For more than a decade, the combination of gemcitabine (Gemzar®; Eli Lilly and Company) and cisplatin (Platinol, Platinol-AQ; Bristol-Myers Squibb) has been considered the standard of care for the first-line treatment of patients diagnosed with advanced, untreated metastatic or unresectable biliary tract cancer.
The phase III KEYNOTE-966 clinical trial demonstrates that the addition of pembrolizumab (Keytruda®; Merck & Co) to gemcitabine and cisplatin improved overall survival in patients with untreated metastatic or unresectable biliary tract cancer.
These results were presented at the annual meeting of the American Association for Cancer Research (AACR), being held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida, and simultaneously published in The Lancet. 
Biliary tract cancers or BTC, are rare malignancies arising in the gallbladder, bile ducts (both inside and outside the liver), and the ampulla of Vater (which is located in the small intestine) and includes intrahepatic cholangiocarcinoma (IhCCA), extrahepatic cholangiocarcinoma (EhCCA) and Gallbladder cancer (GBC). Due to their slow growing nature, non-specific and late symptomatology, these malignancies are often diagnosed in advanced stages with poor patient outcomes.  Biliary tract cancers constitutes approximately 3% of all gastrointestinal malignancies and is the most common hepatobiliary cancer after hepatocellular carcinoma. Unfortunately, the mortality rate for patients diagnosed with biliary tract cancers is very high.
“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,” explained presenting author Robin “Katie” Kelley, MD, a 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,” she added.
Kelley and colleagues conducted the multinational KEYNOTE-966 phase III clinical trial to determine whether adding the immune checkpoint inhibitor pembrolizumab to standard chemotherapy would impact survival outcomes for patients with advanced stages of biliary tract cancer.
The trial enrolled 1,069 patients with metastatic or unresectable biliary tract cancers who had not received prior systemic therapy for their cancers. Patients were randomly assigned (1:1) to receive either pembrolizumab (533 patients; 200 mg) or placebo (536 patients) administered IV on day 1 Q3W for ≤35 cycles in combination with gemcitabine (1000 mg/m2 administered IV on days 1 and 8 Q3W until disease progression) and cisplatin (25 mg/m2 administered IV on days 1 and 8 Q3W for ≤8 cycles)
The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR).
The final analysis of the trial showed that patients in the pembrolizumab arm had a median (95% CI) overall survival (mOS) of 12.7 months (11.5–13.6), as compared with 10.9 months (9.9–11.6) among those in the placebo arm (HR 0.83; 95% CI 0.72–0.95; P = 0.0034). After a median follow-up of 25.6 months (range 18.3–38.4), patients treated with pembrolizumab had a 17% lower risk of death than patients who received chemotherapy alone.
While objective response rates (ORR) did not differ between the arms, patients in the pembrolizumab arm experienced a longer duration of response with a median duration of 9.7 months (1.2+ to 22.7+) vs. 6.9 months (0.0+ to 19.2+); however, Kelley noted that the prolonged duration of response should be considered descriptive, as comparative statistical analyses were not performed. In addition, patients treated with pembrolizumab had a 14% lower risk of disease progression or death after a median follow-up of 13.6 months, but this difference did not meet the study’s prespecified requirements for statistical significance.
Median progression-free survival was 6.5 months (5.7–6.9) and 5.6 months (5.1–6.6) for the pembrolizumab and placebo arms, respectively (HR 0.86; 95% CI 0.75–1.00; P = 0.0225).
Grade 3-5 adverse events were observed at similar rates between treatment arms (85.3% of 529 patients) in the pembrolizumab arm vs. 84.1% of 534 in the placebo arm; drug related, 71.3% vs 69.3%).
Among patients who received pembrolizumab plus chemotherapy, 1.5% experienced a drug-related grade 5 adverse event, compared with 0.6% of those treated with placebo and chemotherapy. Potentially immune-mediated events and infusion reactions were observed in 22.1% of the pembrolizumab arm and 12.9% of the placebo arm.
“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.”
In September 2022, another immune checkpoint inhibitor, durvalumab (Imfinzi®; AstraZeneca), was approved by the United States Food and Drug Administration (FDA) in combination with chemotherapy as a first-line therapy for patients with advanced biliary tract cancers.
The approval was based on results from the TOPAZ-1 clinical trial, a randomized, double-blind, placebo-controlled, multiregional trial that enrolled 685 patients with histologically confirmed locally advanced unresectable or metastatic biliary tract cancers who had not previously received systemic therapy for advanced disease.
“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,” said Kelley, adding that the KEYNOTE-966 trial included a larger sample size with more patients enrolled from non-Asian countries.
“Another key difference between the two studies was that patients in the TOPAZ-1 trial discontinued chemotherapy after six months but continued durvalumab or placebo as maintenance therapy, while patients in the KEYNOTE-966 trial were permitted to continue gemcitabine with pembrolizumab or placebo beyond six months, which reflects different treatment practices in many parts of the world,” Kelley added.
A limitation of the KEYNOTE-966 study is that patients with intrahepatic bile duct cancers were overrepresented in the study population compared with the incidence of the disease in the general population, resulting in smaller sample sizes of patients with extrahepatic and gall bladder sites of origin.
The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co.
Pembrolizumab (MK-3475) Plus Gemcitabine/Cisplatin Versus Placebo Plus Gemcitabine/Cisplatin for First-Line Advanced and/or Unresectable Biliary Tract Carcinoma (BTC) (MK-3475-966/KEYNOTE-966) (KEYNOTE-966) – NCT04003636
Pembrolizumab (MK-3475) Plus Gemcitabine/Cisplatin Versus Placebo Plus Gemcitabine/Cisplatin for First-Line Advanced and/or Unresectable Biliary Tract Carcinoma (BTC) (MK-3475-966/KEYNOTE-966)-China Extension Study – NCT04924062
Durvalumab or Placebo in Combination With Gemcitabine/Cisplatin in Patients With 1st Line Advanced Biliary Tract Cancer (TOPAZ-1) – NCT03875235
Highlights of Prescribing Information
Gemcitabine (Gemzar®; Eli Lilly and Company)[Prescribing Information]
Cisplatin (Platinol®/Platinol-AQ® ; Bristol-Myers Squibb)[Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co)[Prescribing Information]
Durvalumab (Imfinzi®; AstraZeneca)[Prescribing Information]
 Kelley RK, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klümpen HJ, Chan SL, Vogel A, Ozaka M, Verslype C, Bouattour M, Park JO, Barajas O,
Pelzer, Valle JW, Yu L, Malhotra U, Siegel AB, Edeline J, Ueno M. Pembrolizumab (pembro) in combination with gemcitabine and cisplatin (gem/cis) for
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Featured image courtesy 2016 – 2023 © AACR/Todd Buchanan. Used with permission.