A phase 1b/2 trial of SHR-1701 in combination with gemcitabine and nab-paclitaxel in patients with untreated locally advanced or metastatic pancreatic cancer.
Authors: Zhou Jun , Yu Xianjun , Li Zhihua , Zhou Yuhong , Li Jialin , Xue Ran , Xia Ye , Han Hongxia , Wu Yiwen , Shen Lin 
Published: June 2022

e16264

Background: The current standard first-line therapy is nab-paclitaxel plus gemcitabine and prognosis of this patient population remains poor. Immune checkpoint inhibitors in combination with chemotherapy have shown substantial clinical activity in several metastatic malignancies, but evidences in pancreatic cancer are limited. This phase 1b/2 trial is designed to evaluate the antitumor activity and safety of SHR-1701 (a bifunctional fusion protein targeting PD-L1 and TGF-β) combined with chemotherapy in patients with untreated locally advanced or metastatic pancreatic cancer. Methods: Eligible patients had histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic adenocarcinoma and had never received systemic antitumor therapy for advanced or metastatic diseases. Patients received SHR-1701 (30 mg/kg) on day 1 plus gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on day 1 and 8 of each 3-week cycle by intravenous infusion. The primary endpoint of phase 1b part was recommended phase 2 dose (RP2D). In the phase 2 part, the primary endpoint was ORR per investigator according to RECIST v1.1. Results: No dose-limiting toxicities were observed among the first six patients; the RP2D of SHR-1701 was 30 mg/kg. From Dec 03, 2020 to Sep 17, 2021, a total of 56 patients were enrolled and received at least one dose of study drug treatment. As of data cutoff on Nov 19, 2021, with a median follow-up period of 4.2 months (range 0.2-10.6), 28 (50.0%) of the 56 patients were still on treatment. Of the 56 patients, ORR per investigator was 33.9% (95% CI 21.8-47.8; n = 19, with 13 patients confirmed) and DCR was 75.0% (95% CI 61.6-85.6; n = 42, all confirmed). Of the 52 patients who had at least one post-baseline radiographic assessment, the ORR was 36.5% (95% CI 23.6-51.0) and DCR was 80.8% (95% CI 67.5-90.4). 20 (35.7%) PFS events and 9 (16.1%) OS events occurred in the 56 patients as of data cutoff, and both PFS and OS data were immature. Treatment-related AEs of any grade or grade ≥3 were reported in 56 (100%) or 25 (44.6%) patients, respectively. The incidence of SHR-1701-related AEs was 92.9% (52 patients). Grade ≥3 SHR-1701-related AEs occurred in 13 (23.2%) patients, with increased gamma-glutamyltransferase (3 patients, 5.4%) and decreased white blood cell count (3 patients, 5.4%) as the most common ones. Serious SHR-1701-related AEs occurred in 6 (10.7%) patients and SHR-1701-related death occurred in 1 (1.8%, gastrointestinal hemorrhage) patient. Conclusions: Combination of SHR-1701 with gemcitabine and nab-paclitaxel showed preliminary antitumor activity in untreated locally advanced or metastatic pancreatic cancer. This combination therapy was well tolerated without unexpected safety signal. Further clinical investigations are warrant to confirm our results. Clinical trial information: NCT04624217.