Editor's Note: In the field of biliary tract cancer (BTC) treatment, significant advancements have been made recently. BTC is a highly heterogeneous group of malignancies originating from the epithelium of the bile ducts, presenting challenges in treatment and typically leading to short survival periods for patients. Traditionally, the primary treatment for advanced BTC has been chemotherapy. However, recent developments in immunotherapy combined with chemotherapy as a first-line treatment have shown promise. Additionally, a deeper understanding of the genomic and proteomic characteristics of biliary tumors has led to a clearer classification of molecular subtypes and the discovery of several molecular biomarkers. This has spurred active research in targeted therapies for second-line BTC treatment, significantly altering the treatment landscape for this condition.

Professor Yang MingDr. Ming Yang from Beijing Tsinghua Chang Gung Hospital provides an overview of the latest advancements in systemic treatment of BTC over the past year. This includes a detailed review of BTC classification and the latest treatment regimens, offering valuable insights for clinicians in the systemic treatment of BTC.

  1. Classification and Epidemiology of BTC

Biliary tract cancers (BTC) are a diverse group of tumors. Depending on the location of the tumor, BTC is classified into gallbladder cancer (GBC) and cholangiocarcinoma (CCA). CCA is further divided into intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA). eCCA is then subdivided into perihilar CCA (pCCA) and distal CCA (dCCA). In terms of prevalence, iCCA accounts for 10-20%, pCCA for 50-60%, and dCCA for 20-30% of cases[1-2].

CCA ranks sixth among global digestive system malignancies and second in the hepato-biliary system, comprising 3% of all digestive system cancers[3]. Epidemiological data from the European Cholangiocarcinoma Network show significant geographical variations in the epidemiological characteristics of CCA and its subtypes, reflecting different exposure to risk factors[4]. Liver fluke infection is a common risk factor in East Asia, while primary sclerosing cholangitis is closely related to CCA in Europe. From an epidemiological and clinical perspective, hepatitis B virus (HBV) and hepatitis C virus (HCV) related liver diseases are also associated with CCA. In Europe and other Western countries, HCV infection is the main risk factor, whereas in Asian countries, HBV infection predominates[2].

CCA constitutes 10-15% of primary liver cancers[5]. According to the 2016 report by China’s National Cancer Center, there were between 95,000 to 114,000 new cases of BTC, with 38,900 to 58,000 cases of CCA, and 56,000 cases of GBC. The incidence rate of GBC was 2.39 per 100,000, with a mortality rate of 1.73 per 100,000 (world standardized rate)[6].

  1. Evolution of the BTC Systemic Treatment Landscape

The treatment landscape for BTC is evolving rapidly with the advent of immunotherapy, targeted therapy, and various new treatment modalities. The focus is gradually shifting from chemotherapy-based treatments to combinations of targeted, immune, and chemotherapies.

1) First-Line Treatments

a) 1. Double/Triple Drug Combination Chemotherapy

The ABC-02 study[7], involving 410 patients from 37 UK research centers with inoperable, recurrent, or metastatic BTC, set a new standard in BTC treatment. These patients, with an ECOG PS of 0-2 and expected survival of more than three months without brain metastasis, were randomly assigned to either a GemCis (gemcitabine + cisplatin) group or a gemcitabine-only group. Treatment lasted up to eight cycles or until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), quality of life (QoL), and adverse effects (AEs). The study demonstrated a significant survival advantage for the combination therapy without a notable increase in AEs. As a result, the GemCis regimen has become the standard first-line treatment for advanced BTC. Subsequent studies[8] comparing the efficacy of gemcitabine + S-1 with gemcitabine + cisplatin, capecitabine + oxaliplatin, and gemcitabine + oxaliplatin showed non-inferiority for gemcitabine + S-1 but no major breakthroughs. The NCCN Guidelines 2021[9] recommend gemcitabine + cisplatin as the first choice for treatment, and the CSCO Guidelines[10] 2021 list gemcitabine + cisplatin, gemcitabine + S-1, capecitabine + oxaliplatin, and gemcitabine as first-line recommendations.

Table 1 presents the survival outcomes for patients in the GemCis group compared to the Gem group.

The KHBO1401 study[11], a phase III randomized controlled trial, compared the efficacy of gemcitabine + cisplatin + tegafur (GCS) against CisGem in treating inoperable/recurrent BTC. The results showed that the GCS group had better overall survival (OS) of 13.5 and 12.6 months, and progression-free survival (PFS) of 7.4 and 5.5 months, with a higher objective response rate (ORR) of 41.5% compared to 15%. Another multicenter phase II single-arm study[12] evaluated the effectiveness of gemcitabine + cisplatin + albumin-bound paclitaxel as a first-line treatment for BTC, showing promising results with an OS of 19.2 months, a PFS of 11.8 months, and an ORR of 45.0%. These studies suggest that triple drug combination chemotherapy may be more effective. However, the SWOG 1815 phase III randomized controlled trial[13] did not definitively confirm that the triple chemotherapy regimen of gemcitabine + cisplatin + albumin-bound paclitaxel (GCN) was superior to the double chemotherapy regimen of gemcitabine + cisplatin (GC). The triple regimen also resulted in increased adverse events (AEs), although subgroup analysis indicated that patients with GBC seemed to benefit more. This marks a pause in efforts to improve the efficacy of systemic treatment for BTC solely through chemotherapy.

b) Chemotherapy Combined with Immunotherapy

The TOPAZ-1[14] and KEYNOTE-966 studies[15] mark the official entry of advanced BTC first-line treatment into the era of immunotherapy. The NCCN Clinical Guidelines for Biliary Tract Cancers 2023 v2 V2[16] recommend durvalumab + gemcitabine + cisplatin as the only preferred first-line option for advanced BTC, and the 2023 CSCO Guidelines[17] for Malignant Biliary Tract Diseases recommend durvalumab + gemcitabine + cisplatin and pembrolizumab + gemcitabine + cisplatin as first-line treatments for advanced BTC. TOPAZ-1[14] is the first phase III clinical study in first-line immunotherapy for advanced BTC to achieve positive results. Patients included those with newly diagnosed locally advanced or metastatic BTC or disease recurrence within six months of curative surgery or adjuvant therapy, with an ECOG PS of 0 or 1. They were randomized 1:1 to receive durvalumab 1500mg Q3W + GemCis (up to eight cycles) or placebo Q3W + GemCis (up to eight cycles), followed by sequential durvalumab 1500mg or placebo Q4W treatment until PD. The primary endpoint was OS, with secondary endpoints including ORR, PFS, etc. Study data first published at ASCO GI 2022[14] showed that the immunotherapy combination group had better OS, PFS, and ORR (Table 2). OS subgroup analysis indicated more significant benefits in ICC patients undergoing immunotherapy. Exploratory analysis showed that durvalumab + GemCis was effective in patients with clinically significant mutations and high incidence mutations[18].

Table 2. OS, PFS, and ORR of the two groups of patients.

The phase III KEYNOTE-966 study[15] included patients with untreated inoperable locally advanced or metastatic extrahepatic CCA (eCCA), intrahepatic CCA (iCCA), or gallbladder cancer (GBC), all with an ECOG PS of 0 or 1. Participants were randomized 1:1 to receive pembrolizumab 200 mg Q3W (up to 35 cycles) or a placebo, with the chemotherapy regimen consisting of gemcitabine 1000 mg/m2 on days 1 and 8 every three weeks (without a maximum cycle limit) and cisplatin 25 mg/m2 on days 1 and 8 every three weeks (up to 8 cycles). The primary endpoint was overall survival (OS), with secondary endpoints including objective response rate (ORR) and progression-free survival (PFS). The KEYNOTE-966 study also reached its statistical endpoint for OS, with subgroup analysis showing that ICC patients benefited more from immunotherapy, further confirming the effectiveness of immunotherapy in the treatment of advanced BTC.

c) Chemotherapy Combined with Immunotherapy and Targeted Therapy

A phase II open-label, single-arm study[19] explored the effects of tislelizumab + lenvatinib + GEMOX as a four-drug combination first-line treatment for advanced inoperable ICC. The results showed an ORR of 80.0%, a disease control rate (DCR) of 93.3%, a median PFS of 10.0 months, a median duration of response (DOR) of 9.8 months, and a median OS of 22.5 months with a 12-month OS rate of 73.3%, all indicating good safety. Based on these findings, the randomized double-blind, placebo-controlled, multicenter phase III JS001-039-III-ICC study[20] was initiated, planning to enroll 480 patients across three groups: tislelizumab + lenvatinib + GEMOX or GC, tislelizumab + oral placebo + GEMOX or GC, and injectable placebo + oral placebo + GEMOX or GC. Tislelizumab/placebo treatment will last for 35 cycles, with lenvatinib 8 mg daily orally and GEMOX or GC for 8 cycles, continuing until PD, unacceptable toxicity, or decision by the researcher/patient to withdraw. The final results of this study are highly anticipated.

The phase II randomized, double-blind, placebo-controlled Imbrave151 study[21] explored the effect of bevacizumab combined with atezolizumab and gemcitabine/cisplatin as a first-line treatment for BTC. In this study, 162 advanced BTC patients were enrolled 1:1 to receive gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1 and 8, and atezolizumab 1200 mg Q3W ± bevacizumab 15 mg/kg Q3W. The primary endpoint was PFS, with key secondary endpoints being ORR and DOR. The results did not show a clear benefit from adding anti-angiogenic drugs to the base of immunotherapy and chemotherapy.

d) Local Treatment Combined with Systemic Treatment

An open-label, single-arm, single-center, prospective phase II study[22] explored the effects of hepatic artery infusion chemotherapy combined with bevacizumab and tislelizumab for the treatment of advanced, initially treated CCA. The regimen included bevacizumab 300 mg on day 1, oxaliplatin 40 mg/m2 on days 1-3, 5-fluorouracil 800 mg/m2 on days 1-3, and tislelizumab 240 mg on day 1 every four weeks for six cycles, followed by tislelizumab 240 mg on day 1 and bevacizumab 300 mg on day 1 every four weeks until PD, unacceptable toxicity, or voluntary withdrawal. Mid-term results, as shown in Table 3, suggest that this treatment may help shift the paradigm of first-line therapy for patients with advanced BTC.

Table 3. Mid-term Treatment Results

e) 5. Targeted Therapy Combined with Immunotherapy

Studies[23] have explored the efficacy of tislelizumab combined with lenvatinib as a first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC), showing an objective response rate (ORR) of 32.3% with manageable safety, warranting further investigation.

2) Second-Line and Subsequent Treatments

a) 1. mFOLFOX as the Standard Regimen for Second-Line BTC Treatment

Large-scale phase III studies for second-line chemotherapy are scarce. The ABC-06 study[24], a phase III randomized controlled trial, compared active symptom control (ASC) + FOLFOX with ASC alone, showing overall survival (OS) of 6.2 and 5.3 months, respectively. A phase II study[25] assessed the efficacy of irinotecan + capecitabine, reporting OS of 10.1 and 7.3 months. Another phase IIb study[26] using liposomal irinotecan + 5-FU + folinic acid showed OS of 8.6 and 5.5 months. Based on these results, FOLFOX is recommended as a second-line treatment for patients who progress after first-line treatment with gemcitabine + cisplatin. Alternative combinations, such as irinotecan + capecitabine or liposomal irinotecan + 5-fluorouracil + folinic acid, may also be considered.

b) 2. Targeted Therapy Combined with Immunotherapy

The LEAP-005 study, a phase II single-arm trial[27], evaluated the efficacy of pembrolizumab + lenvatinib as a second-line treatment for advanced BTC in 31 patients who had previously undergone first-line treatment. Patients received pembrolizumab 200 mg Q3W + lenvatinib 20 mg qd until progression of disease (PD), intolerable toxicity, 35 cycles, or withdrawal of consent. The results showed an ORR of 10%, a disease control rate (DCR) of 68%, progression-free survival (PFS) of 6.1 months, and OS of 8.6 months. Adverse events (AEs) occurred in 97% of patients, with grade 3 AEs in 48% and immune-related AEs in 45%. Another phase Ib clinical study[28] assessed the efficacy of anlotinib + PD-L1 inhibitor as a second-line treatment for advanced BTC, showing an OS of 18.92 months and a PFS of 6.87 months, with good tolerance. Thus, the 2023 CSCO Guidelines for Malignant Biliary Tract Diseases[17] added anlotinib + PD-1/PD-L1 inhibitor as a second-line treatment. Second-line treatments combining immunotherapy with targeted drugs for ICC, such as pembrolizumab + ramucirumab, avitinib + regorafenib, are under active exploration[29-32]. The current consensus recommendation is that for ICC patients with unknown driver genes, targeted therapy in combination with immunotherapy, such as triplizumab in combination with lenvatinib, may be selected after systemic chemotherapy has progressed.

c) 3. Precision Targeted Therapy and Immunotherapy

Advancements in genetic testing have led to the emergence of new precision targeted drugs for BTC, targeting mutations such as IDH1 (10-20% in iCCA), FGFR2 (9-15% in iCCA), NTRK (<1%), HER2 (5-20% in CCA, 15-20% in GBA), BRAF (1-5%), MEK, and MSI-H (1-3%)[33]. FGFR2 mutation in iCCA can be targeted with Pemigatinib, Derazatinib, Infigratinib, Futibatinib, Erdafitinib; Ivosidenib, Enasidinib for IDH1 mutation; KRAS G12C inhibitors for eCCA and GBC carrying KRAS G12C mutation (30-45%); Zanidatamab, pertuzumab + trastuzumab, trastuzumab, lapatinib, and Varlitinib for HER2 mutation[34]; dabrafenib and trametinib for BRAF mutation[35]; and PARP inhibitors for homologous recombination deficiency (5-15%) including ARIDIA, BAPI, ATM, BRCA2, CHEK2, PALBB2 mutations. DMMR/MSI-H (2-5%) BTC are sensitive to immune checkpoint inhibitors.

Currently, FGFR2 inhibitors are primarily used for second-line and beyond treatment in advanced FGFR fusion/rearrangement CCA patients, with ORR ranging from 20-40%, and 63% for RLY-4008. These results still need to be verified in large sample size studies, and FGFR2 inhibitors have begun to enter the advanced first-line therapy, and the results are worthy of expectation[36, 37]. HER2-targeted drugs include small molecule TKIs, large molecule monoclonal antibodies, conjugated drugs (trastuzumab deruxtecan), and bispecific antibodies (ZW25). Data shows higher efficacy rates for trastuzumab deruxtecan and ZW25, with ORRs of 36.4% and 40%, respectively. In addition, dextrastuzumab also showed some efficacy in patients with low HER2 expression[38-44]. DNA damage defects occur in 28.9%-63.5% of BTC, with BRCA1/2 being the most extensively studied, showing a mutation rate of 1%-7% in BTC patients. PARP inhibitors combined with other drugs are being evaluated for efficacy[45, 46].

Many clinical studies combining targeted drugs with immunotherapy are underway, with the potential to further clarify the benefits of combined immunotherapy.

BTC, a group of highly aggressive and heterogeneous tumors, has shown limited survival and poor prognosis with traditional chemotherapy. The TOPAZ-1 study is a milestone, recommended by domestic and international guidelines as a new standard treatment, with the KN966 study reaffirming the role of immunotherapy. The molecular characteristics of BTC, with high heterogeneity and targeting multiple points such as FGFR, IDH1, HER2, offer new hope for treatment. Combined local and systemic treatment also holds the potential to change the treatment dilemma for some BTC patients.

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Dr. Ming Yang Ming

Dr. Yang Ming holds a medical doctorate and serves as an Associate Chief Physician and Associate Professor at Beijing Tsinghua Chang Gung Hospital. ShHe is the secretary of the Liver Cancer Group under the Hepatology Branch of the Chinese Medical Association and a member of the Youth Committee of the Beijing Medical Association’s Hepatology Branch. His Her primary research interests include hepatobiliary and pancreatic tumors, viral hepatitis, and fatty liver disease. Dr. Yang has been involved in national key research and development projects as well as major national science and technology projects for the prevention and treatment of infectious diseases during China’s 11th, 12th, and 13th Five-Year Plans. ShHe has been supported by the Fogarty Global Health Fellowships from the National Institutes of Health (NIH) in the United States and has participated in multiple clinical drug trials.

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Last updated on 2024.03.12