Around 60–70% of patients will be diagnosed with advanced disease, which is defined as inoperable or metastatic disease. For these patients, palliative treatment is the only choice of treatment at the moment. Unfortunately, survival outcome is historically poor in this patient group.

The phase III ABC-02 trial published in 2010 has established cisplatin plus gemcitabine as the first-line standard in patients with advanced biliary tract cancer [12]. Compared to single-agent gemcitabine, the platinum-based combination improved median overall survival (mOS) by 3.6 months (11.7 vs. 8.1 months), which translated into a 36% mortality reduction (HR 0.64; p < 0.001).

In recent months it has been shown that mOS can be slightly improved by adding immunotherapy to chemotherapy regardless of Microsatellite instability (MSI) status.

The phase III TOPAZ‑1 trial explored the addition of the anti-PD-L1 antibody durvalumab. Patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease were included. In all, 685 patients were randomly assigned to durvalumab (n = 341) or placebo (n = 344) with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity.

The median survival in the immunotherapy combination group was 12.8 months, which was marginally, but significantly longer. Here the mOS was 11.5 months. The hazard ratio is given as 0.8; the p value is 0.021. The survival curves diverge after 6 months. After 24 months, the OS in the study group was 24.9% and in the placebo group only 10.4% [13].

KEYNOTE-966 was a randomized, double-blind, placebo-controlled, phase 3 trial performed at 175 medical centers globally. Again, patients with previously untreated, unresectable, locally advanced or metastatic biliary tract cancer where included. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). There were 1069 patients randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n = 533) or placebo plus gemcitabine and cisplatin (placebo group; n = 536). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p = 0·0034 [significance threshold, p = 0·0200]) [14]. This clearly proves that the combination of chemotherapy with immunotherapy is the new therapeutic standard in the first-line treatment of CC regardless of its origin.

As already mentioned in the introduction in recent years we also have learned CC is a role model for precision medicine in the gastrointestinal (GI) tract. For this reason, the European Society of Medical Oncology (ESMO) guidelines recommend molecular testing using next generation sequencing (NGS).

Experts are still discussing the timing of testing (at the beginning of first-line therapy or after it fails). Aside from that, there is currently no general recommendation about which tests are essential. In any case, all common targets should be recorded and the time of testing should be early enough. At least, if the question of second-line therapy arises.

With the volume of biomarker-informed and -agnostic data, current treatment has changed over the past years. Consequently, this led to numerous new approvals by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), and some new substances are waiting to enter everyday clinical practice.