Abstract
Sintilimab plus gemcitabine and cisplatin as a first-line treatment for patients with advanced biliary tract cancer: A biomolecular exploratory, phase II clinical trial.
Author
person
Zhen-gang Yuan
Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
info_outline
Zhen-gang Yuan, Tian-mei Zeng, Guang Yang, Cheng Lou, Wei Wei, Chen-jie Tao, Xi-yun Chen, Qin Han, Zhuo Cheng, Pei-pei Shang, Yu-long Dong, He-ming Xu, Lie-ping Guo, Dong-sheng Chen, Yunjie Song, Chuang Qi, Wanglong Deng
Full text
Authors
person
Zhen-gang Yuan
Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
info_outline
Zhen-gang Yuan, Tian-mei Zeng, Guang Yang, Cheng Lou, Wei Wei, Chen-jie Tao, Xi-yun Chen, Qin Han, Zhuo Cheng, Pei-pei Shang, Yu-long Dong, He-ming Xu, Lie-ping Guo, Dong-sheng Chen, Yunjie Song, Chuang Qi, Wanglong Deng
Organizations
Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China, Eastern Hepatobiliary Surgery Hospital, Shanghai, China, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China, Department of Oncology, Eastern Hepatobiliary Surgery Hospital, the Naval Medical University, Shanghai, China, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
Abstract Disclosures
Research Funding
No funding received
None.
Background:
The prognosis of biliary tract cancer (BTC) remains unsatisfactory. Thus, this study aimed to determine the efficacy, safety, and predictive biomarkers of the immune checkpoint inhibitor sintilimab in combination with gemcitabine and cisplatin (GemCis) in advanced BTCs.
Methods:
In this single-arm, phase II study (Trial registration number: ChiCTR2000036652), gemcitabine (1000 mg/m²) plus cisplatin (25 mg/m²) were administered on days 1 and 8, respectively, while 200 mg sintilimab was administered on day 1 of each 21-day cycle for 6–8 weeks, followed by sintilimab alone up to 2 years. The primary endpoint was overall survival (OS). The second endpoints were objective response rate (ORR), progression-free survival (PFS), and disease control rate, assessed using RECIST V.1.1. Multiomics biomarkers associated with clinical response were assessed as exploratory objectives.
Results:
Thirty patients were enrolled between August 2020 and May 2022. The median follow-up duration, OS, and PFS were 12.3 months (95% confidence interval [CI]: 9.1–16.0), 15.9 months (95% CI: 8.6–not reached), and 5.1 months (95% CI: 4.3–8.7), respectively. Here, 36.7% of patients were found to achieve an objective response. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations (median, PFS: 9.8 vs. 4.5 months, p = 0.023; OS: NR vs. 9.0 months, p = 0.014; ORR: 77.8% vs. 19%, p = 0.004) or loss-of-function mutations in chromatin remodeling genes (median, PFS: 8.7 vs. 4.2 months, p = 0.021; ORR: 63.6% vs. 21.1%, p = 0.046) presented better tumor response and survival outcomes. Furthermore, transcriptome analysis of the tumor immune microenvironment revealed a markedly longer PFS, and tumor response were associated with higher expression of 3-gene effector T cell signature (median, PFS: 7.8 vs. 4.3 months, p = 0.02; ORR: 64.2% vs. 7.1%, p = 0.004) and 18-gene inflamed T cell signature (median, PFS: 8.6 vs. 4.3 months, p = 0.01; ORR: 64.2% vs. 7.1%, p = 0.004). Moreover, our findings highlighted the adverse predictive value of mast cells in immuno-chemotherapy for BTCs for the first time.
Conclusions:
Sintilimab plus GemCis displayed a promising antitumor activity and acceptable safety profile as a first-line treatment in patients with advanced BTC. Multiomics potential predictive biomarkers are identified and warrant further verification. Clinical trial information: ChiCTR2000036652.
Clinical status
Clinical
6 organizations
3 drugs
4 targets
Organization
Department of Oncology and Haematology, Division of Oncology, University Hospital of Modena, Modena, ItalyOrganization
Eastern Hepatobiliary Surgery HospitalOrganization
Shanghai Eastern Hepatobiliary Surgery HospitalOrganization
the Naval Medical UniversityOrganization
Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd.Organization
Nanjing Yoko BiomedicalDrug
sintilimabDrug
FF-10832Drug
CisplatinTarget
PD-1Target
DNA