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Combination Treatment for Biliary Tract Cancer Shows Promising Results in Trial

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A new clinical trial has found that adding pembrolizumab, an immune checkpoint inhibitor, to the current standard treatment for advanced biliary tract cancer can significantly improve overall patient survival. The research is published in The Lancet.

Poor outcomes for biliary tract cancers

The biliary tract consists of the gallbladder, bile ducts and associated structures that connect to the liver. This system stores and releases bile, a yellow liquid that helps to break down fats during digestion as well as remove waste products from the liver.

Cancers of the biliary tract are relatively rare, with approximately 8,000 new diagnoses in the US every year. However, incidence is increasing worldwide, and the disease is associated with very poor prognosis. Those diagnosed early, before the disease has spread, have a 5-year survival rate of 24%, compared to just 2% for those diagnosed after the cancer has spread to distant parts of the body (metastasized).

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“The median overall survival for people with advanced biliary tract cancers treated with the standard chemotherapy regimen of gemcitabine plus cisplatin is less than a year, and treatment options after progression are limited,” said Prof. Robin “Katie” Kelley, lead author of the study and professor of clinical medicine at the Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco. “There is an urgent need for more effective treatments and combinations for biliary tract cancers.”

The researchers therefore sought to understand if adding an immunotherapy drug to the current standard-of-care – chemotherapy drugs gemcitabine and cisplatin – could help to improve outcomes for patients with advanced biliary tract cancers. They added pembrolizumab, an immune checkpoint inhibitor family drug. Pembrolizumab blocks a protein called programmed cell death protein 1 (PD-1) on the surface of T cells, thereby preventing cancer cells from binding to PD-1 and blocking the T cells’ anti-tumor activity.

Promising results with new combination

The trial, titled KEYNOTE-966, recruited over 1,000 patients with metastatic or inoperable biliary tract cancers who had not received previous systemic therapy (e.g., chemotherapy). Along with gemcitabine and cisplatin, 533 patients received pembrolizumab and 536 patients received a placebo, and the researchers measured the survival rate of these patients as well as how their tumors responded to treatment.

At the end of the study, the researchers observed that the pembrolizumab group had a significantly higher median overall survival of 12.7 months, compared to 10.9 months for the placebo group. Additionally, after a median 25.6-month period, they found that patients receiving pembrolizumab had a 17% lower risk of death than the placebo group.

Nonetheless, differences in objective response rates (the percentage of tumors that reduce in size or disappear with treatment) between the two groups were not statistically significant. Additionally, the pembrolizumab group had a 14% lower risk of progression of their disease or death after a median follow-up period of 13.6 months – however, this also did not meet the study’s threshold for statistical significance. Median progression-free survival was 6.5 months and 5.6 months for the pembrolizumab and placebo groups, respectively.

Advances in biliary cancer treatment

“These data reinforce that patients with advanced biliary tract cancer may have durable immune responses and prolonged survival when an immune checkpoint inhibitor, such as pembrolizumab, is combined with first-line gemcitabine plus cisplatin chemotherapy,” said Kelley. “The durability of responses and proportion of patients with prolonged survival are really meaningful in this difficult-to-treat family of cancers.”

The results of the current trial build upon results from a previous trial, TOPAZ-1, which led to the approval of another immune checkpoint inhibitor, durvalumab, by the US Food and Drug Administration (FDA) for advanced biliary tract cancers.

Notably, the authors highlight an important limitation of the KEYNOTE-966 study, stating that there were more patients with intrahepatic bile duct cancers (cancers within the liver) than would be expected in the general population. This means that there were smaller sample sizes of patients with cancers originating in the gallbladder or outside the liver (extrahepatic).

Kelley also added that KEYNOTE-966 included a larger sample size with more patients enrolled from non-Asian countries than the TOPAZ-1 study. “The KEYNOTE-966 and the TOPAZ-1 studies both mark significant advances in the field and together validate the role of immune checkpoint inhibition in combination with chemotherapy as first-line therapy to improve survival and achieve prolonged durations of response for patients with advanced stages of biliary tract cancers,” Kelley summarized.

Reference: Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2023;0(0). doi: 10.1016/S0140-6736(23)00727-4

This article is a rework of a press release issued by the American Association of Cancer Research. Material has been edited for length and content.

Meet the Author
Sarah Whelan, PhD
Sarah Whelan, PhD
Science Writer