Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-ß receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. CONCLUSIONS: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03710265.