Since 2010, gemcitabine plus cisplatin has been the standard of care for patients with advanced biliary tract cancer, based on the results reported by the ABC-02 trial (1). Over the next decade, numerous trials were conducted to identify more effective regimens, such as S-1, oxaliplatin, capecitabine, irinotecan, and fluorouracil (2–7). However, increasing the median overall survival (OS) to over 12 months has proven to be challenging. Even worse, the 2-year survival rate remains extremely low for patients with advanced biliary tract cancer (8).

Significant efforts have been made in targeted therapy; however, the results have been unsatisfactory. The ABC-03 trial showed that adding cediranib to gemcitabine plus cisplatin chemotherapy (OS: 14.1 months; progression-free survival [PFS]: 8.0 months) failed to improve survival outcomes compared with gemcitabine plus cisplatin chemotherapy alone (OS: 11.9 months; PFS: 7.4 months) in advanced biliary tract cancer (9). Bevacizumab combined with gemcitabine and cisplatin did not significantly prolong survival time (OS: 10.2 months; PFS: 8.1 months) compared with historical controls in first-line treatment (10). In a phase I trial for advanced cholangiocarcinoma with EGFR overexpression, participants received afatinib plus gemcitabine and cisplatin, resulting in a 7.7-month OS and a 6.0-month PFS (11).

Fortunately, a significant advancement brought by the TOPAZ-1 trial in 2022 has cheered clinicians and patients (12). Patients treated with durvalumab (anti-PD-L1 therapy) plus gemcitabine and cisplatin achieved a median OS of 12.8 months and a median PFS of 7.2 months. Based on these results, the combination therapy of durvalumab, gemcitabine, and cisplatin has been recommended as the preferred regimen for advanced biliary tract cancer by the National Comprehensive Cancer Network (NCCN) guidelines (13).

Progress in immunotherapy for advanced biliary tract cancer continued in 2023. The KEYNOTE-966 trial demonstrated that the median OS (12.7 months vs. 10.9 months) and PFS (6.5 months vs. 5.6 months) were significantly improved by adding pembrolizumab (anti-PD-1 therapy) to gemcitabine and cisplatin (14). According to the data from the KEYNOTE-966 trial, the latest NCCN guideline for biliary tract cancer has suggested gemcitabine and cisplatin in combination with pembrolizumab as the first-line treatment for advanced patients.

More specifically, detailed information should not be overlooked. For instance, patients enrolled in the TOPAZ-1 trial received durvalumab plus gemcitabine and cisplatin for up to eight cycles, followed by durvalumab every four weeks until disease progression or unacceptable toxicity (12). However, participants in the KEYNOTE-966 trial were treated with pembrolizumab (limited to 35 cycles), gemcitabine (without a maximum), and cisplatin (limited to eight cycles) until disease progression or unacceptable toxicity (14). Subsequently, more questions may arise. Which is more effective, anti-PD-L1 therapy or anti-PD-1 therapy? Does gemcitabine-maintenance therapy contribute to the survival time? Is the less-than-two-month increase in survival time meaningful for patients with advanced biliary tract cancer?

In this study, we collected the Kaplan-Meier survival curves from the TOPAZ-1 and KEYNOTE-966 trials and survival curves for gemcitabine plus cisplatin from all published randomized clinical trials. Patient-level data were reconstructed to conduct mimic head-to-head comparisons among the groups. Through our analysis, we aimed to provide not only more extensive survival data but also deeper insights for future treatments of advanced biliary tract cancer.

Through systematic searching, we collected 689 and 1,069 records from the PubMed and Web of Science databases, respectively. Twelve randomized clinical trials published from 2009 to 2023 were eligible, including the TOPAZ-1 and KEYNOTE-966 trials (1–7, 9, 12, 14, 19, 20). Six of the twelve trials were phase 3 studies, and three were double-blind. In the pembrolizumab plus gemcitabine and cisplatin group, patients were treated with pembrolizumab (200 mg on day 1), gemcitabine (1,000 mg/m² on days 1 and 8), and cisplatin (25 mg/m² on days 1 and 8) every 21 days. In the durvalumab plus gemcitabine and cisplatin group, patients were treated with durvalumab (1,500 mg on day 1), gemcitabine (1,000 mg/m² on days 1 and 8), and cisplatin (25 mg/m² on days 1 and 8) every 21 days. Although both groups received immunotherapy combined with chemotherapy, some differences existed. Pembrolizumab was administered for up to 35 cycles, while durvalumab was administered without a maximum limit. In the KEYNOTE-966 trial, there was no limit on the number of cycles of gemcitabine, but in the TOPAZ-1 trial, it was limited to 8 cycles. Considering the contribution of gemcitabine maintenance treatment to survival outcomes, we also collected survival data on gemcitabine and cisplatin in advanced biliary tract cancer reported in all randomized clinical trials. The basic characteristics of the included trials are listed in Table 1 . Additionally, the disease characteristics, including gender, performance status, original tumor site, and disease stage, were generally comparable between the immune-chemotherapy group (pembrolizumab/durvalumab + gemcitabine + cisplatin) and the chemotherapy group (gemcitabine + cisplatin ± placebo) ( Table 2 ).

Before conducting the mimic head-to-head comparisons, the patient-level data from the TOPAZ-1 and KEYNOTE-966 trials were reconstructed to confirm the feasibility of the methods used in this analysis. For durvalumab, the reconstructed HRs were 0.79 (95% CI 0.66-0.96; p = 0.019) for OS and 0.76 (95% CI 0.65-0.90; p = 0.001) for PFS (original: OS 0.75, 95% CI 0.63-0.89; p = 0.001, PFS 0.80, 95% CI 0.66-0.97; p = 0.021) ( Figures 1A, B ). The median OS was 12.8 months (95% CI, 11.2-14.2) in the durvalumab arm versus 11.4 months (95% CI, 10.1-12.6) in the placebo arm (original: 12.8 months [95% CI, 11.1-14.0] vs. 11.5 months [95% CI, 10.1-12.5]). The median PFS was 7.2 months (95% CI, 6.7-7.4) in the durvalumab arm compared to 5.8 months (95% CI, 5.5-6.7) in the placebo arm (original: 7.2 months [95% CI, 6.7-7.4] versus 5.7 months [95% CI, 5.6-6.7]). For pembrolizumab, the reconstructed HRs were 0.84 (95% CI 0.73-0.96; p = 0.011) for OS and 0.89 (95% CI 0.75-1.00; p = 0.056) for PFS (original: OS 0.83, 95% CI 0.72-0.95; p = 0.003, PFS 0.86, 95% CI 0.75-1.00; p = 0.023) ( Figures 1C, D ). The median OS was 12.7 months (95% CI 11.5-13.6) in the pembrolizumab arm vs. 10.8 months (95% CI 9.9-11.7) in the placebo arm (original: 12.7 months [95% CI 11.5-13.6] vs. 10.9 months [95% CI 9.9-11.6]). The median PFS was 6.5 months [95% CI 5.7-6.9] in the pembrolizumab arm versus 5.6 months [95% CI 5.1-6.8] in the placebo arm (original: 6.5 months [95% CI 5.7-6.9] vs. 5.6 months [95% CI 5.1-6.6]). Based on the results, our reconstructed Kaplan-Meier survival curves and Cox regression analyses demonstrated satisfactory repeatability compared with the originally published curves and data. Subsequently, patient-level data on gemcitabine plus cisplatin were reconstructed based on other enrolled randomized clinical trials.

In this mimic head-to-head comparative analysis, our results demonstrated that immunotherapy combined with chemotherapy is superior to chemotherapy alone as the first-line treatment for advanced biliary tract cancer (median OS: 12.8 months vs. 11.5 months; median PFS: 6.9 months vs. 6.0 months). Subgroup analysis indicated that durvalumab and pembrolizumab had comparable effects (median OS: 12.8 months vs. 12.7 months; median PFS: 7.2 months vs. 6.5 months). We also found that maintaining gemcitabine treatment statistically significantly prolonged the OS but not PFS compared to the gemcitabine limited to 8 cycles treatment. Curiously, gemcitabine maintenance did not numerically improve survival time (OS: 11.5 months vs. 11.5 months; PFS: 5.6 months vs. 6.5 months). In addition to median survival outcomes, survival rates may partially explain the efficacy of gemcitabine maintenance treatment. The 3-year OS rate was 9.3% in the gemcitabine maintenance group compared to 1.3% in the gemcitabine limited-to-8-cycles group.

Due to the survival benefits associated with immunotherapy, our results highlight the contributions of durvalumab and pembrolizumab in advanced biliary tract cancer. However, in the subgroup analysis of durvalumab and pembrolizumab, superiority in OS was observed in the gemcitabine maintenance group compared to the gemcitabine limited-to-8-cycles group. Nonetheless, the median OS was not significantly improved. A retrospective study reported by Jaewon Hyung and colleagues suggested that advanced biliary tract cancer may not benefit from gemcitabine and cisplatin maintenance therapy (21). The median OS was 22.4 months in the maintenance group versus 20.5 months in the observation group (p = 0.162), while the median PFS was 13.2 months in the maintenance group versus 10.4 months in the observation group (p = 0.320). In our data, we observed that patients treated with gemcitabine maintenance had a higher ORR than those who received gemcitabine limited-to-8-cycles (29% vs. 18.7%). Consequently, some patients may not need immunotherapy when receiving gemcitabine maintenance treatment. Additional supporting evidence comes from the reported response rates in the TOPAZ-1 and KEYNOTE-966 trials. In the TOPAZ-1 trial, patients did not receive gemcitabine maintenance treatment, and the objective response rate (ORR) improved with the addition of durvalumab (26% vs. 18.7%) (12). Conversely, in the KEYNOTE-966 trial, patients who received gemcitabine maintenance treatment, and similar ORRs were observed (29% vs. 29%) (14). However, we cannot yet conclude the direct contribution of gemcitabine maintenance therapy. The difference might be attributed to a combination of factors, including tumor type, race, and geographic region. Due to the lack of original response data, the above analysis may indirectly suggest the contributions of immunotherapy and gemcitabine maintenance treatment. Furthermore, in specific circumstances, like high tumor burden, patients might benefit from gemcitabine maintenance therapy.

Identifying the precise population that could benefit from anti-PD-1 and anti-PD-L1 therapies is a challenging process. Before identifying sensitive populations, we recommend determining which patients are unlikely to benefit from immunotherapy. Common characteristics include: female, age < 65, ECOG performance status 0, gallbladder cancer patients, and PD-L1 score < 1 subgroups. Immunotherapy may be less effective in these subgroups. According to the subgroup analyses in the TOPAZ-1 and KEYNOTE-966 trials (12, 14), the population most likely to benefit from immunotherapy appears to be the PD-L1 ≥ 1 subgroup. Additionally, the percentages of patients with PD-L1 ≥ 1 were over 57% in the TOPAZ-1 trial and 68% in the KEYNOTE-966 trial. This information supports our assumption that some populations are suitable for immunotherapy. However, more detailed subgroup analysis, such as microsatellite instability (MSI) status, HBV or HCV status, and tumor mutation burden, is warranted. A genomic analysis conducted by Xu Yang and colleagues confirmed our hypothesis that advanced biliary tract cancer with MSI-H and PD-L1 ≥ 1 was found to be associated with longer OS and PFS (22). However, in both the TOPAZ-1 and KEYNOTE-966 trials, patients with PD-L1 score ≥ 1 demonstrated a borderline improvement in OS in both TOPAZ-1 (HR: 0.79, 95% CI 0.61-1.00) and KEYNOTE-966 trials (HR: 0.84, 95% CI 0.62-1.14), but a significant improvement in PFS in the TOPAZ-1 trial (HR: 0.73, 95% CI 0.59-0.91). Therefore, whether a higher PD-L1 score cut-off is necessary warrants deeper explorations. Additionally, the long-term survivors in the control group of the TOPAZ-1 trial may benefit from the second or later-line immunotherapy (23). Thus, further trials are needed to identify the suitable population of advanced biliary tract cancer for immunotherapy.

Although the cycles of immunotherapy and chemotherapy differed between the TOPAZ-1 and KEYNOTE-966 trials, this heterogeneity prevents us from determining whether durvalumab or pembrolizumab is more suitable for first-line therapy in patients with advanced biliary tract cancer based on our current analysis. Therefore, we suggest that patients with a PD-L1 score ≥ 1 receive durvalumab or pembrolizumab in combination with gemcitabine and cisplatin. Another important issue is whether the increase in survival time by one to two months due to immunotherapy is meaningful for advanced patients. The answer is affirmative. Both trials updated their follow-up data in 2024 (24, 25). A common finding is that the 2-year OS rate was numerically and significantly elevated with durvalumab (23.6% vs. 11.5%) or pembrolizumab (24.6% vs. 19.2%). Based on our reconstructed data, the 2-year OS rate was 24.9% in the immunotherapy plus chemotherapy group and 17.3% in the chemotherapy-alone group ( Table 3 ). Combining durvalumab or pembrolizumab with gemcitabine and cisplatin has resulted in survival benefits since the ABC-02 trial. In a recent real-world study by Rimini, patients with advanced biliary tract cancer treated with durvalumab plus gemcitabine and cisplatin achieved a median OS of 15.1 months and a median PFS of 8.2 months (26). The results further support immunotherapy in combination with chemotherapy as a first-line standard of care for advanced biliary tract cancer. This highlights the importance for clinicians to identify the precise population that could benefit from immunotherapy. Additionally, more effective regimens for less responsive populations warrant further exploration.

Several limitations exist in the analysis. All the mimic head-to-head comparisons are indirect. Although there was a low risk of bias among the enrolled trials (Supplement 1), inherent heterogeneities existed between the groups due to the reconstructed patient-level data. Because response data could not be reconstructed, we did not set ORR and DCR as endpoints. Additionally, the safety profiles of durvalumab and pembrolizumab have been confirmed in multiple clinical trials, and both drugs are widely used in real-world clinical practice; therefore, treatment-related adverse events were not included in this analysis.

Finally, this analysis demonstrates the survival benefits of adding immunotherapy to chemotherapy in patients with advanced biliary tract cancer. Detailed reconstructed survival data can inform future clinical practice. Identifying the appropriate population for immunotherapy requires more prospective clinical trials and real-world studies.