KEYNOTE-811
Pembrolizumab/Placebo Plus Trastuzumab Plus Chemotherapy in Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-811/KEYNOTE-811)
Phase 3N = 698NCT03615326
- Population
- Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction adenocarcinoma, without previous first-line treatment.
- Design
- Randomised double-blind placebo-controlled phase 3 trial at 168 centres in 20 countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab 200 mg or placebo, each combined with trastuzumab and chemotherapy (fluoropyrimidine plus platinum) every 3 weeks for up to 35 cycles; stratified by region, PD-L1 status and chemotherapy. Dual primary endpoints: progression-free survival and overall survival, analysed by intention to treat. The first interim analysis (434 randomised to the data cutoff) assessed objective response in the first 264 patients enrolled (133 and 131); the later interim analyses in the Lancet report cover 698 randomised patients.
- Primary endpoint
- PFS, OS
- Arms
- Placebo plus trastuzumab and chemotherapy (control, n = 348): Placebo with trastuzumab and chemotherapy (capecitabine plus oxaliplatin or fluorouracil plus cisplatin)
- Pembrolizumab plus trastuzumab and chemotherapy (experimental, n = 350): Pembrolizumab 200 mg every 3 weeks with trastuzumab and chemotherapy
- People
- Janjigian YY, senior author Chung HC, KEYNOTE-811 Investigators
Δ ORR+22.5 pointsPFSHR 0.72 (95% CI 0.60–0.87)Δ median PFS+1.9 monthsOSHR 0.87 (95% CI 0.72–1.06)Δ median OS+3.1 monthsOSHR 0.84 (95% CI 0.70–1.01)
Show the numbers
| Endpoint | Analysis | Pembrolizumab plus trastuzumab and chemotherapy | Placebo plus trastuzumab and chemotherapy | Effect |
|---|---|---|---|---|
| ORREfficacy population: first 264 participants enrolled (133 pembrolizumab, 131 placebo)Objective response by RECIST 1.1 per blinded independent central review | interimJanjigian 2021 | 74.4% (66.2–81.6%) | 51.9% (43.0–60.7%) | P=0.00006Protocol-specified first interim analysis, data cutoff 17 June 2020; absolute difference 22.7% (95% CI 11.2-33.7). Complete responses 11.3% versus 3.1%. |
| PFS | interimJanjigian 2023 | median 10 months (8.6–11.7) | median 8.1 months (7.0–8.5) | HR 0.72 (95% CI 0.60–0.87)P=0.0002Second interim analysis; median follow-up 28.3 months (IQR 19.4-34.3) with pembrolizumab and 28.5 months (20.1-34.3) with placebo. |
| OS | interimJanjigian 2023 | median 20 months (17.8–23.2) | median 16.9 months (15.0–19.8) | HR 0.87 (95% CI 0.72–1.06)P=0.084Second interim analysis; the abstract states the difference did not meet the prespecified significance criteria. Data cutoff 25 May 2022 (FDA Approval Summary full text). |
| OS | interimJanjigian 2023 | median 20 months (17.8–22.1) | median 16.8 months (15.0–18.7) | HR 0.84 (95% CI 0.70–1.01)Third interim analysis (median follow-up 38.4 and 38.6 months); the abstract states it did not meet prespecified criteria for significance and would continue to the final analysis. Data cutoff 29 March 2023 (FDA Approval Summary full text). |
| OSITT (698 randomised) | finalCasak 2026 | median 20 months (17.8–22.1) | median 16.8 months (14.9–18.7) | HR 0.80 (95% CI 0.67–0.94)P=0.004Final overall survival analysis as reported by the FDA authors (open-access full text, data cutoff 20 March 2024; Table 2, ITT N=698). No separate trial-group paper of the final analysis was found in PubMed on 2026-10-21. |
| OSPD-L1 CPS 1 or more (594 of 698 patients, 85%) | exploratoryCasak 2026 | — | — | HR 0.79 (95% CI 0.66–0.95)Exploratory subgroup analysis of the final OS analysis (data cutoff 20 March 2024); the full text gives median OS 20.1 versus 15.7 months in this subgroup. |
| OSPD-L1 CPS below 1 (15% of patients) | exploratoryCasak 2026 | — | — | HR 1.10 (95% CI 0.72–1.68)Exploratory subgroup analysis of the final OS analysis (data cutoff 20 March 2024); the authors state pembrolizumab did not show improvement in this subgroup. |
| Endpoint | Analysis | Pembrolizumab plus trastuzumab and chemotherapy | Placebo plus trastuzumab and chemotherapy | Effect |
|---|---|---|---|---|
| ORREfficacy population: first 264 participants enrolled (133 pembrolizumab, 131 placebo)Objective response by RECIST 1.1 per blinded independent central review | interimJanjigian 2021 | 74.4% (66.2–81.6%) | 51.9% (43.0–60.7%) | P=0.00006Protocol-specified first interim analysis, data cutoff 17 June 2020; absolute difference 22.7% (95% CI 11.2-33.7). Complete responses 11.3% versus 3.1%. |
| PFS | interimJanjigian 2023 | median 10 months (8.6–11.7) | median 8.1 months (7.0–8.5) | HR 0.72 (95% CI 0.60–0.87)P=0.0002Second interim analysis; median follow-up 28.3 months (IQR 19.4-34.3) with pembrolizumab and 28.5 months (20.1-34.3) with placebo. |
| OS | interimJanjigian 2023 | median 20 months (17.8–23.2) | median 16.9 months (15.0–19.8) | HR 0.87 (95% CI 0.72–1.06)P=0.084Second interim analysis; the abstract states the difference did not meet the prespecified significance criteria. Data cutoff 25 May 2022 (FDA Approval Summary full text). |
| OS | interimJanjigian 2023 | median 20 months (17.8–22.1) | median 16.8 months (15.0–18.7) | HR 0.84 (95% CI 0.70–1.01)Third interim analysis (median follow-up 38.4 and 38.6 months); the abstract states it did not meet prespecified criteria for significance and would continue to the final analysis. Data cutoff 29 March 2023 (FDA Approval Summary full text). |
| OSITT (698 randomised) | finalCasak 2026 | median 20 months (17.8–22.1) | median 16.8 months (14.9–18.7) | HR 0.80 (95% CI 0.67–0.94)P=0.004Final overall survival analysis as reported by the FDA authors (open-access full text, data cutoff 20 March 2024; Table 2, ITT N=698). No separate trial-group paper of the final analysis was found in PubMed on 2026-10-21. |
| OSPD-L1 CPS 1 or more (594 of 698 patients, 85%) | exploratoryCasak 2026 | — | — | HR 0.79 (95% CI 0.66–0.95)Exploratory subgroup analysis of the final OS analysis (data cutoff 20 March 2024); the full text gives median OS 20.1 versus 15.7 months in this subgroup. |
| OSPD-L1 CPS below 1 (15% of patients) | exploratoryCasak 2026 | — | — | HR 1.10 (95% CI 0.72–1.68)Exploratory subgroup analysis of the final OS analysis (data cutoff 20 March 2024); the authors state pembrolizumab did not show improvement in this subgroup. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.72 | 0.6–0.87 |
| OS | 0.87 | 0.72–1.06 |
| OS | 0.84 | 0.7–1.01 |
| OS | 0.8 | 0.67–0.94 |
| OS | 0.79 | 0.66–0.95 |
| OS | 1.1 | 0.72–1.68 |
- Pembrolizumab plus trastuzumab and chemotherapy (experimental)
- Placebo plus trastuzumab and chemotherapy (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Pembrolizumab plus trastuzumab and chemotherapy | Placebo plus trastuzumab and chemotherapy |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 6 | 66.0% | 59.8% |
| 13 | 40.6% | 32.9% |
| 19 | 26.8% | 19.7% |
| 25 | 17.7% | 11.8% |
- Pembrolizumab plus trastuzumab and chemotherapy (experimental)
- Placebo plus trastuzumab and chemotherapy (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Pembrolizumab plus trastuzumab and chemotherapy | Placebo plus trastuzumab and chemotherapy |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 13 | 63.7% | 58.7% |
| 25 | 42.0% | 35.9% |
| 38 | 26.8% | 21.0% |
| 50 | 17.7% | 12.9% |
Appears in
Sources
Janjigian YY, Kawazoe A, Yañez P, Li N, Lonardi S, Kolesnik O, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600(7890):727-730.
Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023;402(10418):2197-2208.
Casak SJ, Zhang Y, Song C, Mishra-Kalyani PS, Tang S, Auth D, et al. FDA Approval Summary: Pembrolizumab for the Treatment of HER2-Positive Gastric Cancer. Clin Cancer Res. 2026;32(10):1923-1927.