profile, MTD, and RP2D of SHR-1701. Results: 17 pts (1 mg/kg Q3W [n = 1]; 3, 10, 20 and 30 mg/kg Q3W [n = 3 each]; 30 mg/kg Q2W [n = 4]) were enrolled in dose escalation part. No DLT was observed and MTD was not reached. Another 32 pts (10 mg/kg Q3W [n = 8]; 20 and 30 mg/kg Q3W [n = 9 each]; 30 mg/kg Q2W [n = 6]) were enrolled in dose expansion part. Of 49 enrolled pts, 33 pts (67.3%) had received ≥2 lines of prior systemic therapy. As of data cutoff on Oct 30, 2020, the median duration of SHR-1701 exposure was 6.0 weeks (range, 2.0-78.6). The most common reported TRAEs were increased ALT/AST, anemia, hypothyroidism, and increased bilirubin/conjugated bilirubin, with incidence > 15%. The incidence of irAEs reported by the investigator was 46.9% and 4 pts received systemic corticosteroids. Hypothyroidism and rash were the most common irAEs with incidence > 10%. The incidence of Grade ≥3 TRAEs was 18.4%. The incidence of Grade ≥3 irAEs was 10.2%. 1 pt suffered early death for liver failure more likely caused by tumor progression. PK analysis showed a linear dose-exposure relationship with SHR-1701 dosing from 1 to 30 mg/kg. The peripheral PD-L1 target occupancy rate exceeded 90%, and nearly complete TGF-β1 trapping was detected in all dose groups. Of 49 enrolled pts, 45 pts completed at least once efficacy evaluation. The ORR was 17.8% (95% CI, 8.0%-32.1%), with 8 pts achieving PR (2 lung adenocarcinoma, 1 HCC, 1 ESCC, 1 dMMR-CRC, 1 renal cancer, 1 epiglottis cancer, and 1 pancreatic acinar cell carcinoma). The DCR was 40.0% (18/45; 95% CI, 25.7%-55.7%). Majority of responses (7/8) were still ongoing, and the median DoR had not been reached yet. Based on data of saftety, PK, PD, and efficacy, we recommended 30 mg/kg Q3W as the RP2D. Conclusions: SHR-1701 showed acceptable safety profile and encouraging antitumor activity in refractory solid tumors, establishing the foundation for further exploration. Clinical trial information: NCT03710265.