Biliary Tract Cancers (BTCs) - Market Insight, Epidemiology and Market Forecast - 2034

Key Highlights

• Biliary tract cancers (BTC) constitute epithelial malignancies of the biliary tree and include the following: gallbladder cancer (GBC) and cholangiocarcinoma (CCA). CCA is further divided into intrahepatic CCA, perihilar CCA (Klatskin’s tumor), and distal CCA.
• The clinical features of BTC depend on the location of the tumor. Patients with extrahepatic tumors usually present with painless jaundice from biliary obstruction, and patients with intrahepatic tumors usually present with pain. Common complaints include pruritus, abdominal pain, malaise, fatigue, pruritus jaundice, and fever.
• Biliary tract cancer (BTC) is usually diagnosed with the clinical examination of the abdomen, using imaging scans, ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT), and biopsy.
• In 2023, Japan accounted for the highest number of total incident cases of BTC in the 7MM.
• In the United States, BTC occurs majorly in the age group of 70-79 years, constituting approximately ~30% of the total age-specific cases of BTC.
• Among the EU4 and the UK, the mutation-specific cases of BTC were highest in TP53 mutations, followed by KRAS mutations in 2023.
• Treatment options for the early-stage disease include surgery, followed by adjuvant chemotherapy. For patients with locally advanced disease, loco-regional therapies (e.g., trans-arterial chemoembolization [TACE] and external beam radiation therapy [EBRT]) may be considered. For patients with locally advanced and metastatic disease, the combination of gemcitabine and cisplatin has been shown to improve survival.
• In the 7MM, the United States accounted for the highest market size, with nearly 48% of the market share of the BTC market as compared to EU4 and the UK and Japan in 2023.
• In 2023, among EU4 and the UK, Italy accounted for the largest market size, while Spain accounted for the smallest share.
• Chemotherapy regimens dominate the current market. A few emerging therapies in the pipeline, including CX-4945 and CTX-009, are expected to bring a positive shift in the BTC treatment landscape during the forecast period (2024-2034).
• PEMAZYRE (pemigatinib) and LYTGOBI (futibatinib) are two FGFR2 inhibitors that have been approved by the U.S. Food and Drug Administration (FDA). Another target researchers have been studying in relation to BTC treatment is the immune checkpoint molecule PD-1. The most recent FDA approval related to BTC came in October 2023 with an expanded indication for KEYTRUDA (pembrolizumab), an immunotherapy that blocks PD-1, to be used in combination with gemcitabine and cisplatin for the treatment of locally advanced unresectable or metastatic BTC.
• Beyond targeting PD-1 or FGFR2, researchers are looking into other mutations found in BTC tumors as they attempt to discover more treatment options for more patients. TAFINLAR (dabrafenib) + MEKINIST (trametinib) have been approved for use in the United States for the treatment of BRAFV600E solid tumors. Whereas, VITRAKVI (larotrectinib) and ROZLYTREK (entrectinib) are being used for the treatment of NTRK fusion-positive solid tumors.
• Analysis of real-world data reveals evolving treatment patterns and survival outcomes in BTC, highlighting variations in regimen utilization across different lines of therapy. Despite advancements in treatment options, challenges such as low overall survival rates, high mortality rates, and factors like advanced age and disease stage contribute to the complexity of treatment decision-making and patient outcomes.

Report Summary

• The report offers extensive knowledge regarding the epidemiology segments (by region, total incident cases of BTC, age-specific cases, mutation-specific cases, stage-specific cases, and total treated cases) and predictions, presenting a deep understanding of the potential future growth in diagnosis rates, disease progression, and treatment guidelines. It provides comprehensive insights into these aspects, enabling a thorough assessment of the subject matter.
• Additionally, an all-inclusive account of the current management techniques and emerging therapies such as CX-4945 and CTX-009 and the elaborative profiles of late and mid-stage (Phase III and Phase II) and prominent therapies that would impact the current treatment landscape and result in an overall market shift has been provided in the report.
• The report also encompasses a comprehensive analysis of the BTC market, providing an in-depth examination of its historical and projected market size (2020-2034). It also includes the market share of therapies, detailed assumptions, and the underlying rationale for our methodology. The report also includes drug outreach coverage in the 7MM region.
• The report includes qualitative insights that provide an edge while developing business strategies by understanding trends through SWOT analysis and expert insights/KOL views, including experts from various hospitals and prominent universities, patient journey, and treatment preferences that help shape and drive the 7MM BTC market.

Market

Various key players, such as TransThera Sciences, AstraZeneca/ Compugen, Jazz Pharmaceuticals/ Zymeworks and others, are involved in developing therapies for BTC. The expected launch of emerging therapies and other treatments will lead to a significant increase in the market size during the forecast period [2024-2034].

• In 2023, the total market size of BTC was around USD 1.00 billion, which is expected to increase by 2034 during the study period (2020-2034) in the 7MM.
• Among the 7MM, the United States accounted for the highest market size in 2023, followed by the Japan for BTC.
• During the forecast period (2024-2034), pipeline candidates such as CX-4945 and CTX-009 are expected to drive the rise in BTC market size.
• By 2034, in the US, among all the therapies, the largest market size is expected to be generated by chemotherapy regimens, i.e., USD 360 million.

BTC Drug Chapters

The section dedicated to drugs in the BTC report provides an in-depth evaluation of pipeline drugs (Phase III and Phase II) related to BTC.

The drug chapters section provides valuable information on various aspects related to clinical trials of BTC, such as the pharmacological mechanisms of the drugs involved, designations, approval status, patent information, and a comprehensive analysis of the pros and cons associated with each drug. Furthermore, it presents the most recent news updates and press releases on drugs targeting BTC.

Marketed Therapies

PEMAZYRE (pemigatinib): Incyte

PEMAZYRE is a kinase inhibitor indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

PEMAZYRE is a small molecule kinase inhibitor that targets FGFR1, 2, and 3 with IC50 values of less than 2 nM. PEMAZYRE also inhibited FGFR4 in vitro at a concentration approximately 100 times higher than those that inhibit FGFR1, 2, and 3. PEMAZYRE inhibited FGFR1-3 phosphorylation and signaling and decreased cell viability in cancer cell lines by activating FGFR amplifications and fusions that resulted in constitutive activation of FGFR signaling. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. PEMAZYRE exhibited anti-tumor activity in mouse xenograft models of human tumors with FGFR1, 2, or FGFR3 alterations resulting in constitutive FGFR activation, including a patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR2-Transformer-2 beta homolog (TRA2b) fusion protein and the KG1 leukemia model that carries a translocation of FGFR1 (FGFR1OP2-FGFR1).

On February 13, 2019, the US FDA granted breakthrough designation (BTD) to PEMAZYRE for the treatment of patients with previously treated advanced/metastatic or unresectable cholangiocarcinoma with an FGFR2 fusion based on the results of an interim analysis of Study INCB 54828-202.

IMFINZI (durvalumab): AstraZeneca

IMFINZI is a programmed death-ligand 1 (PD-L1) blocking antibody indicated in combination with gemcitabine and cisplatin as treatment of adult patients with locally advanced or metastatic BTC.The approval for the treatment of adult patients with locally advanced or metastatic by the US FDA was based on the results from the TOPAZ-1 Phase III trial.

Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production. Durvalumab is a human immunoglobulin G1 kappa (IgG1?) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses without inducing antibody-dependent cell-mediated cytotoxicity (ADCC). PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

In September 2022, AstraZeneca announced that IMFINZI had been approved in the US for the treatment of adult patients with locally advanced or metastatic BTC in combination with chemotherapy (gemcitabine plus cisplatin).

In December 2022, IMFINZI was approved in the European Union (EU) for the first-line treatment of adult patients with unresectable or metastatic BTC in combination with chemotherapy (gemcitabine plus cisplatin).

Emerging Therapies

CTX-009: Compass Therapeutics

CTX-009 is a bispecific antibody that simultaneously blocks Delta-like ligand 4/Notch (DLL4) and vascular endothelial growth factor A (VEGF-A) signaling pathways, which are critical to angiogenesis and tumor vascularization. Preclinical and early clinical data of CTX-009 suggest that blockade of both pathways provides robust antitumor activity across several solid tumors, including colorectal, gastric, cholangiocarcinoma, pancreatic, and non-small cell lung cancer. Partial responses to CTX-009 as monotherapy have been observed in heavily pre-treated patients with cancer who were resistant to currently approved anti-VEGF therapies.

Compass holds the global rights to CTX-009 (also known as ABL001) except for rights in Korea, held by Handok, and rights in China, which were out-licensed to Elpiscience Biopharma.

Currently, CTX-009 is in the Phase III stage of clinical development for the treatment of BTC.

Zanidatamab: Jazz Pharmaceuticals/Zymeworks

Zanidatamab is a novel, late-stage oncology asset with the potential to transform the standard of care in multiple HER2-expressing cancers. It has demonstrated compelling data in biliary tract cancers and gastroesophageal adenocarcinoma with the potential to benefit patients across multiple tumor types.A pivotal Phase II clinical trial evaluating zanidatamab monotherapy in patients with previously treated advanced or metastatic HER2-amplified BTC.

In November 2020, Zymeworks received BTD from the US FDA for zanidatamab in patients with BTC.The US FDA had also granted FTD to zanidatamab as monotherapy for refractory BTC. Zanidatamab had also received ODD from the FDA as well as the European Medicines Agency for the treatment of BTC.

These designations mean zanidatamab is eligible for Accelerated Approval, Priority Review, and Rolling Review, as well as intensive FDA guidance on an efficient drug development program. Zanidatamab has also received Orphan Drug designations from the FDA as well as the European Medicines Agency for the treatment of biliary tract and gastric cancers.

On April 25, 2023, Jazz and Zymeworks entered into a Stock and Asset Purchase Agreement to, among other things, transfer to Jazz certain assets, contracts, and employees associated with the development of zanidatamab.

BTC Market Outlook

Bile duct cancer begins when healthy cells in the bile duct change and grow out of control, forming a mass called a tumor. A tumor can be benign or cancerous. A benign tumor can grow but will not spread. A cancerous tumor is malignant, meaning it can grow and spread to other parts of the body.

Treatment options for the early-stage disease include surgery, followed by adjuvant chemotherapy. For patients with locally advanced and metastatic disease, the combination of gemcitabine and cisplatin has been shown to improve survival.

After receiving initial approval in the United States in 2018 in the form of VITRAKVI, biliary tract cancer has seen approvals for various patient segments. A notable recent development is the approval from the US FDA in November 2023 for Merck’s KEYTRUDA in combination with chemotherapy (gemcitabine and cisplatin), presenting competition to AstraZeneca’s IMFINZI. While KEYTRUDA showed a slightly lower reduction in the risk of death compared to IMFINZI, both demonstrated improvements in first-line biliary tract cancer, with IMFINZI gaining FDA approval in September 2022.

Apart from this approval, LYTGOBI was approved in September 2022, which gave competition to Incyte’s PEMAZYRE, approved in April 2020. To date, other therapies are approved for biliary tract cancer, including ROZLYTREK, TIBSOVO, and the combination of TAFINLAR and MEKINIST.

Key players involved in developing targeted therapies to treat biliary tract cancer include Tinengotinib (TransThera Sciences), Rilvegostomig (AstraZeneca/ Compugen), Zanidatamab (Jazz Pharmaceuticals/ Zymeworks) and others. Some of these have recently entered the late stage of development; the analyst's analysts anticipate their launch in the US market to treat BTC.

In a nutshell, potential therapies are being investigated for treating BTC. Even though it is too soon to comment on the above-mentioned promising candidate to enter the market during the forecast period (2024-2034), it is safe to assume that the future of this market is promising. Eventually, the drugs, if approved, shall create a significant difference in the landscape of BTC in the coming years. The treatment space is expected to experience a significant impact in the coming years, owing to the increase in healthcare spending worldwide.

BTC Disease Understanding and Treatment

BTC Overview

The biliary tract comprises of gallbladder and intra and extrahepatic biliary tree. Bile is directed through these ducts to the second part of duodenum at major duodenal papilla. The epithelium of the biliary tract is lined with cells called cholangiocytes. Carcinoma of the biliary tract arises from the malignant transformation of the epithelium of the bile ducts which is made up of these cholangiocytes, and is categorized on the basis of its anatomical location as; 1) Intrahepatic cholangiocarcinoma 2) Extrahepatic cholangiocarcinoma, which includes; perihilar tumor also known as Klatskin tumor (originating from the epithelium of the bile duct at the junction of right and left hepatic ducts with the cystic duct where it forms the common bile duct) and distal cholangiocarcinoma outspreading to encompass the gallbladder, ampulla of Vater and pancreatic biliary ducts.

Chronic inflammatory conditions predispose the biliary tract epithelium to modify under stress and undergo transformation that give rise to the cancer of the biliary tract. The most established chronic inflammatory condition associated with biliary tract cancer is primary sclerosing cholangitis (PSC), which is associated with chronic inflammatory bowel disease, particularly ulcerative colitis.

The clinical features of BTC depend on the location of the tumor. Most of the tumors are initiated at the hepatic duct bifurcation, and the rest occur in the distal common bile duct or within the liver. Patients with extrahepatic tumors usually present with painless jaundice from biliary obstruction, and patients with intrahepatic tumors usually present with pain.

BTC Diagnosis

The diagnosis of BTC at an early stage remains a significant challenge since, in most cases, patients can remain asymptomatic for a long period during the early stages of BTCs, or symptoms can be unspecified. BTC diagnosis involves abdominal clinical examination, imaging scans (ultrasound, MRI, CT), and biopsy, with staging based on tumor size and metastasis to lymph nodes, liver, lungs, and peritoneum. Late-stage cases often exhibit distant metastasis, guiding treatment decisions.

BTC Treatment

Surgical resection remains the mainstay of cure for BTC. Adjuvant therapy for 6 months with capecitabine is recommended after surgery. For locally advanced and metastatic disease, gemcitabine and cisplatin combination therapy have demonstrated improved survival outcomes.

The role of locoregional therapies, such as transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), has increasingly been investigated for BTC patients. In retrospective studies, TACE with cisplatin has improved survival in unresectable iCCA.

Liver transplantation has been associated with rapid tumor recurrence and low survival and has historically not been recommended as a treatment for unresectable CCA.

Drugs such as entrectinib, larotrectinib, pembrolizumab, dostarlimab-gxly, nivolumab plus ipilimumab, dabrafenib plus trametinib, futibatinib, pemigatinib, ivosidenib, trastuzumab plus pertuzumab, pralsetinib, and selpercatinib, may benefit certain patients with advanced disease harboring specific genomic mutations.

BTC Epidemiology

The BTC epidemiology chapter in the report provides historical as well as forecasted epidemiology segmented by total incident cases, age-specific cases, mutation-specific, stage-specific cases, and total treated cases in the United States, EU4 countries (Germany, France, Italy, Spain) and the United Kingdom, and Japan from 2020 to 2034.

• In 7MM, the United States accounted for the highest number of total incident cases of BTC, which is around 30% of the total incident cases of BTC in the 7MM, in 2023.
• In the US, among the mutation-specific cases of BTC, TP53 cases were highest, followed by KRAS cases in 2023.
• Among the EU4 and the UK, Italy accounted for the highest number of BTC cases, followed by Germany, whereas Spain accounted for the lowest number of BTC cases.
• In 2023, as far as stage-specific cases are concerned, Stage IV accounted for the highest number of cases in Japan. These cases are anticipated to increase by 2034.

KOL Views

To stay abreast of the latest trends in the market, we conduct primary research by seeking the opinions of Key Opinion Leaders (KOLs) and Subject Matter Experts (SMEs) who work in the relevant field. This helps us fill any gaps in data and validate our secondary research.

We have reached out to industry experts to gather insights on various aspects of BTC, including the evolving treatment landscape, patients’ reliance on conventional therapies, their acceptance of therapy switching, drug uptake, and challenges related to accessibility. The experts we contacted included medical/scientific writers, professors, and researchers from prestigious universities in the US, Europe, the UK, and Japan.

Our team of analysts connected with more than 10 KOLs across the 7MM. By obtaining the opinions of these experts, we gained a better understanding of the current and emerging treatment patterns in the BTC market, which will assist our clients in analyzing the overall epidemiology and market scenario.

Some expert opinions have been provided below:

Qualitative Analysis

We perform Qualitative and Market Intelligence analysis using various approaches, such as SWOT analysis and Conjoint Analysis. In the SWOT analysis, strengths, weaknesses, opportunities, and threats in terms of disease diagnosis, patient awareness, patient burden, competitive landscape, cost-effectiveness, and geographical accessibility of therapies are provided. These pointers are based on the Analyst’s discretion and assessment of the patient burden, cost analysis, and existing and evolving treatment landscape.

Conjoint analysis analyzes multiple approved and emerging therapies based on relevant attributes such as safety, efficacy, frequency of administration, designation, route of administration, and order of entry. Scoring is given based on these parameters to analyze the effectiveness of therapy. In efficacy, the trial’s primary and secondary outcome measures are evaluated. Based on these, the overall efficacy is evaluated.

Further, the therapies’ safety is evaluated wherein the acceptability, tolerability, and adverse events are majorly observed, and it sets a clear understanding of the side effects posed by the drug in the trials. In addition, the scoring is also based on the route of administration, order of entry and designation, probability of success, and the addressable patient pool for each therapy. According to these parameters, the final weightage score and the ranking of the emerging therapies are decided.

Market Access and Reimbursement

Because newly authorized drugs are often expensive, some patients escape receiving proper treatment or use off-label, less expensive prescriptions. Reimbursement plays a critical role in how innovative treatments can enter the market. The cost of the medicine, compared to the benefit it provides to patients who are being treated, sometimes determines whether or not it will be reimbursed. Regulatory status, target population size, the setting of treatment, unmet needs, the number of incremental benefit claims, and prices can all affect market access and reimbursement possibilities.

The report further provides detailed insights on the country-wise accessibility and reimbursement scenarios, cost-effectiveness scenario of approved therapies, programs making accessibility easier and out-of-pocket costs more affordable, insights on patients insured under federal or state government prescription drug programs, etc.

BTC Report Insights

• Patient Population
• Therapeutic Approaches
• BTC Market Size and Trends
• Existing Market Opportunity

BTC Report Key Strengths

• Eleven-year Forecast
• The 7MM Coverage
• BTC Epidemiology Segmentation
• Key Cross Competition

BTC Report Assessment

• Current Treatment Practices
• Reimbursements
• Market Attractiveness
• Qualitative Analysis (SWOT, Conjoint Analysis, Unmet needs)

Key Questions

• Would there be any changes observed in the current treatment approach?
• Will there be any improvements in BTC management recommendations?
• Would research and development advances pave the way for future tests and therapies for BTC?
• Would the diagnostic testing space experience a significant impact and lead to a positive shift in the treatment landscape of BTC?
• What kind of uptake will the new therapies witness in the coming years in BTC patients?