[Column] Metastatic bile duct cancer: Is the same treatment for all patients the right answer?

Cholangiocarcinoma is a malignant tumor that develops in the epithelial cells of the bile ducts, which are the pathways through which bile is excreted. Depending on its location, it is classified into hilar and distal cholangiocarcinoma, gallbladder cancer, and intrahepatic cholangiocarcinoma. In Korea, approximately 8,000 new cases are diagnosed annually as of 2022, ranking ninth among all cancers, with a five-year survival rate reported to be less than 30 percent, making it one of the cancers with the poorest prognoses.

Korea ranks second globally in bile duct cancer incidence and first in mortality, making it a country requiring special attention to this disease. Treatment methods vary depending on anatomical location and disease stage, including surgery, radiation therapy, local therapy, and chemotherapy. However, for patients with metastatic or locally advanced disease where surgery is not feasible, chemotherapy is the cornerstone of survival extension.

Shifting standard of bile duct cancer treatment by combining immune-oncology drugs

For over a decade, the standard first-line treatment for bile duct cancer has been “GemCis,” the combination therapy of gemcitabine and cisplatin. However, recent treatments that incorporate immune-oncology drugs are redefining this paradigm.

In the TOPAZ-1 clinical trial, a group treated with GemCis plus durvalumab demonstrated a significant improvement in overall survival compared to the standard regimen. The combination group achieved a progression-free survival (PFS) of 7.2 months and an objective response rate (ORR) of 27 percent, compared to 5.7 months and 18.7 percent in the standard group, respectively.

Three-year follow-up results published in 2025 confirmed the survival benefit of combination therapy, with median overall survival (OS) of 12.9 months in the combination group and 11.3 months in the monotherapy group (HR 0.74), and 36-month survival rates of 14.6 percent vs. 6.9 percent, more than double the monotherapy group.

Notably, the proportion of patients surviving 30 months or longer (eLTS) was 17.0 percent in the combination group, nearly twice that of the monotherapy group (8.7 percent), and the tolerability of combination therapy was maintained.

Meanwhile, the KEYNOTE-966 study, which combines pembrolizumab with Gemcitabine, also showed similar results. The combination group showed a significantly longer overall survival (OS) of 12.7 months compared to 10.9 months in the monotherapy group (HR 0.83; 17 percent reduction in the risk of death), and a trend toward superior progression-free survival (PFS) of 6.5 months vs. 5.6 months. Although the overall response rate (ORR) was similar at 29 percent in both groups, the duration of response was longer in the combination group.

Based on these two study results, combination therapy including immunotherapy has established itself as a new standard for first-line treatment of metastatic bile duct cancer. However, limitations remain, including the absence of predictive biomarkers to identify patients who will respond to immunotherapy and the lack of evidence that the survival benefit of combination therapy is overwhelmingly superior to that of standard therapy. In this context, future efforts should focus on developing precision medicine strategies based on individual molecular and biological characteristics, as well as reliable biomarkers that can predict immune responses.

Precision medicine paves the way for second-line treatment of metastatic bile duct cancer

Although combination therapy with immunotherapy has become the standard for first-line treatment, there is still no clear standard treatment for second-line treatment. In this situation, where treatment options are limited, a treatment approach based on precision medicine is gaining attention.

In particular, a strategy involving genetic analysis using NGS (Next-Generation Sequencing) to identify “actionable targets” and targeting them with targeted therapies is gaining traction.

Notable examples include IDH1 mutations and FGFR2 fusions. IDH1 mutations, found in 10–15 percent of intrahepatic cholangiocarcinoma patients, can be treated with ivosidenib, an oral targeted therapy. In the ClarIDHy study, ivosidenib demonstrated disease progression delay and survival extension, leading to FDA approval in 2021 and making it currently available in the United States.

FGFR2 fusion is also identified in 10–15 percent of intrahepatic cholangiocarcinoma cases, and pemigatinib has been developed as a targeted inhibitor for this mutation. In the FIGHT-202 study, this drug demonstrated a response rate of 35.5 percent and a progression-free survival (PFS) of 6.9 months, proving its efficacy, and is currently used as a treatment both domestically and internationally.

In addition, targeted therapies applicable to various genetic abnormalities, such as HER2 overexpression, BRAF V600E, NTRK fusion, and KRAS G12C mutations, are being increasingly developed. Some of these show higher response rates than existing anticancer agents, suggesting the possibility of long-term survival and attracting attention.

Although precision medicine strategies are emphasized, universally applicable second-line treatment options still exist. The FOLFOX regimen is the only second-line chemotherapy proven to extend survival in the ABC-06 study. Recently, the combination therapy of Onivyde (liposomal irinotecan) plus 5-FU, which has shown efficacy in pancreatic cancer, has emerged as an alternative. Some studies have reported higher response rates and disease control rates (DCR) compared to conventional FOLFOX. However, large-scale randomized studies are still lacking, necessitating selective application.

Second-line treatment for metastatic bile duct cancer remains a challenging area, but FOLFOX remains the most established treatment option to date. Treatment options are expanding to include Onivyde combination therapy, gene-based targeted therapy, and immunotherapy monotherapy. The key is no longer a “one-size-fits-all” approach but rather a personalized approach tailored to the patient's genetic characteristics. Going forward, the key will be to identify optimal treatment strategies for individual patients through personalized approaches enabled by NGS testing and further clinical research.