Durvalumab plus cisplatin and gemcitabine in advanced biliary tract cancer: can we do it better?

Biliary tract cancer (BTC) remains a challenging malignancy with poor prognosis and limited treatment options. The TOPAZ-1 trial marked a significant advance by introducing immunotherapy into this setting. It evaluated adding durvalumab to the first-line standard cisplatin-gemcitabine regimen, established by the ABC-02 trial (1). Results from TOPAZ-1 showed that adding durvalumab to cisplatin–gemcitabine improved overall survival compared with chemotherapy alone, with consistent benefit across clinically relevant subgroups (2,3). The updated TOPAZ-1 results further solidify durvalumab’s role, expanding upon interim data (2). Conducted across 17 countries, the study enrolled 685 patients with unresectable or metastatic BTC, randomized to receive durvalumab plus cisplatin-gemcitabine or placebo plus chemotherapy. With a median follow-up of 23.4 vs. 22.4 months, overall survival (OS) data maturity was 76%. The OS hazard ratio improved from 0.80 to 0.76 over time. Final OS rates at 12-, 18-, and 24-month were 54.3% vs. 47.1%, 34.8% vs. 24.1%, and 23.6% vs. 11.5%, respectively. Objective response rate (ORR) was 27% vs. 19%. Impressively, median OS for responders in the durvalumab arm reached 19.5 months. No new safety signals emerged. The analysis also highlighted a greater proportion of long-term survivors (≥18 months) in the durvalumab arm (26% vs. 19%). These findings, alongside the doubled 24-month survival rate and improved OS hazard ratio (HR), suggest an increasing survival benefit over time with durvalumab, reflected by the ‘tail’ of the Kaplan-Meier OS curve. This pattern of durable benefit is consistent with immunotherapy effects in other cancers such as non-small cell lung cancer (NSCLC) and melanoma (4-6), likely mediated by long-lasting T cell memory (7). Unlike chemotherapy’s transient cytotoxicity, immunotherapy can sustain anti-tumor immunity by reactivating tumor-specific T cells, explaining the delayed curve separation and plateau observed in long-term responders in TOPAZ-1 (4-7). In addition to the phase III TOPAZ-1 trial, real-world studies are providing important complementary evidence on the use of durvalumab combined with cisplatin and gemcitabine in advanced BTC (8). Our global retrospective study, the largest to date, analyzed 666 patients treated across 39 centers in 11 countries. The results largely confirm and extend those of TOPAZ-1: median OS was 15.1 months and median progression-free survival (PFS) 8.2 months, both favorable compared to the phase III data. The overall response rate was 32.6%, with a disease control rate of 77.8%. Importantly, in a comparative analysis with a historical cohort treated with chemotherapy alone, the addition of durvalumab significantly improved both OS and PFS.

Several key aspects of the study design warrant further discussion. First, we would like to focus on the exclusion criteria: one of the most important in the TOPAZ-1 trial, patients who experienced disease recurrence within 6 months of surgery or completion of adjuvant therapy were excluded. This criterion was likely intended to minimize heterogeneity in the study population and to avoid the confounding effect of recent chemotherapy exposure, given that early relapsing patients tend to have disease characterized by more biological aggressiveness and chemoresistance. In addition, including such patients could have underestimated the observed benefit of chemoimmunotherapy and complicated the interpretation of first-line efficacy data in a registrational setting. However, this approach inevitably excluded a substantial proportion of patients who commonly relapse early in clinical practice and who potentially could experience a benefit from treatment with durvalumab. Our research group recently published a real-world analysis conducted across a large international cohort of 178 patients with BTC receiving first-line durvalumab plus cisplatin-gemcitabine. The study demonstrated that durvalumab in addition to cisplatin-gemcitabine retains its efficacy and safety profile irrespective of the timing of relapse. In particular, OS (23.4 months vs. not reached; HR 1.26; P=0.45) and PFS (7.0 vs. 9.8 months; HR 1.38; P=0.13) were comparable between patients with early (≤6 months) and late (>6 months) recurrence (9). Of course, these data are retrospective and require prospective validation. However, given the high incidence of early recurrence in this disease setting, we believe that future first-line clinical trials should carefully consider including early-relapsing patients, to better reflect real-world clinical practice and address an important unmet need.

Another important point is the definition of biomarker able to define which patients could benefit from the addition of immunotherapy. In the TOPAZ-1 trial, programmed death-ligand 1 (PD-L1) expression was assessed using the Tumor Area Positivity (TAP) score, a method less commonly used and validated in solid tumors compared to the Combined Positive Score (CPS) employed in studies such as KEYNOTE-966 (10). Nevertheless, both the TOPAZ-1 and KEYNOTE-966 trial highlighted the absence of a relationship between higher PD-L1 expression and improved outcomes with chemoimmunotherapy, even despite the use of different PD-L1 assays and scoring methods. Thus, although the TOPAZ-1 trial employed the TAP score, a method currently less commonly used and validated in the broader oncology field, the available evidence indicates that PD-L1 expression, regardless of the scoring method applied, is not a reliable standalone biomarker to identify patients likely to benefit from immunotherapy in BTC. In addition, an exploratory post hoc analysis no molecular biomarkers were identified as predictive of treatment benefit with durvalumab plus chemotherapy. Further research is therefore warranted to better define predictive biomarkers in this setting.

Finally, a discussion could be open about the design of the treatment for the experimental arm with durvalumab. The rationale for combining chemotherapy and immunotherapy in BTC is grounded in the well‑documented immunomodulatory effects of platinum compounds, particularly cisplatin, which are capable of inducing immunogenic cell death, enhancing tumor antigen presentation, and reprogramming the tumor microenvironment towards increased susceptibility to checkpoint inhibitors. This concept is further supported by the limited efficacy observed with singleagent PD-(L)1 blockade in BTC, suggesting a need for strategic combinations (11-13). In other words, in BTC chemotherapy seems to “boost” the T-cell responses thus increasing the efficacy of immune checkpoint inhibitors. In this context, the design of the TOPAZ-1 trial is particularly appealing: it employs an induction phase with the triplet regimen (gemcitabine, cisplatin, and durvalumab), leveraging the strong cytotoxic backbone of chemotherapy for up to 8 cycles, followed by maintenance with durvalumab alone. This strategy not only aligns with the underlying rationale but also avoids prolonged chemotherapy exposure, which is especially relevant given the need to preserve bone marrow reserve for future lines of treatment in these patients. Starting from that premises, we could speculate that progression during maintenance in some long responders could reflect loss of chemotherapy’s “boost” rather than true resistance to PD-L1 blockade. If so, maybe the reintroduction of cisplatin and gemcitabine during ongoing durvalumab, as an “immunogenic rechallenge” might restore antigenic stimulation and re-sensitize tumors thus prolonging disease control in first line setting and delaying second- and further line therapies in a setting with limited therapeutic options. Given the enrichment of long-term survivors observed in the durvalumab arm, alongside a doubled 24-month OS rate, it is reasonable to consider that a significant subset of patients derives deep and durable benefit from checkpoint inhibition. These patients might further benefit from an integrated approach of intermittent chemotherapy rechallenge during durvalumab maintenance, helping to sustain immunological momentum and preserve marrow function. In the current absence of validated biomarkers to identify such responders, this strategy could represent a pragmatic way to maximize the benefit of chemoimmunotherapy across the broader BTC population. Emerging evidence from other tumor types supports the feasibility and potential clinical benefit of chemotherapy rechallenge during ongoing immune checkpoint inhibitors’ maintenance. In a retrospective study of 154 patients with advanced NSCLC who had previously received first-line chemo-immunotherapy, a subgroup received a rechallenge with chemotherapy without discontinuing the ICI upon disease progression, while others continued ICI alone or switched to a different regimen (14). Results confirmed that reintroducing chemotherapy in the context of ongoing immune checkpoint blockade is both feasible and capable of producing measurable clinical benefit, even if modest, without the need to interrupt immunotherapy. Further prospective studies exploring this approach would be of particular interest, as the long-term outcomes reported in the TOPAZ-1 trial suggest that selected patients may indeed benefit from such a strategy.

In conclusion, the updated results of the TOPAZ-1 trial further consolidate the role of immunotherapy in the treatment of advanced BTC, offering durable survival benefits for a subset of patients. As the field moves forward, refining patient selection criteria and optimizing treatment strategies, such as the potential use of chemotherapy rechallenge during immunotherapy maintenance, represent promising avenues for future research. Ultimately, a better understanding of the immunobiology of BTC and the identification of reliable predictive biomarkers will be key to fully realizing the potential of chemoimmunotherapy and improving outcomes for this challenging disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-393/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-393/coif). The authors have no conflicts of interest to declare.

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