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KEYNOTE-966

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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

Phase 3N = 1,069NCT04003636

Population
Adults with previously untreated, unresectable, locally advanced or metastatic biliary tract cancer, measurable disease per RECIST version 1.1 and ECOG performance status 0 or 1
Design
Randomised (1:1), double-blind, placebo-controlled phase 3 trial at 175 medical centres worldwide. Pembrolizumab 200 mg or placebo every 3 weeks (maximum 35 cycles) with gemcitabine 1000 mg/m2 (no maximum duration) and cisplatin 25 mg/m2 (maximum 8 cycles) on days 1 and 8 of each 3-week cycle; stratified by geographical region, disease stage and site of origin. The primary end point was overall survival in the intention-to-treat population.
Primary endpoint
OS
Arms
  • Pembrolizumab plus gemcitabine and cisplatin (experimental, n = 533): Pembrolizumab 200 mg every 3 weeks (maximum 35 cycles) plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 every 3 weeks (cisplatin maximum 8 cycles)
  • Placebo plus gemcitabine and cisplatin (control, n = 536): Placebo every 3 weeks plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 every 3 weeks (cisplatin maximum 8 cycles)
People
Kelley RK
OSHR 0.83 (95% CI 0.72–0.95)Δ median OS+1.8 monthsOSHR 0.86 (95% CI 0.75–0.98)Δ median OS+1.8 monthsΔ 24-month OS+6 points
Show the numbers
Results reported for KEYNOTE-966
EndpointAnalysisPembrolizumab plus gemcitabine and cisplatinPlacebo plus gemcitabine and cisplatinEffect
OSfinalmedian follow-up 25.6 monthsKelley 2023median 12.7 months (11.5–13.6)median 10.9 months (9.9–11.6)HR 0.83 (95% CI 0.72–0.95)P=0.0034 (one-sided)One-sided P value; the abstract gives a significance threshold of p=0.0200. Median study follow-up at the final analysis was 25.6 months (IQR 21.7 to 30.4).
OSlong term-updatemedian follow-up 36.6 monthsUeno 2026median 12.7 months (11.5–13.6); 25% at 2 y (21–28%); 13% at 3 y (11–17%)median 10.9 months (9.9–11.6); 19% at 2 y (16–23%); 11% at 3 y (8–14%)HR 0.86 (95% CI 0.75–0.98)Median study follow-up 36.6 months (IQR 32.7 to 41.4); updated data are reported without P values because the primary end point was met at the final analysis. Hazard ratio and 36-month rates are in the abstract; the medians and the 24-month rates are from the open full text (PMC13679299, Results).
Results reported for KEYNOTE-966
EndpointAnalysisPembrolizumab plus gemcitabine and cisplatinPlacebo plus gemcitabine and cisplatinEffect
OSfinalmedian follow-up 25.6 monthsKelley 2023median 12.7 months (11.5–13.6)median 10.9 months (9.9–11.6)HR 0.83 (95% CI 0.72–0.95)P=0.0034 (one-sided)One-sided P value; the abstract gives a significance threshold of p=0.0200. Median study follow-up at the final analysis was 25.6 months (IQR 21.7 to 30.4).
OSlong term-updatemedian follow-up 36.6 monthsUeno 2026median 12.7 months (11.5–13.6); 25% at 2 y (21–28%); 13% at 3 y (11–17%)median 10.9 months (9.9–11.6); 19% at 2 y (16–23%); 11% at 3 y (8–14%)HR 0.86 (95% CI 0.75–0.98)Median study follow-up 36.6 months (IQR 32.7 to 41.4); updated data are reported without P values because the primary end point was met at the final analysis. Hazard ratio and 36-month rates are in the abstract; the medians and the 24-month rates are from the open full text (PMC13679299, Results).
Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.
OSOS0.512◀ experimentalcontrol ▶
Data table
EndpointHR95% CI
OS0.830.72–0.95
OS0.860.75–0.98
Illustrative — modelled from reported values, not trial data. OS, final.
0%25%50%75%100%051015202530Months (modelled)
  • Pembrolizumab plus gemcitabine and cisplatin (experimental)
  • Placebo plus gemcitabine and cisplatin (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsPembrolizumab plus gemcitabine and cisplatinPlacebo plus gemcitabine and cisplatin
0100.0%100.0%
864.6%60.1%
1641.8%36.2%
2427.0%21.7%
3217.4%13.1%
Illustrative — modelled from reported values, not trial data. OS, long term-update.
0%25%50%75%100%0102030Months (modelled)
  • Pembrolizumab plus gemcitabine and cisplatin (experimental)
  • Placebo plus gemcitabine and cisplatin (control)
Data table (modelled values)
MonthsPembrolizumab plus gemcitabine and cisplatinPlacebo plus gemcitabine and cisplatin
0100.0%100.0%
1066.2%62.7%
1937.3%31.3%
2918.2%13.5%
3913.0%11.0%
Primary publication: Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, 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. Lancet. 2023;401(10391):1853-1865. PubMedDOI

Appears in

Sources

  1. Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, 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. Lancet. 2023;401(10391):1853-1865.

    PubMedDOI

  2. Ueno M, Yoo C, Ren Z, Furuse J, Kelley RK, Chan SL, et al. Pembrolizumab plus gemcitabine and cisplatin for advanced biliary tract cancer: longer-term follow-up from the randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-966 trial. EClinicalMedicine. 2026;100:104213.

    PubMedDOI