The first-line standard of care treatment with gemcitabine + cisplatin of patients diagnosed with advanced or metastatic biliary tract cancer (BTC) has remained unchanged for nearly 12 years. However, with the approval by the US Food and Drug Administration (FDA) of durvalumab (Imfinzi®; AstraZeneca) this has now changed.

The newly approved agent, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients diagnosed with locally advanced or metastatic biliary tract cancer in combination with chemotherapy (gemcitabine + cisplatin). While indicated in an adult population, at this time, safety and effectiveness of durvalumab have not been established in pediatric patients.

TOPAZ-1 study
The approval was based on the results from the TOPAZ-1 Phase III trial. In an interim analysis of TOPAZ-1, durvalumab plus chemotherapy reduced the risk of death by 20% versus chemotherapy alone (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.66-0.97; p=0.021).

An estimated one in four (25%) patients treated with durvalumab plus chemotherapy were still alive at two years compared to one in 10 (10%) treated with chemotherapy alone. Results were consistent across all prespecified subgroups, regardless of PD-L1 expression or tumor location.

Incidence and Risk Factors
Biliary tract cancer is a group of rare and aggressive cancers that occur in the bile ducts and gallbladder. [1][2] They arise from the epithelium of the biliary system and comprise the second most common type of hepatobiliary cancer worldwide. This group of cancers is sub-classified as intrahepatic cholangiocarcinoma (iCCA), perhilar/hilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA), and gallbladder carcinoma. Each of these diseases is, due to the differences in their etiologic risk factors, pathogenesis, and molecular and genetic characteristics, considered a separate disease. [1]

Advertisement #3

In the United States, approximately 23,000 people are diagnosed with BTC each year. [1] These patients have a poor prognosis, with approximately 5% to 15% of patients with BTC surviving five years.[3]

The incidence of biliary tract cancer is increasing in the developed world. One reason is that gallstones, biliary cysts, carcinogen exposure, typhoid, and Helicobacter pylori infection, and abnormal pancreaticobiliary duct junctions are all considered risk factors in the development of the disease, accounting for its geographical, ethnic and sex distribution.[5]

In addition, genetics also plays a strong role in the development of the disease, as about a quarter of cases are considered familial, and certain ethnicities, such as Native Americans, are at far higher risk for the neoplasm.[5]

“After minimal progress for more than a decade in advanced biliary tract cancer, the TOPAZ-1 results are a tremendous advance for our patients, showing a clear survival benefit for IMFINZI added to chemotherapy compared to standard of care with a remarkable safety profile,” noted Do-Youn Oh, MD, Ph.D, Professor, Division of Medical Oncology, Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine, and principal investigator in the TOPAZ-1 Phase III trial.

The results of the TOPAZ-1 study show compelling evidence that long term survival is possible – and may results in a new standard of care for this group of patients.

“This combination will provide a desperately needed and potentially practice-changing new treatment option in a setting where the current prognosis is devastating,” Oh added.

Summary of efficacy resultsi:

 Durvalumab +
Placebo +
Percentage of patients with event58.165.7
Median OS (95% CI) (in months)12.8 (11.1, 14.0)11.5 (10.1, 12.5)
HR (95% CI)
2-sided p-value
0.80 (0.66, 0.97)
OS rate at 18 months (95% CI) (%)35.1 (29.1, 41.2)25.6 (19.9, 31.7)
OS rate at 24 months (95% CI) (%)24.9 (17.9, 32.5)10.4 (4.7, 18.8)
Percentage of patients with event80.986.3
Median PFS (95% CI) (in months)7.2 (6.7, 7.4)5.7 (5.6, 6.7)
HR (95% CI)
2-sided p-value 
0.75 (0.64, 0.89)
ORR (%)26.718.7

i.    Analysis was done at 62% maturity in OS data.
ii.    Investigator-assessed OS data cut-off date was 11 August 2021.
iii.    Median follow-up in censored patients at DCO: 13.7 months (range 0.4-27.2) for durvalumab plus chemotherapy, 12.6 months (range 0.7-26.0) for chemotherapy alone.
iv.    Investigator-assessed PFS data cut-off date was 11 August 2021.
v.    Median follow-up in censored patients at DCO: 9.2 months (range 0.0-24.0) for durvalumab plus chemotherapy, 6.9 months (range 0.0-20.4) for chemotherapy alone.


Major step
“This approval represents a major step forward for patients with advanced biliary tract cancer, who urgently need new, well-tolerated and effective treatment options after more than a decade of limited innovation,” explained Aiwu Ruth He, MD, PhD, Associate Professor of Medicine, Leader of the GI Cancer Program, Georgetown Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington DC, and a lead investigator in the TOPAZ-1 Phase III trial.

“The combination of durvalumab and chemotherapy should become a new standard of care in this setting, having demonstrated significantly improved survival for these patients who have historically faced a poor prognosis,” He added.

Immunotherapy-based treatment
“For the first time, patients in the US with advanced biliary tract cancer have an immunotherapy-based treatment option that meaningfully extends survival and is well-tolerated,” said Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca.

“This approval for durvalumab and chemotherapy advances our ambition to challenge treatment expectations and transform care for patients with gastrointestinal cancers with high unmet need,” Fredrickson noted.

Stacie Lindsey, Founder & CEO of the Cholangiocarcinoma Foundation.

Waiting for a new therapy
“Patients have been waiting a long time for a new, first-line treatment option for biliary tract cancer. This is the first change to the standard of care in 12 years. The Foundation congratulates AstraZeneca for engaging in rare cancer research, which impacts patients and families nationwide,” Stacie Lindsey, Chief Executive Officer of the Cholangiocarcinoma Foundation.

“We are especially grateful to the patients who participated in this trial, making it possible for the broader rare disease community to benefit from this treatment,” Lindsey added.

“We are excited to see positive clinical trials results that improve overall survival with an immunotherapy combination versus chemotherapy. We are more hopeful than ever about the many treatment options that are moving down the pipeline through clinical trials, hopefully toward approval. We are grateful for the patients who participated in this trial and all who supported them. The greater the participation in clinical trials the greater the access to new, innovative and possibly lifesaving options for patients,” Lindsey concluded.

Study results
The TOPAZ-1 Phase III trial results were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium and published in the New England Journal of Medicine Evidence. Durvalumab plus chemotherapy was generally well tolerated and did not increase the discontinuation rate due to adverse events compared to chemotherapy alone.

In July 2022, durvalumab plus chemotherapy was added to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as a Category 1 preferred regimen as 1st-line therapy for locally advanced or metastatic BTC based on the data from TOPAZ-1. [4]

Project Orbis
The US regulatory submission for TOPAZ-1 was reviewed under Project Orbis, which provides a framework for concurrent submission and review of oncology medicines among participating international partners.

As part of Project Orbis, durvalumab plus chemotherapy is also under regulatory review for the same indication by the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency (ANVISA), Health Canada, Israel’s Ministry of Health Pharmaceutical Administration, Singapore’s Health Sciences Authority, Switzerland’s Swissmedic and the UK’s Medicines and Healthcare products Regulatory Agency.

The approval was granted after securing Priority Review and Orphan Drug Designation for durvalumab in the US in this setting. Regulatory applications are also currently under review in Europe, Japan and several other countries based on the TOPAZ-1 results.

Adverse events
In the TOPAZ-1 clinical study, adverse events have been observed in patients diagnosed with locally advances or metastatic billiard tract cancer receiving durvalumab (n=338).

  • The most common adverse reactions (occurring in ≥20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia
  • Discontinuation due to adverse reactions occurred in 6% of the patients receiving durvalumab plus chemotherapy. Serious adverse reactions occurred in 47% of patients receiving durvalumab plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving durvalumab plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), upper gastrointestinal hemorrhage (2 patients)

Clinical trials
Durvalumab or Placebo in Combination With Gemcitabine/Cisplatin in Patients With 1st Line Advanced Biliary Tract Cancer (TOPAZ-1) (TOPAZ-1) – NCT03875235

Highlights of Prescription information
Durvalumab (Imfinzi®; AstraZeneca) [Prescribing Information]

[1] Marcano-Bonilla L, Mohamed EA, Mounajjed T, Roberts LR. Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations. Chin Clin Oncol. 2016 Oct;5(5):61. doi: 10.21037/cco.2016.10.09. PMID: 27829275.
[2] ESMO. What is Biliary Tract Cancer. European Society for Medical Oncology (ESMO). Online. Last accessed on September 4, 2022.
[3] Turkes F, Carmichael J, Cunningham D, Starling N. Contemporary Tailored Oncology Treatment of Biliary Tract Cancers. Gastroenterol Res Pract. 2019 Dec 18;2019:7698786. doi: 10.1155/2019/7698786. PMID: 31929787; PMCID: PMC6935796.
[4] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) V2.2022. © National Comprehensive Cancer Network, Inc. 2022. Online. Last accessed on September 4. 2022.
[5] Rawla P, Sunkara T, Thandra KC, Barsouk A. Epidemiology of gallbladder cancer. Clin Exp Hepatol. 2019 May;5(2):93-102. doi: 10.5114/ceh.2019.85166. Epub 2019 May 23. PMID: 31501784; PMCID: PMC6728871.
[6] Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Rizvi S, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. doi: 10.1038/s41575-020-0310-z. Epub 2020 Jun 30. PMID: 32606456; PMCID: PMC7447603.

Featured image: Histopathology of gallbladder adenocarcinoma incidentally found in a cholecystectomy specimen. At higher maginification. H&E stain. Photo courtesy: KGH/licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Advertisement #5