Novel Therapeutic Strategies for Biliary Tract Tumors: A Comprehensive Comprehension of Genetic Testing for Biliary Trac

On May 21, 2026, the official website of the Center for Drug Evaluation (CDE) declared that the IDH1 inhibitor TQB3454 developed by CHIA TAI TIANQING is to be incorporated into the priority review for the treatment of patients with locally advanced, recurrent, and/or metastatic biliary tract cancer carrying IDH1 mutations who have not responded to gemcitabine and fluorouracil regimens.

In March 2026, the TQB3454 - III - 01 study on patients with IDH1 - mutant advanced biliary tract cancer successfully achieved the primary endpoints in the pre - set interim analysis. Both the progression - free survival (PFS) and the overall survival (OS) exceeded the pre - established efficacy criteria of the program. This trial represents the second phase III study of IDH1 inhibitors globally and the first in China to yield positive results in the field of biliary tract cancer. It is also the first domestic IDH1 inhibitor to complete phase III clinical development. Data analysis indicates that, in comparison with the control treatment, TQB3454 can significantly reduce the risk of disease progression or death in patients with advanced biliary tract cancer and notably prolong PFS and OS. The safety profile of the drug is consistent with known risks, and no new safety concerns have emerged[1].

Biliary tract cancer (BTC) primarily encompasses cholangiocarcinoma (intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma) and gallbladder cancer, accounting for approximately 3% of digestive system tumors. In 2021, there were over 200,000 new cases globally, and the incidence rate continues to increase. The disease is predominantly adenocarcinoma, characterized by a high degree of malignancy and extremely poor prognosis, with a 5 - year survival rate of less than 5%. Owing to its high aggressiveness, the majority of patients are already in the middle and late stages at the time of initial diagnosis. Only about 10% - 20% of patients meet the criteria for radical surgery, and the postoperative recurrence rate is as high as 60%.

TQB3454 is anticipated to be the first domestically produced IDH1 inhibitor for patients with biliary tract cancer.

Genetic Testing for Biliary Tract Tumors

Molecular diagnosis is extensively applied in various aspects of clinical diagnosis, treatment plan formulation, efficacy assessment, and prognosis determination of hepatobiliary tumors, and relevant research is constantly innovating. A series of drug clinical trials targeting specific molecules or signaling pathways have been successively conducted both at home and abroad, and some of these studies have achieved positive outcomes. Therefore, optimizing one or more molecular assays in the clinical diagnosis and treatment of hepatobiliary tumors may offer patients more effective curative treatment options, thereby extending patients' survival time and enhancing their quality of life.

The content of genetic testing for biliary tract tumors primarily encompasses two parts:

1. Advanced patients can precisely match the treatment plan through genetic testing/molecular typing, which is commonly referred to as precision medication.

2. Genetic risk screening for patients and their families.

Precision Medication:

1.IDH: Mutations in IDH1 represent the most prevalent targeted mutations in intrahepatic cholangiocarcinoma (ICC). It is advisable that patients with non - resectable/metastatic ICC undergo testing for IDH1 mutations at the earliest opportunity. For patients with IDH1 mutations, second - line treatment with IDH1 inhibitors is recommended.

2.FGFR: FGFR2 fusion/rearrangement serves as a crucial biomarker for intrahepatic bile duct cancer. Routine detection of intrahepatic bile duct cancer is recommended to be carried out promptly. Testing can be considered for patients with late - stage gallbladder cancer (GBC) and extrahepatic cholangiocarcinoma (ECC). For patients with advanced bile duct cancer who test positive for FGFR2 fusion/rearrangement, FGFR inhibitors are the preferred choice for second - line and subsequent treatment. In patients with advanced bile duct cancer who test negative for FGFR2 fusion/rearrangement but present with other FGFR variants (such as FGFR1/3/4), FGFR inhibitors can be considered for second - line and subsequent treatment. Novel FGFR inhibitors like Tengotinib can overcome the resistance of traditional inhibitors, and their use is recommended after the development of resistance.

3.BRAF: The BRAF V600E mutation is a potential therapeutic target. It is recommended that patients testing positive for this mutation receive combined anti-BRAF V600Etherapy.

4.HER2 (ErbB2): High expression of HER2 is an important biomarker of BTC, especially GBC and ECC. It is recommended that BTC patients undergo routine immunohistochemistry to detect the expression of HER2. GBC and ECC are more preferred recommendations. For HER2-positive patients, considering their personal circumstances, anti-HER2 treatment can be added to first-line treatment.

5.NTRK/NRG1/RET fusion mutations represent rare mutations in biliary tract cancer (BTC), exhibiting a mutation frequency of less than 1%. Nevertheless, the efficacy of clinical targeted drug therapy is well - established, and it is advisable that patients testing positive for these mutations undergo targeted therapy at the earliest opportunity.

6.KRAS: Presently, only KRAS G12C has been approved as a pharmaceutical target within the RAS pathway. It is recommended as one of the second - line treatment options. Patients are encouraged to participate in clinical trials. The guidelines propose Adagrasib as a subsequent treatment option for patients with KRAS G12C mutant biliary tract cancer experiencing disease progression.

Genetic Risk Screening: The vast majority of biliary tract tumors are non-hereditary (i.e., sporadic), yet approximately 10% - 15% of patients still possess a genetic predisposition background. Currently, genetic testing for such tumors has not yet established a unified population screening standard. Generally, genetic counseling or pre - implantation genetic testing may be recommended when a patient meets any of the following criteria: being diagnosed at a young age (typically, an age of<45 years is regarded as early - onset), having a clear personal or family history of cancer, or potentially having germline mutations in tumor molecular tests.

For hepatocellular carcinoma (HCC)/biliary tract cancer (BTC) patients planning to receive systemic treatment, the mutation status of homologous recombination repair (HRR) genes, including somatic and germline mutations, can be detected via validated next - generation sequencing (NGS) methods. At present, separate testing for homologous recombination deficiency (HRD) status is not recommended. For patients with advanced metastatic HCC/BTC after the failure of conventional treatment, pathogenic/suspected pathogenic mutations in germline HRR genes, particularly the BRCA1 and BRCA2 genes, can be detected, and poly (ADP - ribose) polymerase inhibitor (PARPi) treatment can be attempted.

Liquid biopsy: The gene mutation profiles of liquid biopsy and tissue biopsy show a high degree of consistency in high - frequency mutant genes in advanced BTC. When tissue biopsy is difficult or insufficient, liquid biopsy, including ctDNA and cfDNA, can be considered in a qualified NGS laboratory.

At present, pathological diagnosis remains the gold standard for cancer diagnosis, and accurate molecular testing requires a sufficient amount of high - quality tumor tissue specimens. Therefore, the whole process of standardized pathology technology, including fixation, material acquisition, and pretreatment, is essential to ensure the accuracy of detection and the selection of targeted and immunotherapy treatments. Samples need to be strictly controlled in terms of quality, processing process, etc., and backup samples should be kept to ensure that the test results are traceable, verifiable, and can be re - tested.

Combining clinical, imaging, laboratory, and pathological diagnostic information, molecular testing methods are optimized and selected according to patient diagnosis and treatment needs. Generally, for initial screening, immunohistochemistry/PCR is prioritized, NGS is used for comprehensive molecular spectroscopy screening, and FISH is used for gene fusion/rearrangement/amplification verification to avoid over - detection [2].

Summary

Biliary tract tumors belong to tumors of the digestive system. Although the absolute number of biliary tract tumors in the Chinese population is not large, the number of cases accounts for approximately 25% of the global proportion. Moreover, the cases are showing a trend of younger age and more advanced stages, and the increase in the number of cases is becoming increasingly evident. Research on biliary tract tumors is also continuously advancing. Currently, genetic testing for biliary tract tumors has attracted increasing attention, particularly in the aspect of precise medication. The localization of targeted drugs for various testing targets is in full - fledged progress. It is anticipated that more domestically produced drugs will be launched in the future, and more drugs will be included in the medical insurance to benefit a large number of patients.

Reference:

1.Drug Review Center of the State Drug Administration

2. Chinese expert consensus on precision diagnosis and treatment of biliary tract malignancies