Highlight
- Durvalumab combined with gemcitabine and cisplatin significantly improves long-term overall survival in advanced biliary tract cancer (aBTC) compared to chemotherapy alone.
- At 48 months, the overall survival rate doubles with durvalumab plus chemotherapy (11.8% vs 4.3%).
- The safety profile is comparable between the durvalumab plus chemotherapy and chemotherapy alone groups, with manageable serious adverse events.
- This evidence supports durvalumab plus chemotherapy as the new first-line standard of care for aBTC.
Study Background and Disease Burden
Biliary tract cancer (BTC) encompasses a heterogeneous group of malignancies including cholangiocarcinoma and gallbladder cancer, characterized by late diagnosis and aggressive clinical course. Advanced biliary tract cancer (aBTC), which includes unresectable, locally advanced, or metastatic disease, carries a poor prognosis with limited treatment options. Historically, gemcitabine plus cisplatin (GemCis) chemotherapy has been the standard first-line systemic treatment, but long-term survival remains unsatisfactory, with median overall survival (OS) around 12 months. The emergence of immunotherapy has opened new therapeutic avenues; in particular, immune checkpoint inhibitors targeting PD-L1, such as durvalumab, have shown promise in combination with chemotherapy across multiple cancers. Thus, establishing effective, safe, and durable treatment regimens for aBTC is a critical unmet need in oncology and gastroenterology.
Study Design
This post hoc analysis evaluated long-term efficacy and safety data from the global, double-blind, placebo-controlled, phase 3 TOPAZ-1 randomized clinical trial (NCT03875235). A total of 685 adults (≥18 years) with histologically confirmed unresectable, locally advanced, or metastatic biliary tract adenocarcinoma were enrolled across 105 sites in 17 countries from April 2019 to December 2020. Participants were randomized to receive intravenous durvalumab 1500 mg or placebo, combined with gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8 every 3 weeks for up to 8 cycles, followed by durvalumab or placebo maintenance monotherapy every 4 weeks. The primary endpoints included overall survival (OS), duration of treatment exposure, incidence of serious adverse events (SAEs), and treatment-related discontinuations, assessed at a data cutoff approximately 48 months after the last patient was randomized (February 28, 2025).
Key Findings and Results
Of 685 randomized participants, 341 received durvalumab plus GemCis (median age 64 years, 50.4% female) and 344 received placebo plus GemCis (median age 64 years, 48.8% female). Median follow-up time for censored patients was 56.9 months (range 1.7–67.2) in the durvalumab group and 50.7 months (range 0.9–62.6) in the placebo group.
The median OS was 13.0 months (95% Confidence Interval [CI], 11.6–14.1) for durvalumab plus GemCis versus 11.4 months (95% CI, 10.1–12.5) for placebo plus GemCis, corresponding to a hazard ratio (HR) of 0.75 (95% CI, 0.64–0.88). This represents a statistically significant 25% reduction in the risk of death with the addition of durvalumab. Importantly, the advantage extended to long-term survival: the 48-month OS rate was 11.8% in the durvalumab arm compared to 4.3% in the control arm, evidencing durable benefit beyond initial therapy.
Regarding safety, serious adverse events possibly related to treatment occurred in 15.4% of participants receiving durvalumab plus GemCis compared to 17.3% in the placebo group, indicating comparable safety profiles. Rates of adverse events leading to discontinuation were similar between the groups: 6.2% with durvalumab plus chemotherapy and 5.3% with chemotherapy alone. These findings underscore that the addition of durvalumab does not meaningfully increase serious toxicity.
Collectively, these data validate durvalumab combined with chemotherapy as an effective frontline strategy, offering improved survival with manageable adverse effects in aBTC.
Expert Commentary
The TOPAZ-1 trial represents a landmark in the management of advanced biliary tract cancer by establishing immunotherapy in combination with cytotoxic chemotherapy as the new treatment paradigm. The observed OS benefit and sustained survival plateau align with immunotherapy’s potential for durable disease control beyond conventional chemotherapy. Importantly, the large multinational cohort and rigorous randomized control design enhance the generalizability of these findings.
Some limitations include the post hoc nature of this long-term analysis and lack of detailed biomarker stratification to identify subsets with differential benefit. Biomarker analyses could clarify the mechanisms underpinning response and resistance, guiding more personalized approaches. Nevertheless, the safety data provide reassurance about tolerability, critical for patients with limited therapeutic tolerance.
Current clinical guidelines are poised to incorporate durvalumab plus GemCis as the preferred frontline therapy, reflecting an important shift after decades without significant treatment advances. Ongoing studies exploring combinations with other immunomodulators and targeted agents may further improve outcomes.
Conclusion
This four-year post hoc analysis of the phase 3 TOPAZ-1 trial confirms that durvalumab added to gemcitabine and cisplatin chemotherapy produces a meaningful and durable survival advantage in patients with advanced biliary tract cancer. The regimen maintains a favorable safety profile comparable to chemotherapy alone. These results support durvalumab plus chemotherapy as a first-line standard of care for aBTC, addressing a critical unmet clinical need and providing hope for improved patient outcomes.
Funding and Trial Registration
The TOPAZ-1 trial was funded by AstraZeneca. Trial registration: ClinicalTrials.gov Identifier: NCT03875235.
References
1. Oh DY, He AR, Qin S, et al. Durvalumab Plus Chemotherapy for Advanced Biliary Tract Cancer: A Post Hoc Analysis of the TOPAZ-1 Randomized Clinical Trial. JAMA Oncol. 2026;7(7):xxx-xxx. doi:10.1001/jamaoncol.2026.42424063.
2. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281.
3. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671-684.
4. National Comprehensive Cancer Network (NCCN) Guidelines Version 1.2026. Biliary Tract Cancers.