Clinical trialPhase 3Liver cancer

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

Lancet · 20231069 patients (533 pembrolizumab, 536 placebo)

Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, et al. Lancet. 2023. 401:1853-1865

Study type: Clinical trial
Study name: KEYNOTE-966
Phase: Phase 3
Design: Randomised (1:1), double-blind, placebo-controlled trial at 175 centres
Sample size: 1069 patients (533 pembrolizumab, 536 placebo)
Source: Lancet · 2023
Trial registration: NCT04003636

In plain words

In patients with advanced bile duct cancer (cholangiocarcinoma and gallbladder cancer), adding the immunotherapy drug pembrolizumab to standard chemotherapy with gemcitabine and cisplatin increased median survival from 10.9 to 12.7 months, without a marked increase in side effects.

Key results

12.7 vs 10.9 months

Median overall survival

HR 0.83 (95% CI 0.72–0.95); one-sided P 0.0034

6.5 vs 5.6 months

Median progression-free survival

HR 0.86 (95% CI 0.75–1.00); not statistically significant; FDA label

29% vs 29%

Objective response rate

Median duration of response 8.3 vs 6.8 months; FDA label

25.6 months

Median follow-up at the final analysis

Drugs in this study:Cisplatin (Platinol)Gemcitabine (Gemzar)Pembrolizumab (Keytruda)

Dose and schedule cards

Gemcitabine + cisplatin + pembrolizumab (KEYNOTE-966)

Unresectable locally advanced or metastatic biliary tract cancer, no prior systemic therapy for advanced diseaseCycle length: Every 21 daysOn the page “Liver cancer” · Advanced biliary tract cancer: first-line

Unresectable locally advanced or metastatic biliary tract cancer, no prior systemic therapy for advanced disease

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg every 3 weeks (or 400 mg every 6 weeks)	IV	Day 1
Gemcitabine	1000 mg/m²	IV	Days 1 and 8, every 3 weeks
Up to 8 cycles
Cisplatin	25 mg/m²	IV	Days 1 and 8, every 3 weeks

Cycle length: Every 21 days
Duration: Pembrolizumab up to 35 cycles (about 24 months); cisplatin up to 8 cycles; gemcitabine may be continued beyond 8 cycles; until progression or intolerable toxicity

Patients with autoimmune disease that required systemic treatment within the past 2 years, or who required immunosuppression, were excluded.

On the page “Liver cancer” · Advanced biliary tract cancer: first-line

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab + gemcitabine–cisplatin

Pembrolizumab 200 mg IV infusion on day 1 of each 3-week cycle, maximum 35 cycles (about 24 months) + gemcitabine 1000 mg/m² IV on days 1 and 8 every 3 weeks, with no maximum duration (until disease progression or unacceptable toxicity; continuation beyond 8 cycles was allowed) + cisplatin 25 mg/m² IV on days 1 and 8 every 3 weeks, maximum 8 cycles.

Patients who had stopped the first course of pembrolizumab with stable disease or better and then progressed could receive a second course of pembrolizumab 200 mg every 3 weeks for up to 17 cycles (ClinicalTrials.gov).

2Placebo + gemcitabine–cisplatin

Placebo matching pembrolizumab, IV on day 1 every 3 weeks (maximum 35 cycles) + the same gemcitabine 1000 mg/m² and cisplatin 25 mg/m² IV on days 1 and 8 every 3 weeks (cisplatin maximum 8 cycles; gemcitabine with no maximum duration).

Source of the regimen details: Abstract of the paper (Lancet 2023); ClinicalTrials.gov NCT04003636 (arm descriptions); FDA label for Keytruda (KEYNOTE-966 study section) — all three sources agree

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with unresectable, locally advanced or metastatic biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer) without previous systemic therapy for advanced disease, with measurable disease per RECIST 1.1 and ECOG performance status 0 or 1. According to the FDA label, patients with autoimmune disease requiring systemic treatment in the past 2 years or conditions requiring immunosuppression were not enrolled.

Endpoints

Primary endpoint: overall survival in the intention-to-treat population.

Other endpoints: safety; and, per the FDA label, progression-free survival, objective response rate and duration of response by independent review per RECIST 1.1.

Safety and side effects

Maximum grade 3 to 4 adverse events: 79% versus 75%; treatment-related grade 3 to 4 adverse events: 70% versus 69%. Deaths due to adverse events: 31 patients (6%) versus 49 patients (9%); treatment-related deaths: 8 patients (2%) versus 3 patients (1%).

According to the FDA label: pembrolizumab was discontinued for adverse events in 15% of patients (most common cause pneumonitis, 1.3%) and treatment was interrupted in 55% (mostly for decreased neutrophil and platelet counts).

Clinical significance and place in guidelines

Together with the TOPAZ-1 trial, it made the addition of immunotherapy to gemcitabine–cisplatin the first-line standard; the ESMO interim guideline update (2025) recommends cisplatin–gemcitabine–pembrolizumab at level I, A.

Limitations

The absolute gain in median survival is about 2 months; patients with poorer performance status were not enrolled.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.