Durvalumab Immunotherapy Receives FDA Approval for Biliary Tract Cancer

For patients with locally advanced or metastatic, stage 4, biliary tract cancer, durvalumab (Imfinzi, AstraZeneca) immunotherapy was approved by the US Food and Drug Administration (FDA) on 2 September 2022 for addition to gemcitabine plus cisplatin chemotherapy.

The First Immunotherapy Approval for Biliary Tract Cancer

Biliary tract cancer, is a rare, often aggressive disease arising in the bile ducts and gallbladder. About 12 thousand people are diagnosed annually in the United States, while the estimated figure for Türkiye is around 2 thousand. Apart from gallbladder cancer, biliary tract cancers are divided into intrahepatic and extrahepatic bile duct cancers, arising inside and outside the liver. Before immunotherapy was used for these cancers, relative 5-year survival for early-stage intrahepatic bile duct cancer was 25% and only 15% for early-stage extrahepatic disease. These cancers are also called cholangiocarcinoma.

FDA Approval Based on TOPAZ-1

A notable oncology development in early 2022 involved advanced biliary tract cancer and the PD-L1 inhibitor immunotherapy durvalumab. The randomised international phase III TOPAZ-1 trial, investigating its combination with gemcitabine and cisplatin, showed that patients receiving durvalumab had a 20% lower risk of death.

Patients receiving cisplatin + gemcitabine + durvalumab had better outcomes than those receiving cisplatin + gemcitabine + placebo, with significantly improved progression-free survival. The findings established durvalumab plus gemcitabine and cisplatin as a new first-line standard of care. Dr Do-Youn Oh and colleagues presented their study at the 2022 ASCO Gastrointestinal Cancers Symposium.

In this double-blind study, previously untreated patients with unresectable locally advanced, recurrent or metastatic biliary tract cancer were randomised 1:1 to durvalumab or placebo. Durvalumab or placebo was then given until disease progression or unacceptable toxicity.

Randomisation was stratified by disease stage, initial unresectability or recurrence, and primary tumour site: intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma or gallbladder cancer. The primary endpoint was overall survival; secondary endpoints included progression-free survival, objective response rate and safety.

Results

At the data cutoff for this interim analysis in August 2021, 685 patients had been assigned: 341 to durvalumab plus gemcitabine/cisplatin and 344 to placebo plus gemcitabine/cisplatin.

• The primary endpoint was met. Compared with placebo plus gemcitabine/cisplatin, durvalumab plus gemcitabine/cisplatin significantly improved overall survival: 12.8 months versus 11.5 months (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.66–0.97, P = 0.021), a 20% reduction in the risk of death.
• Progression-free survival also improved significantly with durvalumab versus placebo: 7.2 months versus 5.7 months (HR = 0.75, 95% CI = 0.64-0.89, P = 0.001), a 25% reduction in the risk of cancer progression.
• The objective response rate was 26.7% with durvalumab and 18.7% with placebo.
• Treatment-related grade 3 or 4 adverse events occurred in 62.7% of patients receiving durvalumab and 64.9% receiving placebo. Treatment-related adverse events led to discontinuation of any study drug in 8.9% of the durvalumab group and 11.4% of the placebo group.

The most common (≥20%) adverse effects were fatigue, nausea, constipation, reduced appetite, abdominal pain, rash and fever.

Why the Study Matters

For unresectable or stage 4 biliary tract cancer, combination chemotherapy had been the standard of care for more than a decade. The TOPAZ-1 trial leading to FDA approval was the first phase III study showing that adding immunotherapy to standard chemotherapy could improve survival without causing new serious adverse effects. It established immunotherapy as a new standard for biliary tract cancer.

The recommended durvalumab dose is 1,500 mg every 3 weeks with gemcitabine and cisplatin for patients weighing ≥30 kg, followed by 1,500 mg as a single agent every 4 weeks until disease progression or unacceptable toxicity.