For unresectable and metastatic advanced biliary tract cancers (BTCs), gemcitabine plus cisplatin (GP regimen) has been established as the standard first-line treatment based on the findings of the ABC-02 trial. As the first large-sample phase III randomized clinical trial enrolling patients with locally advanced or metastatic biliary tract cancers, the ABC-02 study demonstrated that the GP regimen improved the efficacy of chemotherapy for biliary tract malignancies and confirmed the synergistic effect between gemcitabine and cisplatin.
Phase III trials of immunotherapy combined with chemotherapy have also yielded encouraging outcomes in patients with advanced biliary tract cancers (BTCs).
The TOPAZ-1 trial was a global, randomized, double-blind, phase III randomized controlled study evaluating durvalumab or placebo combined with gemcitabine plus cisplatin for advanced biliary tract cancer. A total of 685 patients were randomly assigned to the durvalumab plus GC group (D+GC, n=341) or the placebo plus GC group (PBO+GC, n=344). The median follow-up duration was 23.4 months (20.6-25.2) and 22.4 months (21.4-23.8) for the two groups, respectively.
Median overall survival (mOS) was significantly prolonged in the D+GC group compared with the PBO+GC group (12.9 months vs 11.3 months; HR=0.76, 95% CI: 0.64-0.91). OS hazard ratios (HRs) with corresponding 95% CIs indicated consistent clinical benefits of the D+GC regimen across all pre-specified subgroups: initially unresectable disease (HR=0.79, 95% CI: 0.65-0.95), recurrent disease (HR=0.76, 95% CI: 0.49-1.20); and by primary tumor site: intrahepatic cholangiocarcinoma (HR=0.78, 95% CI: 0.62-0.99), extrahepatic cholangiocarcinoma (HR=0.61, 95% CI: 0.41-0.91), and gallbladder cancer (HR=0.90, 95% CI: 0.64-1.25).
The 12-month, 18-month and 24-month OS rates were 54.3% vs 47.1%, 34.8% vs 24.1%, and 23.6% vs 11.5% (D+GC vs PBO+GC), respectively. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was 60.9% in the D+GC group versus 63.5% in the PBO+GC group. The rate of treatment discontinuation due to any TRAE was 8.9% and 11.4% in the two groups respectively.
KEYNOTE-966 is a randomized, double-blind, placebo-controlled phase III trial conducted across 175 medical centers worldwide. A total of 1069 patients were randomized to receive pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group, n=533) or placebo plus gemcitabine and cisplatin (placebo group, n=536). At the final analysis, the median follow-up time was 25.6 months (IQR: 21.7-30.4).
The median OS was 12.7 months (95% CI: 11.5-13.6) in the pembrolizumab group and 10.9 months (95% CI: 9.9-11.6) in the placebo group (HR=0.83, 95% CI: 0.72-0.95; one-sided p=0.034, with a prespecified significance threshold of p=0.0200).
Among the treated population, grade 3-4 adverse events were reported in 420 of 529 patients (79%) in the pembrolizumab group and 400 of 534 patients (75%) in the placebo group. Grade 3-4 TRAEs occurred in 369 patients (70%) in the pembrolizumab group and 367 patients (69%) in the placebo group.
Deaths attributable to adverse events occurred in 31 patients (6%) in the pembrolizumab group and 49 patients (9%) in the placebo group. Among these, 8 patients (2%) in the pembrolizumab group and 3 patients (1%) in the placebo group died from TRAEs.
Although chemoimmunotherapy has become the standard first-line regimen for advanced biliary tract cancers (BTCs), substantial unmet medical needs remain in clinical practice. First, the survival benefit is modest. In the TOPAZ-1 and KEYNOTE-966 trials, the median overall survival (OS) was prolonged by merely 1.3 to 1.8 months with chemoimmunotherapy versus chemotherapy alone. The objective response rate (ORR) remains below 30%, and disease progression eventually occurs in most patients. Second, there is a lack of validated predictive biomarkers. To date, no reliable biomarkers are available to accurately identify patients most likely to benefit from chemoimmunotherapy. Consequently, some patients fail to achieve satisfactory clinical outcomes while suffering from unnecessary treatment-related toxicities. Third, a subset of patients show poor tolerance to current regimens. Cisplatin-induced adverse events such as nephrotoxicity and gastrointestinal reactions may compromise treatment adherence. Therefore, safer chemotherapy combinations and novel combination strategies are urgently required.
These limitations indicate that current chemoimmunotherapy regimens require further optimization. Novel and more effective combination treatment strategies need to be explored to maximize clinical benefits and improve patient prognosis.