Checkpoint inhibition in advanced biliary tract cancer: progress, limitations, and the search for biomarker-driven strategies

The therapeutic landscape of biliary tract cancer (BTC) has long been defined by scarcity—scarcity of options, scarcity of clinical trial participation, and scarcity of durable responses (1). In this context, the recently published IMbrave151 trial, evaluating atezolizumab combined with chemotherapy with or without bevacizumab in advanced BTC, is a welcome and timely addition to the field (2). Beyond its clinical findings, the trial provides an opportunity for future study designs and invites a broader discussion about the next steps in systemic therapy development for these heterogeneous and challenging tumors.

Setting the scene: challenges in BTCs

BTCs, encompassing intrahepatic and extrahepatic cholangiocarcinoma as well as gallbladder cancer, are rare but aggressive malignancies with rising incidence worldwide. The prognosis has historically been dismal, with median overall survival (OS) in the range of 12 months after first-line chemotherapy. Gemcitabine plus cisplatin has been the established standard of care since the pivotal ABC-02 trial in 2010, yet therapeutic progress since then has been frustratingly slow (3). Targeted approaches including fibroblast growth factor receptor 2 (FGFR2) inhibitors, isocitrate dehydrogenase 1 (IDH1) inhibitors, and human epidermal growth factor receptor 2 (HER2)-directed therapies, have demonstrated efficacy in biomarker-selected subgroups, but most patients lack actionable alterations (4-7). The advent of immune checkpoint inhibitors has raised new hope, especially following the success of the TOPAZ-1 trial, which established durvalumab plus gemcitabine–cisplatin as a new standard of care (8). More recently, the KEYNOTE-966 trial confirmed the benefit of adding pembrolizumab to gemcitabine-cisplatin, further supporting the role of immunotherapy in the frontline BTC setting (9). Beyond clinical trials, real-world studies have provided valuable confirmation of the applicability of chemo-immunotherapy in real-world BTC population. A large, multicenter real-world analysis, conducted by Rimini et al. (10) evaluated the outcomes of durvalumab plus gemcitabine-cisplatin in patients with advanced BTC across multiple international centers in Europe, United States and Asia. The study included over 600 patients and confirmed the robust effectiveness of the regimen, with a median OS of 15.1 months and a median progression-free survival (PFS) of 8.2 months, results that not only align with but exceed those reported in TOPAZ-1. The overall response rate (ORR) was approximately 33%, and the disease control rate (DCR) approached 78%, underscoring meaningful antitumor activity. In 2025, several meta-analyses have consolidated the immunotherapy addition benefit to chemotherapy backbone in advanced BTC, strengthening the conclusions of individual trials. A pooled analysis of TOPAZ-1 and KEYNOTE-966 encompassing 1,754 patients demonstrated consistent improvements in both OS [hazard ratio (HR): 0.80, 95% confidence interval (CI): 0.72–0.89] and PFS (HR: 0.81, 95% CI: 0.73–0.90), with no evidence of heterogeneity or publication bias, thereby confirming the robustness of chemo-immunotherapy benefit (11). Similarly, a meta-analysis by Wang et al. (12) reported a median OS gain of 1.7 months and median PFS gain of 1.2 months, at the cost of increased immune-related adverse events but with comparable ORR. In this context, IMbrave151 explores a different checkpoint inhibitor backbone, atezolizumab, with and without vascular endothelial growth factor (VEGF) blockade, providing valuable data on both clinical efficacy and correlative biomarkers.

Key findings from IMbrave151

IMbrave151 was a randomized phase II study evaluating atezolizumab in combination with gemcitabine-cisplatin, with or without bevacizumab. The trial enrolled patients with untreated advanced BTC, stratified by anatomic location, metastatic disease and geographic region. The primary endpoint was investigator-assessed PFS.

The results demonstrated encouraging antitumor activity with atezolizumab-chemotherapy, consistent with the immunotherapy-chemotherapy synergy observed in other tumor types (13-16). In particular, the addition of bevacizumab to atezolizumab and gemcitabine-cisplatin was associated with a modest improvement in the primary endpoint of PFS [8.3 vs. 7.9 months, HR 0.67 (95% CI: 0.46–0.95)]. However, the study did not show significant improvement of OS, although trends suggested potential benefit in certain biomarker-defined subgroups. Importantly, the safety profile was manageable, with toxicities consistent with expectations for immune checkpoint inhibition and VEGF blockade.

Biomarker analyses have provided important insights into the immunobiology of BTC (17,18). Overall, tumor mutational burden was low, while PD-L1 expression showed considerable variability. Exploratory evaluations of immune-related gene signatures and tumor microenvironmental features suggested potential predictive value, highlighting the complexity of immune responsiveness in BTC (Table 1). Within this framework, a noteworthy finding from the post hoc exploratory correlative analyses of IMbrave151 was the association between high VEGFA gene expression and improved PFS in patients treated with bevacizumab, pointing to a possible biomarker-driven benefit from VEGF inhibition. However, these results should be interpreted cautiously, as the exploratory nature of the analysis, the modest effect size, and the lack of prospective validation limit the immediate clinical applicability of VEGF as a predictive biomarker.

Placing IMbrave151 in context

The trial’s relevance lies not only in its clinical results but also in its positioning within the rapidly evolving BTC therapeutic landscape. Durvalumab plus gemcitabine-cisplatin (TOPAZ-1) has already secured global approval, and pembrolizumab plus gemcitabine-cisplatin (KEYNOTE-966) delivered broadly consistent outcomes, strengthening the notion that programmed death 1/programmed death-ligand 1 [PD-(L)1] inhibitors confer benefit in BTC when combined with chemotherapy (8,9). In IMbrave151, the addition of atezolizumab to chemotherapy resulted in encouraging antitumor activity, with PFS and OS outcomes that were broadly comparable to those reported in TOPAZ-1 and KEYNOTE-966, although the study was not powered for definitive survival comparisons. While the addition of bevacizumab did not lead to a statistically significant improvement in the overall study population, numerical trends in efficacy endpoints suggested potential benefit in selected subgroups. While cross-trial comparisons must be made with caution, results from IMbrave151 appear aligned with these pivotal phase III studies, supporting a potential class effect of PD-(L)1 inhibitors in the frontline BTC setting (Figure 1). The absence of a clear incremental benefit from bevacizumab in the unselected population may reflect the marked biological heterogeneity of BTC, differences in tumor vascular architecture compared with hepatocellular carcinoma, and the possibility that VEGF-driven angiogenesis is not a dominant mechanism in all BTC subtypes.

Figure 1 First-line chemoimmunotherapy in advanced BTC. Key trials at a glance: bargraph comparing median OS and PFS across pivotal trials in advanced BTC—ABC-02 (GemCis vs. Gem alone), TOPAZ-1 (GemCis + durvalumab vs. GemCis), KEYNOTE-966 (GemCis + pembrolizumab vs. GemCis) and IMbrave151 (GemCis + atezolizumab ± bevacizumab). BTC, biliary tract cancer; Cis, cisplatin; Gem, gemcitabine; OS, overall survival; PFS, progression-free survival.

The bevacizumab question is more nuanced. Anti-angiogenic strategies have long been hypothesized to enhance immunotherapy by modulating the tumor vasculature and immune microenvironment (15,16). In hepatocellular carcinoma, the atezolizumab-bevacizumab combination transformed the standard of care (13). The absence of a similar dramatic effect in BTC suggests fundamental biological differences between hepatocellular carcinoma and cholangiocarcinoma/gallbladder cancer. Nonetheless, exploratory biomarker findings from IMbrave151 provide new intriguing hypotheses: high VEGFA gene expression was associated with improved PFS in the bevacizumab arm, suggesting that angiogenic signatures might help define subsets most likely to benefit from VEGF inhibition. These signals merit further validation, ideally through larger prospective trials and integrated translational programs. Future studies incorporating molecular stratification and angiogenic biomarkers will be critical to clarify whether bevacizumab can be deployed as part of a biomarker-driven precision strategy rather than as a universal addition to frontline therapy. Moving forward, bevacizumab may still find a role in biomarker-driven precision strategies, particularly when combined with immunotherapy in rationally selected patient populations.

Lessons for clinical trial design in BTC

IMbrave151 also illustrates important principles in clinical trial design for rare cancers. The global, multicenter collaboration enabled adequate enrollment despite BTC’s rarity. The inclusion of extensive biomarker analyses ensures that the trial’s impact extends beyond headline efficacy numbers, generating hypotheses for future trials. The randomized phase II design balances feasibility with the need for comparative data and real-world data (10,19), a pragmatic approach in a field where phase III trials are challenging.

Where do we go from here?

The collective lessons from IMbrave151, TOPAZ-1 and KEYNOTE-966 highlight three future directions.

First, immunotherapy is now firmly established in BTC, but further optimization is required—whether through novel checkpoint inhibitors, combination strategies, or sequencing approaches.

Second, biomarker development must move beyond PD-L1 and tumor mutational burden to integrate transcriptomic, proteomic, and spatial profiling. Transcriptomic profiling, through gene expression-based analyses, can delineate immune-inflamed, immune-excluded, or immune-desert tumor phenotypes, identify angiogenic or immunosuppressive signatures, and uncover oncogenic pathways that shape sensitivity or resistance to immunotherapy. Proteomic profiling provides complementary functional information by directly measuring protein expression, signaling pathway activation, and cytokine or chemokine networks that govern immune cell recruitment and checkpoint activity, which may not be fully predicted by genomic alterations alone. Spatial profiling further refines this framework by mapping the localization and interactions of immune cells, stromal components, and tumor cells within the tumor microenvironment—an especially relevant consideration in BTC, which is characterized by pronounced desmoplasia and spatial immune heterogeneity.

The integration of these multidimensional platforms has the potential to transform immunotherapy development from empiric treatment selection toward biologically driven patient stratification. Such approaches could enable identification of patients most likely to benefit from checkpoint inhibition alone, those requiring rational combination strategies (e.g., targeting angiogenesis, myeloid suppression, or stromal barriers), and those unlikely to respond without alternative therapeutic interventions.

Third, the BTC field must sustain global collaborative efforts to ensure equitable access to innovative therapies and robust trial enrollment. Large, internationally coordinated studies with embedded translational programs will be essential to validate emerging biomarkers and ensure their generalizability across diverse patient populations.

An intriguing question is whether immunotherapy can be extended into earlier disease settings. Adjuvant and neoadjuvant trials are ongoing, building on the rationale that immunotherapy may be more effective in the setting of minimal residual disease. Parallel efforts to integrate targeted therapy in molecularly selected populations could enable a future of truly personalized therapy in BTC.

Conclusions

IMbrave151 represents an important contribution to the evolving treatment paradigm for BTC, confirming the clinical relevance of checkpoint inhibition while providing a more reserved perspective on VEGF blockade. However, the modest magnitude of benefit observed underscores the need for more effective strategies and highlights the limitations of current approaches. Importantly, the trial emphasizes the value of rigorous study design and integration of translational research to guide future development. Ultimately, the incorporation of advanced biomarker platforms and rational combination strategies will be central to converting incremental clinical gains into durable survival benefits for a broader BTC patient population.

Acknowledgments

The authors would like to acknowledge the EORTC-PAMM and GI groups network for the fruitful discussions.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-837/prf

Funding: This work was supported by Bennink Foundation, PANOMIC grant (Fondazione Pisa).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-837/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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