Biliary Tract Cancers: Pharmacologic Management

Biliary tract cancers are a rare but deadly form of cancer that account for 2% to 3% of all malignancies in the United States.¹ Biliary tract cancer typically presents between the ages of 60 and 70 years.¹

Biliary tract cancers include gallbladder cancers and bile duct cancers. Gallbladder cancers are usually adenocarcinomas, and they make up approximately two-thirds of all biliary tract cancers. Gallbladder cancers have a 5-year survival rate of 20%.² Bile duct cancers are cholangiocarcinomas. They can be described as intrahepatic — affecting the bile duct within the liver — or extrahepatic — affecting the bile duct outside of the liver. Intrahepatic bile duct cancers have a 5-year survival rate of 9%. For extrahepatic bile duct cancers, the 5-year survival rate is approximately 11%.³

Resection is the only curative method for biliary tract cancers. Approximately 20% of gallbladder cancers are localized and can be removed.⁴ The percentage of cholangiocarcinomas that can be surgically removed is lower than that for gallbladder cancers. The majority of treatments recommended for biliary tract cancers are performed with the goal of lengthening lifespan and improving quality of life.⁵

Symptoms of biliary tract cancers often do not present until the late stages of the disease, which makes it difficult to identify them at a stage when resection would be possible. Symptoms of biliary tract cancers include elevated bilirubin levels and jaundice, gastrointestinal (GI) distress, abdominal swelling, fever, weight loss, and dark urine.⁵

Because biliary tract cancers are so rare, there are few large, double-blind, randomized controlled clinical trials to support definitive treatment recommendations. Although the National Comprehensive Cancer Network (NCCN) offers guidelines for treatment, the recommendations are, in many cases, off-label or from small, low-powered studies.⁶

Determining a Treatment Plan for Biliary Tract Cancers

Treatment plans and outlook for biliary tract cancers depend primarily on whether the tumor is resectable or unresectable. The tumors can also be described as^2,3:

• Localized (the tumor is confined to the gallbladder or bile ducts); 
• Regional (the tumor has spread to nearby organs or lymph nodes); or
• Distant (also known as metastatic disease, in which the cancer has spread to distant organs).

The biliary tract is located deep within the body, presenting a challenge for proper diagnosis of malignancy in this region. Diagnostic tools include extensive imaging, liver function testing, and biopsy procedures. Diagnosis can also involve testing for the presence of certain tumor markers indicative of biliary tract cancers. These markers include carcinoembryonic antigen (CEA) and CA 19-19.

Pharmacotherapy Management for Biliary Tract Cancers

Surgically removing the tumor is the only possible curative strategy for biliary tract cancers. However, pharmacologic treatment is frequently employed, either on its own or in combination with surgical options to lengthen lifespan. Pharmacologic regimens can be given at different times during the overall treatment course.⁶

Neoadjuvant therapy refers to treatment that is intended before surgery. The NCCN only recommends neoadjuvant therapy for locally advanced gallbladder cancer. Neoadjuvant therapies are typically recommended for 2 to 6 months. Treatment should be reassessed every 2 to 3 months.

Adjuvant therapy refers to treatment administered following surgery. Adjuvant therapies are generally recommended for patients who have undergone surgery for biliary tract cancers. These treatments are associated with longer survival rates. Although these therapies are typically administered for up to 6 months, the timeline of treatment can vary based on the specific regimen.

For unresectable or metastatic disease, systemic therapy is the preferred treatment option. Patients with unresectable or metastatic disease may not be healthy enough to undergo surgery, they may have tumors that are too advanced, or the location of the tumor may render it inoperable. Treatments for unresectable and metastatic disease are usually given until there is disease progression or the toxicity of the medication becomes intolerable.

Recurrent disease is cancer that returns or progresses following treatment, requiring additional treatment strategies. When the preferred regimen has already been employed, nonpreferred regimens can be tried at this point. Typically, if chemotherapy has previously been used, subsequent-line therapies will not use the main chemotherapy agent.

Tables 1, 2, and 3 review dosing and management guidelines for the single-agent use of chemotherapy, immunotherapy, and targeted therapy in biliary tract cancer. 

Table 1. Guidelines for Single-Agent Chemotherapy for Biliary Tract Cancer Management

Drug	Dosage	Recommended Use	Treatment Duration
Capecitabinea	1250 mg/m2 orally twice daily	Preferred adjuvant therapy and with RT	Adjuvant therapy: administer on days 1-14 of 21-d cycle for 8 cycles
5-Fluorouracila	40 mg/m2 orally twice daily	Adjuvant therapy and with RT	Adjuvant therapy: administer for first 4 wk of 6-wk cycle for 4 cycles

RT = radiation treatment.

^aRepresents off-label use of agent as recommended by the NCCN.

From FDA-approved prescribing information and clinical trials.^7-10

From NCCN biliary tract cancers treatment guidelines.⁶

Table 2. Guidelines for Immunotherapy for Biliary Tract Cancer Management

Drug	Dosage	Recommended Use	Treatment Duration
Pembrolizumab	200 mg IV infusion every 3 wk OR 400 mg IV infusion every 6 wk	MSI-H/dMMR and TMB-H tumors (recurrent disease, but not if the patient has previously undergone treatment with a checkpoint inhibitor)	Until disease progresses or toxicity is intolerable

dMMR = mismatch repair deficient; IV = intravenous; MSI-H = high microsatellite instability; TMB-H = high tumor mutational burden.

From FDA-approved prescribing information.¹¹

From NCCN biliary tract cancers treatment guidelines.⁶

Table 3. Guidelines for Targeted Therapy for Biliary Tract Cancer Management

Drug	Dosage	Recommended Use	Treatment Duration
Entrectinib	600 mg/d oral	NTRK gene fusion-positive tumors for unresectable and metastatic disease	Until the disease progresses or toxicity is intolerable
Futibatinib	20 mg/d oral	FGFR2 fusion or arrangement for intrahepatic and extrahepatic cholangiocarcinoma; unresectable and metastatic disease	Until the disease progresses or toxicity is intolerable
Lactrotrectinib	100 mg/m2/d oral	NTRK gene fusion-positive; unresectable and metastatic disease	Until the disease progresses or toxicity is intolerable
Infigratinib	125 mg/d oral	FGFR2 fusion or rearrangement for intrahepatic and extrahepatic  cholangiocarcinoma; for unresectable and metastatic disease	Administer for 21 d followed by 7 d without therapy (28-d cycle) until the disease progresses or toxicity is intolerable
Ivosidenib	500 mg/d oral	IDH1 mutations for intrahepatic and extrahepatic  cholangiocarcinoma; unresectable and metastatic disease	Until the disease progresses or toxicity is intolerable
Pemigatinib	13.5 mg/d oral	FGFR2 fusion or arrangement for intrahepatic and extrahepatic cholangiocarcinoma; recurrent disease; unresectable and metastatic disease	Administer for 14 d followed by 7 d without therapy (21-d cycle) until the disease progresses or toxicity is intolerable
Selpercatinib	120 mg twice daily oral for individuals weighing <50 kg OR 160 mg twice daily oral for individuals weighing >50 kg	RET gene fusion for intrahepatic and extrahepatic  cholangiocarcinoma; for unresectable and metastatic disease	Until the disease progresses or toxicity is intolerable

From FDA-approved prescribing information.^12-18

From NCCN biliary tract cancers treatment guidelines.⁶

Although combination regimens are the preferred systemic therapies for unresectable and metastatic disease, NCCN does not advise dosing strategies for biliary tract cancers. All dosing information in Table 4 is from the relevant clinical trials that NCCN used to make recommendations.

Table 4. Guidelines for Combination Regimens for Biliary Tract Cancer Management

Regimen	Dosagea	Recommended Use	Treatment Duration
CAPOX	Oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1000 mg/m2 on days 1-14	Neoadjuvant therapy; adjuvant therapy; unresectable and metastatic disease	Adjuvant therapy: 21-d cycle for up to 6 mo
Durvalumab + gemcitabine + cisplatin	Durvalumab 1500 mg IV infusion on day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 IV infusion on days 1 and 8	Preferred unresectable and metastatic disease; neoadjuvant therapy	IV infusions on days 1 and 8 of 21-d cycle up to 8 cycles
Dabrafenib + trametinib	Dabrafenib 150 mg twice daily plus trametinib 2 mg daily orally	BRAF V600E in recurrent disease; unresectable and metastatic disease	Until the disease progresses or toxicity is intolerable
Gemcitabine + capecitabine	Gemcitabine 1000 mg/m2 IV plus capecitabine 1500 mg/m2 IV	Neoadjuvant therapy; adjuvant therapy; unresectable and metastatic disease	Adjuvant therapy:  Four 21-d cycles of gemcitabine on days 1 and 8 and capecitabine on days 1-14
Gemcitabine + cisplatin	Unresectable and metastatic disease: Gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2	Neoadjuvant therapy; adjuvant therapy; unresectable and metastatic disease	Adjuvant therapy: Up to 6 mo Unresectable and metastatic disease: 21-d cycle with gemcitabine 30 min on days 1 and 8 and cisplatin 2 h on day 1
FOLFOX	Oxaliplatin 85 mg/m2, folinic acid 175 mg, fluorouracil 400 mg/m2 via bolus, and fluorouracil 2400 mg/m2 IV over 46 h	Neoadjuvant therapy; adjuvant therapy; preferred second-line for unresectable and metastatic disease	Unresectable and metastatic disease: Every 2 wk
Nivolumab + ipilimumab	Nivolumab 240 mg IV plus ipilimumab 1 mg/kg	TMB-H recurrent disease; unresectable and metastatic disease	Nivolumab once every 2 wk and ipilimumab once every 6 wk
Trastuzumab + pertuzumab	Trastuzumab 8 mg/kg plus pertuzumab 840 mg IV as the initial dose followed by trastuzumab 6 mg/kg plus pertuzumab 420 mg IV	HER2-positive; recurrent disease; unresectable and metastatic disease	Every 3 wk

CAPOX = capecitabine plus oxaliplatin; FOLFOX = folinic acid, fluorouracil, and oxaliplatin.; IV = intravenous; TMB-H = high tumor mutational burden.

^aNCCN does not provide dosing recommendations for combination therapies for the treatment of biliary tract cancers.

From NCCN biliary tract cancers treatment guidelines.⁶

From clinical trials.^19-26

Adverse Events, Drug-Drug Interactions, and Special Populations in Biliary Tract Cancers

Table 5. Side Effect Profiles for Chemotherapy for Biliary Tract Cancers

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Capecitabinea,b	Hand-and-foot syndrome, abdominal pain, indigestion, skin rash, hair loss, fever, headache, dizziness, fatigue, taste disorders, infections, severe weight loss, nose bleeds, low neutrophil count Warnings: Severe diarrhea, coagulopathy, DPD deficiency, cardiotoxicity, severe skin reactions, dehydration, kidney failure, low blood cell counts, excess bilirubin	Anticoagulants,  nephrotoxic drugs, leucovorin, CYP2C9 substrates, phenytoin, vitamin K antagonists, allopurinol	Use with caution in geriatric population and individuals with kidney and liver disease
Cisplatina	Kidney toxicity, peripheral nerve damage, nausea and vomiting, myelosuppression, ear toxicity Warnings: Hypersensitivity reactions, ear toxicity, eye toxicity, secondary leukemia	None indicated	Contraception should be used by female patients for 14 mo and by male patients for 11 mo after the final dose; may cause infertility; pediatric patients are at increased risk of developing hearing problems; geriatric patients are at increased risk of developing myelosuppression
5-fluorouracila,b	Warnings: Cardiotoxicity, low DPD, ammonia-induced swelling of the brain, hand-and-foot syndrome, inflammation of the oral mucosa, myelosuppression, neurotoxicity, increased risk of elevated INR with anticoagulants	CYP2C9 substrates and anticoagulants	Individuals should refrain from conceiving for 3 mo following treatment
Gemcitabinea	Nausea and vomiting, anemia, elevated liver enzymes, decreased neutrophils, decreased leukocytes, elevated ALP, proteinuria, fever, hematuria, rash, low platelet count, shortness of breath  Warnings: Myelosuppression, lung toxicity, kidney and liver toxicity, radiation toxicity, worse toxicity with increased infusion time and frequency	None indicated	Myelosuppression is more common in geriatric patients; use with caution in geriatric population and individuals with kidney and liver disease; women may experience higher-grade reactions
Oxaliplatina,b	Peripheral sensory neuropathy, reduced neutrophils, reduced platelets, anemia, elevated liver enzymes, increased ALP, fatigue, inflammation of the oral mucosa Warnings: Peripheral sensory neuropathy, severe myelosuppression, PRES, lung toxicity, liver toxicity, QT-interval prolongation, rhabdomyolysis, hemorrhage	Anticoagulants, drugs that are cleared by the kidneys, drugs that prolong the QT interval	Breastfeeding should only be performed 3 mo after discontinuation of use; contraception should be used by female patients for 9 mo and by male patients for 6 mo after the final dose; use with caution in geriatric patients, pediatric patients, and those with kidney or liver disease

ALP = alkaline phosphatase; DPD = dihydropyrimidine dehydrogenase; INR = international normalized ratio; PRES = posterior reversible encephalopathy syndrome.

^aDo not use in pregnant or lactating individuals. 

^bGastrointestinal symptoms (nausea, vomiting, diarrhea, constipation).

From FDA-approved prescribing information.^7-10,27-29

From NCCN biliary tract cancer treatment guidelines.⁶

Table 6. Side Effect Profiles for Immunotherapy for Biliary Tract Cancers

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Durvalumaba	Cough, fatigue, lung injury, upper respiratory tract infections, shortness of breath, rash Warnings: Immune-mediated reactions (pneumonitis, hepatitis, colitis, nephritis, dermatologic reactions), infection, infusion-related reactions	None indicated	Breastfeeding should only be performed 3 mo after discontinuation of use; female patients should use contraception for 3 mo after the final dose
Ipilimumaba,b	Fatigue, rash, itchy skin, musculoskeletal pain, fever, cough, reduced appetite, abdominal pain, shortness of breath, upper respiratory infection, joint pain, headache, underactive thyroid, weight loss, dizziness Warnings: Severe immune-mediated reactions, infusion-related reactions, complications with allogeneic HSCT	None indicated	Breastfeeding should only be performed 3 mo after discontinuation of use; female patients should use contraception for 3 mo after the final dose; geriatric population may experience higher rates of adverse events
Nivolumaba,b	Fatigue, rash, itchy skin, musculoskeletal pain, fever, abdominal pain, cough, joint pain, reduced appetite, shortness of breath, upper respiratory infection Warnings: Immune-mediated reactions (pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, skin reactions, encephalitis), infusion reactions, complications with allogeneic HSCT	None indicated	Female patients should use contraception for 5 mo after the final dose; geriatric population may experience higher rates of adverse events
Pembrolizumaba,b	Fatigue, musculoskeletal pain, rash, fever, cough, reduced hunger, itchy skin, shortness of breath, pain, abdominal pain, underactive thyroid Warnings: Immune-mediated reactions, infusion-related reactions, complications with HSCT	None indicated	Breastfeeding should only be performed 4 mo after discontinuation of use

HSCT = hematopoietic stem cell transplantation.

^aDo not use in pregnant or lactating individuals. 

^bGastrointestinal symptoms (nausea, vomiting, diarrhea, constipation).

From FDA-approved prescribing information.^11,30-33

From NCCN biliary tract cancers treatment guidelines.⁶

Table 7. Side Effect Profiles for Targeted Therapy for Biliary Tract Cancers

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Dabrafeniba,b	Fever, chills, fatigue, rash, abdominal pain, peripheral swelling, cough, headache, joint pain, night sweats, reduced hunger, muscle pain Warnings: New malignancies, melanoma in BRAF wild-type tumors, hemorrhage, venous thromboembolism, cardiomyopathy, eye toxicities, severe febrile response, skin toxicity, hyperglycemia, glucose-6-phosphate dehydrogenase deficiency	Strong inhibitors and inducers of CYP3A4 or CYP2C8; sensitive substrates of CYP3A4, CYP2C8, CYP2C19, and CYP3A4	Contraception should be used for 4 mo following the last dose; may cause infertility
Entrectiniba,b	Fatigue, taste abnormalities, swelling, dizziness, chronic pain,  shortness of breath, muscle pain, cognitive impairment, weight gain, cough, fever, joint pain, vision disorders Warnings: CHF, nervous system dysfunction, fractures, liver toxicity QT-interval prolongation, vision disorders	Strong and moderate CYP3A inducers and inhibitors	Breastfeeding should only be performed 7 d after discontinuation of use; females should use contraception for 5 wk after the final dose; males should use contraception for 3 mo after the final dose
Futibatiniba,b	Nail toxicity, musculoskeletal pain, fatigue, dry mouth, hair loss, inflammation of the oral mucosa, abdominal pain, dry skin, joint pain, taste abnormalities, dry eye, reduced appetite, UTI, hand-and-foot syndrome, elevated phosphate levels, elevated creatinine levels, reduced hemoglobin, elevated glucose, elevated calcium, reduced sodium, reduced phosphate, elevated ALT, elevated ALP, reduced lymphocyte count, elevated AST, reduced platelets, elevated aPTT, reduced leukocytes, reduced albumin, reduced neutrophils, elevated creatine kinase, elevated bilirubin, reduced glucose, elevated prothrombin INR, reduced potassium Warnings: Ocular toxicity, elevated phosphate and soft tissue mineralization	Dual P-gp and strong CYP3A inducers and inhibitors	Breastfeeding should only be performed 1 wk after discontinuation of use; contraception should be used for 1 wk after the final dose
Lactrotrectiniba,b	Fatigue, dizziness, elevated liver enzymes, cough Warnings: Neurotoxicity, liver toxicity	Strong CYP3A4 inhibitors and inducers; sensitive CYP3A4 substrates	Breastfeeding should only be performed 1 wk after discontinuation of use; contraception should be used for 1 wk after the final dose; a lower dose is recommended for use in individuals with impaired liver function
Infigratiniba,b	Nail toxicity, mouth inflammation, dry eye, fatigue, hair loss, hand-and-foot syndrome, joint pain, taste abnormalities, abdominal pain, dry mouth, eyelash changes, dry skin, reduced hunger, blurred vision, elevated creatinine, elevated phosphate, reduced phosphate, elevated ASP, reduced hemoglobin, elevated ALT, elevated lipase, elevated calcium, reduced lymphocytes, reduced sodium, elevated triglycerides, elevated AST, elevated urate, reduced platelets, reduced leukocytes, reduced albumin, elevated bilirubin, reduced potassium Warnings: Ocular toxicity, elevated phosphate and soft tissue mineralization	Strong and moderate CYP3A inhibitors and inducers; antacids; H2 antagonists	Breastfeeding should only be performed 1 mo after discontinuation of use; contraception should be used for 1 mo after the final dose; lower dose recommendations for use in individuals with impaired liver and kidney function
Ivosideniba,b	Fatigue, abdominal pain, cough, reduced appetite, fluid buildup in the abdomen, anemia, rash, reduced hemoglobin, elevated AST, elevated bilirubin Warnings: QT-interval prolongation, Guillain-Barré syndrome	Strong and moderate CYP3A4 inhibitors; strong CYP3A4 inducers; sensitive CYP3A4 substrates; drugs that prolong the QT interval	Breastfeeding should only be performed 1 mo after discontinuation of use
Pemigatiniba,b	Elevated phosphate, hair loss, nail toxicity, fatigue, taste abnormalities, mouth inflammation, dry eye, dry mouth, reduced appetite, joint pain, abdominal pain, reduced phosphate, back pain, dry skin Warnings: Ocular toxicity, elevated phosphate and soft tissue mineralization	Potent and moderate CYP3A inhibitors and inducers	Breastfeeding should only be performed 1 wk after discontinuation of use; contraception should be used for 1 wk after the final dose
Pertuzumaba,b	Hair loss, low neutrophils, fatigue, rash, peripheral nerve damage Warnings: Infusion-related reactions, hypersensitivity reactions	None indicated	Breastfeeding should only be performed 7 mo after discontinuation of use; contraception should be used for 7 mo after the final dose; geriatric patients may have higher rates of adverse reactions
Selpercatiniba	Elevated AST, elevated ALT, elevated glucose, reduced leukocytes, reduced albumin, reduced calcium, dry mouth,  diarrhea, elevated creatinine, elevated ALP, hypertension, fatigue, swelling, reduced platelets, elevated total cholesterol, skin rash, reduced sodium, constipation Warnings: Liver toxicity, hypertension, QT-interval prolongation, hemorrhage, hypersensitivity reactions, impaired wound healing	Acid-reducing drugs; strong and moderate CYP3A inhibitors and inducers; CYP2C8 and CYP3A substrates	Breastfeeding should only be performed 1 wk after discontinuation of use; contraception should be used for 1 wk after the final dose; risk of infertility; lower dose recommended for use in individuals with severely impaired liver function
Trametiniba,b	Fever, rash, chills, hypertension, peripheral swelling, headache, joint pain, muscle pain Warnings: New malignancies, hemorrhage, colitis or GI perforation, venous thromboembolism, cardiomyopathy, visual toxicities, ILD, serious febrile reaction, skin toxicity, hyperglycemia	None indicated	Breastfeeding should only be performed 4 mo after discontinuation of use; contraception for females should be used for 4 mo after the final dose; may cause female infertility
Trastuzumab	Reduced neutrophils, fatigue, anemia, inflammation of the oral mucosa, weight loss, upper respiratory infections, fever, low platelet count, ENT infection, taste disturbances Warnings: CHF, decreased LVEF, infusion-related reaction, lung toxicity	Anthracycline-based therapy	Breastfeeding should only be performed 7mo after discontinuation of use; contraception for females should be used for 7 mo after the final dose; may cause female infertility

ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CHF = congestive heart failure; ENT = ear, nose, and throat; GI = gastrointestinal; ILD = interstitial lung disease; INR = international normalized ratio; LVEF = left ventricular ejection fraction; P-gp = P-glycoprotein; UTI = urinary tract infection.

^aDo not use in pregnant or lactating individuals. 

^bGastrointestinal symptoms (nausea, vomiting, diarrhea, constipation).

From FDA-approved prescribing information.^12-18,33-36

From NCCN biliary tract cancer treatment guidelines.⁶

Biliary Tract Cancer Treatment Guidelines

Surgical options are the preferred treatment for gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. Although surgical procedures vary, all types of biliary tract cancers are treated similarly pharmacologically. All recommendations provided for pharmacologic therapy are from the NCCN biliary tract cancer treatment guidelines.⁶

Preferred Therapies 

If the tumor can be removed surgically, that is the first recommendation — although surgical procedures will vary between subtypes of biliary tract cancers. Following surgery, adjuvant therapy is recommended. This is especially true if the tumor has spread to the lymph nodes. If the tumor is unresectable or the patient has metastatic disease, systemic therapy is preferred. For unresectable and metastatic disease, molecular testing is always advised to determine if the patient is a good candidate for molecular immunotherapies and targeted therapies (Table 3).

Although significant evidence is lacking to suggest that neoadjuvant therapy improves outcomes of biliary tract cancer treatment, there may be some instances for which it will be used, such as locally advanced gallbladder cancer. The NCCN does not choose a preferred neoadjuvant strategy, but it does provide some options (Tables 1-4).

Adjuvant therapy with capecitabine is the preferred regimen following surgery. Durvalumab + gemcitabine + cisplatin or gemcitabine + cisplatin are the recommended first-line systemic therapies for unresectable and metastatic disease.

Subsequent Therapies

Due to the aggressive nature of biliary tract cancers, second-line therapies are often needed. Among the options for unresectable and metastatic disease, FOLFOX stands out as a preferred second-line therapy. Clinicians are highly recommended to conduct molecular testing and implement tumor-specific treatment strategies at this stage.

Molecular Tumor Signatures

In biliary tract cancer, immunotherapies and targeted therapies are primarily used for recurrent disease or in specific circumstances. These circumstances may include a tumor expressing a specific molecular signature. Up to 15% of biliary tract cancers express specific molecular signatures that can be targeted.

BRAF V600E

The BRAF protein stimulates the MAPK pathway, and it is involved in cell division and growth. Tumors that express the BRAF protein with the 600th amino acid containing a glutamic acid (E) rather than valine (V) often grow out of control. Dabrafenib + trametinib targets this pathway, and this combination therapy is also recommended for unresectable or metastatic disease when the tumor expresses BRAF V600E.

FGFR Fusions or Rearrangements

Part of the tyrosine kinase receptor pathway, the fibroblast growth factor receptor (FGFR) plays a role in cell proliferation. Between 9% and 12% of intrahepatic cholangiocarcinomas have FGFR fusions. FGFR inhibitors have been useful for the treatment of cholangiocarcinomas with FGFR fusions or rearrangements. Pemigatinib is approved for patients with advanced cholangiocarcinomas who have received at least 1 other therapy. Futibatinib and pemigatinib can be useful for unresectable or metastatic cholangiocarcinomas.

HER2-Positive

The HER2 protein is part of the epidermal growth factor receptor (EGFR) class of receptor tyrosine kinases. Signaling from this pathway is involved in cell proliferation. Overexpression and increased signaling from this protein are involved in oncogenesis. Up to 30% of gallbladder cancers and 20% of all cholangiocarcinomas have increased HER2 expression. Trastuzumab and pertuzumab are HER2 inhibitors that are useful as subsequent-line therapies for unresectable and metastatic disease.

IDH1 Mutations

IDH-1 is a catalytic enzyme involved in the production of D-2-hydroxyglutarate (2-HG). Mutations in the IDH1 gene lead to overactive catalytic activity that results in increased 2-HG. High amounts of 2-HG disrupt cell differentiation and can cause oncogenesis. Between 10% and 20% of intrahepatic cholangiocarcinomas have activating mutations in IDH1. Ivosidenib is an IDH1 inhibitor that is recommended for the treatment of cholangiocarcinomas as subsequent-line therapy for unresectable and metastatic disease.

NTRK Gene Fusions

The NTRK protein is expressed extracellularly and autophosphorylates itself, leading to downstream signaling involved in tumorigenesis. Certain fusions in NTRK1, NTRK2, and NTRK3 genes can exacerbate this pathway. Although NTRK fusion-positive tumors make up less than 1% of biliary tract cancers, entrectinib and larotrectinib have been shown to have some efficacy for patients whose tumors demonstrate these mutations. These can be first-line options for individuals with fusion-positive tumors or second-line for patients with unresectable and metastatic disease.

MSI-H/dMMR/TMB-H

Tumors that have high amounts of certain mutations are often responsive to checkpoint immunotherapy. There are several genes — MLH1, MSH2, MSH6, and PMS2 — that are involved in DNA repair. When these genes contain many mutations, they are called microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Most biliary tract tumors are not high in MSI or dMMR.

Overall tumor mutation burden (TMB) — the total amount of mutations the tumor expresses — is approximately 4% for all biliary tract cancers. Pembrolizumab is recommended as a subsequent-line therapy for unresectable and metastatic disease for tumors with MSI-H, dMMR, or TMB-H. Pembrolizumab is theoretically recommended as a first-line treatment for individuals with this type of tumor, but there is currently not enough clinical data to support that recommendation.

RET Gene Fusion

Although no studies have looked at RET inhibitors in biliary tract cancers, selpercatinib — a RET inhibitor — has shown promise in solid tumors with RET gene fusions. Selpercatinib is recommended as a subsequent-line therapy for patients with unresectable and metastatic disease for tumors with RET gene fusions.

Clinical Trials

As there are limited data to make firm recommendations, the NCCN recommends enrolling patients in clinical trials under certain circumstances. These include:

• Unresectable and metastatic biliary tract cancers; and
• Localized biliary tract cancers following resection.

References

1. Introduction to pancreatic and biliary tract cancers. National Cancer Institute SEER Training Modules. Accessed June 17, 2023. https://www.training.seer.cancer.gov/biliary/intro/
2. Survival rates for gallbladder cancer. American Cancer Society. Updated March 1, 2023. Accessed June 17, 2023. https://www.cancer.org/cancer/types/gallbladder-cancer/detection-diagnosis-staging/survival-rates.html
3. Survival rates for bile duct cancer. American Cancer Society. Updated March 1, 2023. Accessed June 17, 2023. https://www.cancer.org/cancer/types/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html
4. Key statistics for gallbladder cancer. American Cancer Society. Updated January 12, 2023. Accessed June 17, 2023. https://www.cancer.org/cancer/types/gallbladder-cancer/about/key-statistics.html
5. Pancreatic & biliary cancer: signs & symptoms. National Cancer Institute SEER Training Modules. Accessed June 17, 2023. https://www.training.seer.cancer.gov/biliary/intro/symptoms.html
6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®); Biliary Tract Cancers. National Comprehensive Cancer Network. Updated May 10, 2023. Accessed June 14, 2023. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf
7. Xeloda®. Prescribing Information. Genentech, Inc.; 1998. Updated December 2022. Accessed June 16, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020896s044s051lbl.pdf 
8. Primrose JN, Fox RP, Palmer DH, et al; the BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20:663-673. doi:10.1016/S1470-2045(18)30915-X
9. Fluorouracil. Prescribing Information. Spectrum Pharmaceuticals; Inc.; 1962. Updated July 2016. Accessed June 16, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012209s040lbl.pdf
10. Nakachi K, Ikeda M, Konishi M, et al; the Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG-HBPOG). Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202; ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2023;401(10372):195-203. doi:10.1016/S0140-6736(22)02038-4
11. Keytruda. Prescribing Information. DailyMed. Updated April 3, 2023. Accessed June 16, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287&audience=consumer#S2
12. Rozlytrek. Prescribing Information. Genentech, Inc.; 2019. Accessed June 16, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
13. Lytgobi. Prescribing Information. Taiho Oncology, Inc.; 2022. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214801s000lbl.pdf
14. Vitrakvi®. Prescribing Information. Bayer HealthCare Pharmaceuticals Inc.; 2019. Updated March 2021. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210861s006lbl.pdf
15. Truseltiq. Prescribing Information. QED Therapeutics, Inc.; 2021. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214622s000lbl.pdf
16. Tibsovo®. Prescribing Information. Servier Pharmaceuticals LLC; 2018. Updated May 2022. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211192s009lbl.pdf
17. Pemazyre®. Prescribing Information. Incyte Corporation; 2020. Updated February 2021. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213736s001lbl.pdf#:~:text=FULL%20PRESCRIBING%20INFORMATION%20INDICATIONS%20AND%20USAGE%20PEMAZYRE%20is,an%20FDA-approved%20test%20%5Bsee%20Dosage%20and%20Administration%20%282.1%29%5D.
18. Retevmo. Prescribing Information. Eli Lilly and Company; 2020. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf
19. Nehls O, Oettle H, Hartmann JT, et al. Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer. 2008;98:309-315. doi:10.1038%2Fsj.bjc.6604178
20. Oh D-Y, He AR, Qin S, et al; the TOPAZ Investigators. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2200015
21. Subbiah V, Lassen U, Elez E, et al. Dabrafenib plus trametinib in patients with BRAF^V600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020;21(9):1234-1243. doi:10.1016/S1470-2045(20)30321-1
22. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: a phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33(24):2617-2622. doi:10.1200/JCO.2014.60.2219
23. Thongprasert S, Napapan S, Charoentum C, Moonprakan S. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol. 2005;16(2):279-281. doi:10.1093/annonc/mdi046
24. Lamarca A, Palmer DH, Wasan HS, et al; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22(5):690-701. doi:10.1016/S1470-2045(21)00027-9
25. Schenker M, Burotto M, Richardet M, et al. CheckMate 848: a randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. Cancer Res. 2022;82(suppl 12):CT022. doi:10.1158/1538-7445.AM2022-CT022
26. Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021;22(9):1290-1300. doi:10.1016/S1470-2045(21)00336-3
27. Cisplatin. Prescribing Information. WG Critical Care, LLC; 1978. Updated February 2019. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018057s089lbl.pdf
28. Gemzar. Prescribing Information. Eli Lilly and Company; 1996. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020509s064lbl.pdf
29. Eloxatin. Prescribing Information. sanofi-aventis US LLC; 2002. Updated March 2020. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021759s023lbl.pdf
30. Imfinzi®. Prescribing Information. AstraZeneca Pharmaceuticals LP; 2017. Updated June 2020. Accessed June 16, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s020lbl.pdf
31. Yervoy. Prescribing Information. DailyMed. Updated February 15, 2023. Accessed June 16, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2265ef30-253e-11df-8a39-0800200c9a66&audience=consumer
32. Opdivo. Prescribing Information. E.R. Squibb & Sons, LLC; 2014. Accessed June 16, 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394&type=display
33. Tafinlar. Prescribing Information. GlaxoSmithKline; 2013. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202806s002lbl.pdf
34. Perjeta®. Prescribing Information. Genentech, Inc.; 2012. Updated September 2018. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125409s123lbl.pdf
35. Mekinist®. Prescribing Information. Novartis Pharmaceuticals Corporation; 2013. Updated April 2018. Accessed June 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s007lbl.pdf
36. Herceptin®. Prescribing Information. Genentech, Inc.; 1998. Updated February 2021. Accessed June 17, 2023. https://www.gene.com/download/pdf/herceptin_prescribing.pdf

Author Bio

Hannah Actor-Engle, PhD, earned a BS in Neural Science at New York University and a PhD in Neuroscience at the University of Colorado. She is a multidisciplinary neuroscientist who is passionate about scientific communication and improving global health through biomedical research.