Cholangiocarcinoma (CCA) is a relatively rare, aggressive malignancy originating from epithelial cells of the biliary duct that constitutes approximately 3% of the gastrointestinal malignancies. CCAs are anatomically classified into intrahepatic, perihilar, and extrahepatic subtypes, each with a distinct epidemiology and molecular pathogenesis.1 There has been increasing incidence of cholangiocarcinoma globally, including in the United States. A majority of patients present at an advanced stage requiring systemic therapy. Recent advances in genomic profiling and critical understanding of pathophysiology have led to the development of multiple targeted therapies in addition to chemotherapeutic agents.2
Immunotherapy has dramatically altered the treatment paradigm of multiple cancers. In CCA, the role of immunotherapy remains undefined. Immunotherapy is considered a potential target as chronic inflammation including primary sclerosing cholangitis seems to play a role in the development of CCA. CCAs are characterized by a desmoplastic tumor environment consisting of stromal cancer-associated fibroblasts and immune cells, including tumor-associated macrophages, natural killer cells, and T-cells.3 PD-L1 expression has been reported in cholangiocarcinoma neoplastic cells with a wide range of 9% to 72%, as well as inflammatory cell aggregates.4-6 Deficiency in mismatch repair proteins has been reported in a minority of CCA patients suggesting a potential role for immunotherapy. In general, patients with CCA have low tumor burden but there is a subset of patients who have higher tumor mutational burden (TMB) which might be more responsive to immunotherapy.7
Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited activity with an overall response rate (ORR) of 5% to 25% in unselected populations with refractory CCA (Table 1). In the KEYNOTE-028 basket trial, 24 patients with PDL-1–positive biliary tract cancers (BTCs) were treated with pembrolizumab and an ORR of 13% was reported.8 In the larger KEYNOTE-158 trial, 104 patients with advanced, refractory BTCs were enrolled. ORR was only 5.8% with median progression-free survival (PFS) and overall survival (OS) of 2 months and 7.4 months, respectively. Patients with PD-L1–positive tumors had a numerically higher ORR (6.6% vs 2.9%). In a phase 2 trial of 54 patients with advanced BTC, treatment with nivolumab resulted in an ORR of 22%.9 Bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1 demonstrated similar activity, with an ORR of 22% and median PFS of 3.7 months.10
Dual checkpoint inhibitor therapy has also been evaluated in CCA. The combination of durvalumab plus tremelimumab demonstrated an ORR of 10.8%, which was higher than that seen with durvalumab alone (4.8%). The combination of nivolumab plus ipilimumab yielded response rates of 23% with a median PFS of 2.9 months. Unfortunately, with the exception of MSI-high tumors, treatment with ICI rarely leads to long-term disease control in patients with CCA.
ICI plus chemotherapy combination therapy has been proved to be safe and feasible in patients with advanced CCA (Table 2). Nivolumab in combination with gemcitabine plus cisplatin as first-line therapy resulted in median PFS and OS of 8.8 and 10.6 months, respectively.11 A phase 2 trial evaluated the combination of durvalumab with and without tremelimumab and gemcitabine plus cisplatin in the first-line setting.12 Patients receiving durvalumab plus chemotherapy achieved a 100% disease control rate with a median PFS of 11 months. The addition of tremelimumab did not confer any benefit. Bintrafusp alfa was evaluated in combination with gemcitabine plus cisplatin in a randomized phase 2/3 trial. Unfortunately, the trial did not meet its primary end point of OS.
Prior immunotherapy plus chemotherapy studies led to a large phase 3 randomized trial, TOPAZ-1 (N = 685), evaluating the role of the addition of durvalumab to gemcitabine plus cisplatin.13 Standard-of-care chemotherapy was continued for up to 8 cycles in both arms and patients received durvalumab or placebo as maintenance therapy. The study met its primary end point with a median OS of 12.8 months in durvalumab plus chemotherapy compared with 11.5 months in the chemotherapy alone arm (hazard ratio, 0.80; 95% confidence interval, 0.66-0.97; P = .021). Moreover, both the 12-month OS rates (54.1% vs 48%) and the 24-month OS rates (24.9% vs 10%) were higher in the immunotherapy plus chemotherapy arm. Median PFS was also longer in the combination arm compared with the chemotherapy arm (7.2 vs 5.7 months; P = .75). The benefit of the addition of durvalumab was observed in all subgroups but was more pronounced in patients of Asian descent and having locally advanced cancer rather than metastatic disease. ORR was 26.7% in the durvalumab-chemotherapy arm and 18.7% in the chemotherapy-only arm. PD-L1 expression at various cutoffs was not predictive of efficacy outcomes. There was no significant increase in frequency or severity of adverse events with the addition of durvalumab. At the time of presentation, data were not reported for specific subsets, including viral hepatitis, liver fluke disease, and nonalcoholic steatohepatitis. Furthermore, the OS curves between the 2 arms appear to begin separating at 6 months at the same time chemotherapy was discontinued from both arms.
ICI is being evaluated in combination with other therapies, including PARP inhibitors, anti-angiogenic agents, and tyrosine kinase inhibitors. Cancer vaccines utilizing tumor-specific antigens based on peptides and dendritic cells to prime T-cells are also being evaluated. Wilms tumor-1 and Mucin-1 are both overexpressed in CCA and are used as targets for vaccine therapy. Similarly, adoptive cell therapy using chimeric antigen receptors and T-cell receptors are also under investigation for patients with CCA.
The role of immunotherapy in CCA continues to evolve. The TOPAZ-1 trial has established the role of durvalumab in addition to chemotherapy as first-line therapy for patients with advanced CCA. The survival curves in the trial separated after cessation of chemotherapy, which may suggest a greater role for immunotherapy as maintenance therapy. There is an urgent need to develop biomarkers that can help in selecting patients to maximize benefit. Future novel immunotherapeutic approaches including cancer vaccines and CAR-T therapies could potentially revolutionize this treatment approach for CCA, which was traditionally not considered as particularly responsive to immunotherapeutic agents.
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