Patients diagnosed with advanced biliary tract cancer (BTC) have a poor prognosis.  Treatment with first-line standard-of-care* has remained unchanged for more than a decade. However, adding durvalumab (Imfinzi®; AstraZeneca) to the current standard-of-care may have the potential to change treatment for patients diagnosed with BTC.

Updated exploratory results from the TOPAZ-1, a double-blind, placebo-controlled, phase 3 clinical study (ClinicalTrials.gov ID: NCT03875235), showed that durvalumab in combination with standard-of-care chemotherapy demonstrated a clinically meaningful long-term Overall Survival (OS) benefit at three years for patients with advanced biliary tract cancer (BTC).

The updated results, which include the longest survival follow-up ever reported for a global, randomized Phase 3 trial in this setting, will be presented on April 18 at the 2024 Cholangiocarcinoma Foundation Conference in Salt Lake City, Utah.

Rare and aggressive
Biliary tract cancer (BTC) is a group of rare and aggressive gastrointestinal (GI) cancers that form in the cells of the bile ducts (cholangiocarcinoma), gallbladder or ampulla of Vater (where the bile duct and pancreatic duct connect to the small intestine).[1][2]. BTC is typically diagnosed at advanced stages for which curative surgery is not feasible and prognosis is poor.

Approximately 50,000 people in the US, Europe and Japan and about 210,000 people worldwide are diagnosed with BTC each year.[3-5] These patients historically have a poor prognosis, with approximately 5% to 15% of patients with BTC surviving five years. For patients with metastatic disease, the five-year survival rate drops to less than 5%.[7]

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Cholangiocarcinoma is more common in China and Thailand and is on the rise in Western countries.[1][6] Gallbladder cancer is more common in certain regions of South America, India and Japan.[8]

Early-stage BTC affecting the bile ducts and gallbladder often presents without clear symptoms and most new cases of BTC are therefore diagnosed at an advanced stage, when treatment options are limited and the prognosis is poor.[6][8][9][10]

TOPAZ-1
TOPAZ-1 is a randomized, double-blind, placebo controlled, multicenter, global Phase III trial of durvalumab in combination with chemotherapy (gemcitabine plus cisplatin) versus placebo in combination with chemotherapy as a 1st-line treatment in 685 adult patients with unresectable, locally advanced or metastatic BTC including intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer. Patients with ampullary carcinoma were excluded.

The primary endpoint is overall survival and key secondary endpoints included progression-free survival, objective response rate and safety. The trial was conducted in 105 centers across 17 countries including in the US, Europe, South America and several countries in Asia including South Korea, Thailand, Japan and China.

Durvalumab is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.*

At more than three years (median follow-up of 41.3 months), results showed durvalumab i plus chemotherapy reduced the risk of death by 26% versus chemotherapy alone (based on a hazard ratio [HR] of 0.74; 95% confidence interval [CI], 0.63-0.87). The median Overall Survial was 12.9 months for durvalumab plus chemotherapy versus 11.3 months for chemotherapy alone. More than twice as many patients on the durvalumab-based regimen were alive at three years versus chemotherapy alone (14.6% versus 6.9%).

Primary endpoint
The TOPAZ-1 trial met the primary endpoint of Overall Survival in October 2021 at a planned interim analysis, showing that the combination reduced the risk of death by 20% versus chemotherapy alone (based on a HR of 0.80; 95% CI, 0.66-0.97; 2-sided p=0.021 at a statistical significance threshold of 0.03).

“The latest data from TOPAZ-1 show that twice as many patients with advanced biliary tract cancer were still alive at three years with durvalumab and chemotherapy, an especially meaningful advance in a setting where historically the prognosis has been poor. These results reinforce the long-term benefit of this immunotherapy-based combination as a standard of care for patients with this devastating disease,” said Do-Youn Oh, MD, PhD, Professor, Division of Medical Oncology, Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine, and principal investigator of the TOPAZ-1 trial.

Raising the bar
“TOPAZ-1 raised the bar for the treatment of advanced biliary tract cancer, showing a remarkable survival benefit for durvalumab added to chemotherapy with a well-tolerated regimen. These data represent the longest survival follow-up reported for immunotherapy in this setting, and the three-year landmark survival improvement underscores our commitment to improving long-term outcomes in gastrointestinal cancers,” noted Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca.

Meaningful milestone
“AstraZeneca’s longer survival data in advanced biliary tract cancer represents a meaningful milestone in that we are seeing three-year survival data for the first time for these patients. The data spurs hope that research will continue to improve outcomes for patients living with these challenging and rare cancers,” Stacie Lindsey, Chief Executive Officer, Cholangiocarcinoma Foundation.

TOPAZ-1 Summary of updated survival resultsi 

OSi,iiIMFINZI+ chemotherapy

(n=341)

Chemotherapy

(n=344)

Median OS (95% CI in months)12.9

(11.6-14.1)

11.3

(10.1-12.5)

HR (95% CI)iii0.74 (0.63-0.87)
OS rate at 36 months (95% CI) (%)iv14.6

(11.0-18.6)

6.9

(4.5-10.0)

i. 26 months of additional follow-up (data cut-off: 23 October 2023) after the primary analysis, with 89% overall OS event maturity
ii. At data cut-off for this analysis, median (95% CI) follow-up time in all patients calculated using reverse Kaplan-Meier technique was 42.9 (39.8-44.3) months for Imfinzi plus chemotherapy and 41.8 (36.7-46.2) months for chemotherapy
iii. HR and 95% CI calculated using Cox proportional hazards model
iv. OS rates calculated using Kaplan-Meier technique

 

Durvalumab plus chemotherapy continued to be well-tolerated, with no new safety signals observed with longer follow-up. Results showed 15.4% of patients experienced treatment-related serious adverse events with durvalumab plus chemotherapy versus 17.3% with chemotherapy alone.

__

Note: * In addition to its indications in unresectable, Stage III NSCLC and ES-SCLC, IMFINZI is currently approved in a number of countries in combination with a short course of <em>tremelimumab-actl </em>and chemotherapy for the treatment of metastatic NSCLC. Durvalumab is also approved in a number of countries in combination with chemotherapy in locally advanced or metastatic biliary tract cancer and in combination with<em> tremelimumab-actl </em>in unresectable hepatocellular carcinoma (HCC). In Japan and the European Union durvalumab is approved as a monotherapy in unresectable HCC and previously treated patients with advanced bladder cancer in a small number of countries. Since the first approval in May 2017, more than 220,000 patients have been treated with durvalumab. As part of a broad development program, durvalumab is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, breast cancer, several gastrointestinal cancers and other solid tumors.

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

Highlights of Prescribing Information
Durvalumab (Imfinzi®; AstraZeneca) [Prescribing Information]
Gemcitabine (Gemzar®; Eli Lilly and Company) [Prescribing information]
Cisplatin (Platinol®) [Prescribing Information]

Indication
Durvalumab in combination with gemcitabine and cisplatin is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC) and approved in the United States, the European Union, Japan, and other countries around the world.

Reference
[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] What is Biliary Tract Cancer.  ESMO. Online Last Accessed on April 16, 2024
[3] Siegel RL. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7-30.​
[4] ECIS - European Cancer Information System.  Online. Last Accessed on March 16, 2024.​
[5] Nakachi K, Konishi M, Ikeda M, Mizusawa J, Eba J, Okusaka T, Ishii H, Fukuda H, Furuse J; Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group. A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT). Jpn J Clin Oncol. 2018 Apr 1;48(4):392-395. doi: 10.1093/jjco/hyy004. PMID: 29462482.
[6] 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.
[7] Survival Rates for Bile Duct Cancer. American Cancer Society. Online. Last accesses on April 16, 2024.
[8] 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.
[9] 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.
[10] World Cancer Fact Sheet. WHO. Online. Last accesses on April 16, 2024 .

Featured image: Pharmaceuticals Research, AstraZeneca R & D Boston, USA. Courtesy © 2020 – 2023 AstraZeneca. Used with permission.

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