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

Abstract

Background: Dual inhibition of PD-1/PD-L1 and TGF-β 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-β 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.

Keywords: Immunotherapy; PD-L1; SHR-1701; TGF-β; Tumor.

Conflict of interest statement

PL, LW, and XZ are employees of Jiangsu Hengrui Pharmaceuticals. The other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Pharmacokinetic profile and pharmacodynamic activity. A Semi-logarithm mean serum concentration–time profiles of SHR-1701. Error bars represent standard deviation. B PD-1 target occupancy following SHR-1701 treatment. There was a sharp decrease in the patient in the 1 mg/kg every 3 weeks group on C5D1 before administration, which might be caused by delayed treatment (interval between C4D1 and C5D1, 27 days). The patient withdrew from the study after C5D1. In the 10 mg/kg every 3 weeks group, PD-L1 target occupancy of 1 patient decreased to 25% on C5D1, but reached saturated level before administration on C9D1. All the remaining patients had a sustained and saturated PD-L1 target occupancy throughout the study. C TGF-β1 concentrations following SHR-1701 treatment. The free TGF-β1 level in the patient in the 1 mg/kg every 3 weeks group sharply increased on C5D1 before administration. In addition to treatment delay, low dose level might be the reason. PD-L1, programmed death ligand 1; TGF-β1, transforming growth factor-β 1; EOT, end of treatment; EOS, end of study

Fig. 2

Tumor responses in select tumors at the recommended dose (30 mg/kg every 3 weeks). A Best percentage change from baseline in target lesion size. B Tumor responses per RECIST v1.1 over time