A phase 1b/2 study of first-line anti-PD-L1/ TGF-βRII fusion protein SHR-1701 combined with nab-paclitaxel and gemcitabine for advanced pancreatic ductal adenocarcinoma.

Nab-paclitaxel plus gemcitabine (AG) is the standard first-line chemotherapy for advanced or metastatic pancreatic ductal adenocarcinoma and has limited efficacy. This phase 1b/2 study aimed to evaluate SHR-1701 (an anti-PD-L1/TGF-βRII fusion protein) plus AG in this population (NCT04624217). In phase 1b part, the recommended dose of SHR-1701 was identified as 30 mg/kg every 3 weeks, when combined with AG. In phase 2 part, the primary endpoint was objective response rate (ORR). As of Mar 31, 2023, 56 patients were enrolled. Median follow-up was 10.3 months (range, 0.2-24.7). ORR was 32.1% (95% CI, 20.3-46.0). Median progressive-free survival (PFS) was 5.6 months (95% CI, 4.3-6.6), and median overall survival (OS) was 10.3 months (95% CI, 8.8-12.3). Treatment-related adverse events of grade ≥3 were reported in 27 (48.2%) patients, with the most common being decreased neutrophil count. Patients with PD-L1 TPS ≥ 1% showed a higher ORR (66.7% vs. 25.0%), as well as extended median PFS (6.3 vs. 5.3 months) and median OS (18.8 vs. 9.9 months). Additionally, reduction of CA19-9 by at least 80% during treatment and pSMAD2/3 staining intensity of 1+ at baseline were potential monitoring tools and predictive biomarkers for better clinical outcomes, respectively. Tumor-specific T-cell infiltration and pancreatic cancer tumor subtypes were associated with anti-tumor response. The interactions within tumor microenvironment were involved disease progression. Overall, first-line SHR-1701 plus AG showed promising anti-tumor activity and controllable safety in advanced or metastatic pancreatic ductal adenocarcinoma, and features of patients more likely to benefit from the combination were drawn.