1. Fuerst, Mark L.

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The checkpoint immunotherapy durvalumab plus standard chemotherapy with gemcitabine plus cisplatin significantly improves overall survival (OS) in patients with advanced biliary tract cancer compared to those who received placebo plus chemotherapy drugs.

Biliary Tract Cancer... - Click to enlarge in new windowBiliary Tract Cancer. Biliary Tract Cancer

Biliary tract cancer is a rare, heterogenous cancer with poor prognosis. Reports on immunogenic features of the disease suggest checkpoint inhibition may result in antitumor immune responses, and limited clinical activity has been seen with single agents in advanced settings. The PD-L1 inhibitor durvalumab plus gemcitabine-cisplatin has shown promising antitumor activity in advanced biliary tract cancer in a Phase II study.


TOPAZ-1 is a randomized, international, Phase III study evaluating first-line immunotherapy plus gemcitabine-cisplatin in advanced biliary tract cancer. Principal investigator Do-Youn Oh, MD, PhD, Professor in the Division of Medical Oncology, Department of Internal Medicine, at Seoul National University Hospital and Seoul National University College of Medicine, presented results from an interim analysis of the study at the 2022 ASCO Gastrointestinal Cancers Symposium (Abstract 378).


"TOPAZ-1 is the first Phase III trial to show that adding immunotherapy to standard chemotherapy can increase survival in biliary tract cancer, and importantly, does so without inducing any new serious side effects," said Oh.


Patients with biliary tract cancer are often diagnosed when the cancer is already at an advanced stage, which is one of the reasons why survival rates are so low. Gemcitabine plus cisplatin has been the chemotherapy standard of care for most advanced biliary tract cancers in the U.S. In February 2018, the FDA approved durvalumab after chemoradiation for unresectable Stage III non-small cell lung cancer.


About the Study

In this double-blind study, 685 patients previously untreated for unresectable, locally advanced, recurrent, or metastatic biliary tract cancer were randomized to receive durvalumab 1,500 mg every 3 weeks or placebo plus gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 every 3 weeks for up to 8 cycles, followed by durvalumab 1,500 mg every 4 weeks or placebo until disease progression or unacceptable toxicity. Randomization was stratified by disease status (initially unresectable, recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer).


Patients had one of three types of biliary tract cancer: 55 percent had intrahepatic cancers, which arise in the bile ducts inside the liver; 19 percent had extrahepatic cancers, which form outside the liver; and 25 percent had gallbladder cancer. The trial was conducted in the U.S. and 17 countries, including those in Europe and South America. Nearly 55 percent of the patients came from countries in Asia, including South Korea, Thailand, Japan, and China.


Key Findings

The primary objective was met: durvalumab plus gemcitabine-cisplatin significantly improved OS versus placebo plus gemcitabine-cisplatin. Among the 341 patients taking the experimental treatment, median OS was 12.8 months as compared to 11.5 months in the 344 patients on chemotherapy alone. After 18 months on the trial, 35.1 percent of patients who received durvalumab were still alive compared to 25.6 percent for placebo. The 24-month OS was 24.9 percent versus 10.4 percent, respectively.


Median progression-free survival was also significantly better with durvalumab (7.2 months) compared to placebo (5.7 months), representing a 25 percent lower risk of disease progression for those who received the immunotherapy. The overall response rate with durvalumab was 26.7 percent compared to 18.7 percent for the placebo.


The most common side effects were anemia (48.2%), neutropenia (31.7%), and nausea (40.2%). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 62.7 percent of patients receiving durvalumab and 64.9 percent of patients receiving placebo, indicating that the majority of side effects in both arms are from chemotherapy. TRAEs led to discontinuation of any study medication in 8.9 percent of patients receiving durvalumab and 11.4 percent of patients receiving placebo.


Next Steps

"We are hopeful that durvalumab plus gemcitabine and cisplatin will become a new standard of care for advanced biliary tract cancer," Oh noted. "Our first task at this time is boosting communication with patients and family members about the potential for this immunotherapy combination and what it may mean for their ongoing care."


The researchers are hoping to develop more studies to explore a range of immunotherapy options for biliary tract cancer.


ASCO Expert in gastrointestinal cancers, Cathy Eng, MD, FACP, the David H. Johnson Chair in Surgical and Medical Oncology at Vanderbilt-Ingram Cancer Center, commented: "The current standard of care for inoperable biliary tract cancer is combined chemotherapy. That standard has not changed in over a decade. TOPAZ-1 is the first Phase III trial to demonstrate the benefit of immunotherapy for improved OS, in combination with chemotherapy, creating a new standard of care. Patients have a greater reason for hope given the positive results seen with the use of immunotherapy in biliary tract cancers."


Mark L. Fuerst is a contributing writer.