Surufatinib plus sintilimab in patients with advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC): A single-arm, open-label, single-center phase II trial.
Authors: Zhang Dong-Sheng , Liu Fu-Rong , Lu Yun-Xin , Bai Bing , Zhang Yang , Wang Zhi-Qiang , Liu Yu , Chen Jian-Wen , Wang Feng , Xu Rui-Hua 
Published: January 2024

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Background: Anti-PD-1 antibodies plus chemotherapy have become the standard first-line treatment for advanced GC/GEJC with CPS score ≥ 5. However, GC/GEJC still has dismal survival. Preclinical studies have demonstrated that surufatinib (a novel small-molecule kinase inhibitor targeting VEGFR1-3, FGFR and CSF-1R) combined with anti-PD-1 antibodies have synergistic antitumor effects by modulating tumor immune microenvironment. Therefore, a phase II trial to evaluate surufatinib plus sintilimab in patients (pts) with advanced GC/GEJC was conducted. Here we report the results of part A of this trial. Methods: This single arm, open-label, single center phase II trial consisted of two parts: part A (second-line therapy) and part B (first-line therapy). In part A, pts aged 18-75 years who were HER2-negative, failed first-line standard therapy, and immune checkpoint inhibitor therapy naive were enrolled. Part A included safety run-in and dose expansion stages. Six pts in the safety run-in received surufatinib at 250mg once daily as starting dose, in combination with a fixed dose of sintilimab (200 mg, d1, Q3W). If more than 1 DLT occurred in stage 1, the recommended dose of surufatinib for stage 2 (N=11) would de-escalate to 200 mg, otherwise would maintain as 250mg. The primary endpoint was ORR per RECIST v1.1. Secondary endpoints included DCR, PFS, OS and safety. If the ORR of part A was ≥ 30%, the trial would proceed to Part B (N=44), further evaluating this combination treatment in previously untreated advanced GC/GEJC. Results: At data cutoff on 8/10/2023, 16 pts (6 in safety run-in; 10 in dose expansion) were enrolled in part A. The median age was 56 years; 75% male; 69% with ECOG PS 1. Peritoneum (56%) was the most common metastatic site. No DLTs were observed in the safety run-in stage, so the recommended dose of surufatinib for dose expanding stage was 250 mg. Among the 16 pts evaluable for tumor response, 6 pts achieved PR, 4 pts achieved SD. The confirmed ORR and DCR per RECIST v1.1 was 40.0% (95% CI: 15.2- 64.6%) and 66.7% (95% CI: 38.4- 88.2%), respectively. Median DOR was not reached and 50% of responders were estimated to have a response duration ≥ 7.8 months. Median PFS and OS were not yet mature. Most TEAEs (≥ 40%) were grade 1-2, including hypoproteinemia (62.5%), hypertension (50%), proteinuria (50%), lymphocyte count decreased (43.8%). The most common grade ≥ 3 TEAEs reported by 5 pts (31.3%) were blood bilirubin increased (18.8%), hypertension, lymphocyte count decreased, and alanine transaminase elevation (6.3%, respectively). No treatment-related death was reported. Conclusions: The results showed surufatinib plus sintilimab acquired preliminary efficacy and manageable safety profile as the second-line treatment for advanced GC/GEJC. Part B is ongoing, and more data analysis will be reported further. Clinical trial information: NCT05235906 .