Pembrolizumab Receives FDA Approval for First-Line Biliary Tract Cancer
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On 31 October 2023, the FDA (US Food and Drug Administration) approved treatment for locally advanced, unresectable or metastatic biliary tract cancer with gemcitabine and cisplatin plus pembrolizumab (Keytruda, Merck) immunotherapy.
The “Second” 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 cases are diagnosed annually in the United States, compared with an estimated 2 thousand in Türkiye. Apart from gallbladder cancer, it is classified as intrahepatic (within the liver) or extrahepatic (outside it). Before immunotherapy, relative 5-year survival was 25% for early-stage intrahepatic bile duct cancer and only 15% for early-stage extrahepatic disease. It is also called cholangiocancer.
Combination chemotherapy had remained standard for unresectable or stage 4 biliary tract cancer for more than a decade. This changed with the TOPAZ-1 study on 2 September 2022 and durvalumab immunotherapy’s FDA approval. The first phase III trial to show that adding immunotherapy to standard chemotherapy improved survival without new serious adverse effects established immunotherapy as a new standard in biliary tract cancer.
Pembrolizumab Approved Based on KEYNOTE-966
Efficacy was evaluated in KEYNOTE-966, a multicentre, randomised, double-blind, placebo-controlled trial enrolling 1069 patients with locally advanced unresectable or metastatic biliary tract cancer and no previous systemic treatment for advanced disease.
Patients were randomised 1:1 to pembrolizumab plus gemcitabine and cisplatin or placebo plus gemcitabine and cisplatin.
Treatment continued until unacceptable toxicity or progression.
Cisplatin was given for a maximum of 8 cycles, while gemcitabine could continue at the physician’s discretion. Pembrolizumab or placebo continued until progression, unacceptable toxicity or a maximum of 2 years.
Results
The primary efficacy measure was overall survival (OS).
- Pembrolizumab plus chemotherapy significantly improved overall survival versus placebo plus chemotherapy: hazard ratio 0.83 (95% confidence interval [CI]: 0.72, 0.95), one-sided p-value=0.0034. In other words, adding pembrolizumab reduced mortality risk by 17%.
- Median overall survival in the respective arms was 12.7 months (95% CI: 11.5, 13.6) and 10.9 months (95% CI: 9.9, 11.6).
Pembrolizumab was discontinued because of adverse reactions in 55% of patients. The most common adverse reactions or laboratory abnormalities causing discontinuation (≥2%) were reduced neutrophils, reduced platelets, anaemia, reduced white blood cells, fever, fatigue, cholangitis, increased ALT, increased AST and biliary obstruction.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until progression or unacceptable toxicity. When administered on the same day, pembrolizumab should precede chemotherapy.
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Indirect Comparison of TOPAZ-1 (Durvalumab) and KEYNOTE-966 (Pembrolizumab)
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