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Review
. 2025 Jun 10;23(1):228.
doi: 10.1186/s12957-025-03877-0.

PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone as the first line treatment for advanced biliary tract cancer: a pooled analysis of KEYNOTE-966 and TOPAZ-1 trails

Jiashou Wang  1 , Yun Xu  2 , Bo Hong  3 , Qingjian Hou  2 , Wenying Chen  2 , Wenxiong Zhang  4 , Wen Zheng  5
Affiliations
Review

PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone as the first line treatment for advanced biliary tract cancer: a pooled analysis of KEYNOTE-966 and TOPAZ-1 trails

Jiashou Wang et al. World J Surg Oncol. .

Abstract

Background: The efficacy of PD-1/PD-L1 inhibitors plus chemotherapy (PIC) as a first-line treatment for advanced biliary tract cancer (BTC) remains controversial, given inconsistent findings regarding survival benefits and safety concerns. This meta-analysis systematically evaluates the safety and efficacy of PIC versus chemotherapy alone, aiming to provide more definitive guidance for BTC treatment decisions.

Methods: To identify phase 3 randomized controlled trials (RCTs) comparing PIC with chemotherapy alone in patients with advanced BTC, a comprehensive literature search was conducted across six databases. Primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included response rates and adverse events (AEs).

Results: Two phase 3 RCTs (KEYNOTE-966 and TOPAZ-1) involving 1,754 patients met the inclusion criteria. Findings demonstrated that the PIC group had significantly improved OS (hazard ratio [HR]: 0.76 [0.66, 0.87]) and PFS (HR: 0.76 [0.66, 0.87]). The mOS (MD: 1.70 [1.51, 1.90] months) and mPFS (MD: 1.20 [0.61, 1.79] months) were also higher in the PIC group. OS and PFS advantages for the PIC group were confirmed across most subgroups. In the first two years of treatment, survival rates (OS and PFS) and extended duration of response in the PIC group increased over time. Both groups showed comparable total AEs, treatment-related AEs, ORR, and DCR. However, the PIC group had significantly higher rates of immune-related AEs (irAEs) and grade 3-5 irAEs.

Conclusions: PIC is associated with improved OS and PFS in advanced BTC compared to chemotherapy alone, though the elevated risk of irAEs calls for careful monitoring.

Trial registration: PROSPERO ID: CRD42024611835. PROSPERO link: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024611835 .

Keywords: Biliary tract cancer; Chemotherapy; Meta-analysis; PD-1/PD-L1 inhibitors; Randomized controlled trials.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Due to the nature of this study no ethical approval was required. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart
Fig. 2
Fig. 2
Forest plots of overall survival and progression-free survival associated with PIC versus chemotherapy
Fig. 3
Fig. 3
Comparisons of OSR associated with PIC versus chemotherapy. A OSR at 3–36 months between the two groups; B trend of risk ratios in OSR
Fig. 4
Fig. 4
Comparisons of PFSR associated with PIC versus chemotherapy. A PFSR at 3–36 months between the two groups; B trend of risk ratios in PFSR
Fig. 5
Fig. 5
Forest plots of responses associated with PIC versus chemotherapy
Fig. 6
Fig. 6
Funnel plots of survival (A), OSR (B), responses (C), and safety summary (D)
See this image and copyright information in PMC

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