KEYNOTE-775
Lenvatinib plus pembrolizumab versus treatment of physician's choice in advanced endometrial cancer after platinum-based chemotherapy (Study 309/KEYNOTE-775)
Phase 3N = 827NCT03517449
- Population
- Advanced, recurrent or metastatic endometrial cancer of any histology except carcinosarcoma and sarcoma, progressing after one platinum-based regimen (two allowed if one was neoadjuvant or adjuvant); no previous VEGF- or PD-1-targeting therapy
- Design
- Multicentre, open-label phase 3 trial (Study 309/KEYNOTE-775), randomised 1:1 after one previous platinum-based regimen. Lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg every 3 weeks (up to 35 doses) versus doxorubicin 60 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 weekly (3 weeks on, 1 week off). Stratified by MMR status; within pMMR also by ECOG performance status, region and prior pelvic irradiation. Primary endpoints were assessed in the pMMR population and in all patients. 697 patients had pMMR disease and 130 dMMR disease.
- Primary endpoint
- PFS, OS
- Arms
- Lenvatinib plus pembrolizumab (experimental, n = 411): Lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg every 3 weeks (up to 35 doses)
- Chemotherapy of physician's choice (control, n = 416): Doxorubicin 60 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 weekly (3 weeks on, 1 week off)
- People
- Makker V, Study 309/KEYNOTE-775
PFSHR 0.60 (95% CI 0.50–0.72)Δ median PFS+2.8 monthsOSHR 0.68 (95% CI 0.56–0.84)Δ median OS+5.4 monthsPFSHR 0.56 (95% CI 0.47–0.66)Δ median PFS+3.4 months
Show the numbers
| Endpoint | Analysis | Lenvatinib plus pembrolizumab | Chemotherapy of physician's choice | Effect |
|---|---|---|---|---|
| PFSpMMR population (697 of 827 randomised)Progression-free survival by blinded independent central review according to RECIST 1.1 | primaryMakker 2022 | median 6.6 months (5.6–7.4) | median 3.8 months (3.6–5.0) | HR 0.60 (95% CI 0.50–0.72)P<0.001Final analysis of PFS and first interim analysis of OS. Median follow-up 12.2 months (lenvatinib plus pembrolizumab) and 10.7 months (chemotherapy). |
| OSpMMR population (697 of 827 randomised) | interimMakker 2022 | median 17.4 months (14.2–19.9) | median 12 months (10.8–13.3) | HR 0.68 (95% CI 0.56–0.84)P<0.001First interim analysis of overall survival. |
| PFSAll randomised patients (N = 827, intention to treat)Progression-free survival by blinded independent central review according to RECIST 1.1 | primaryMakker 2022 | median 7.2 months (5.7–7.6) | median 3.8 months (3.6–4.2) | HR 0.56 (95% CI 0.47–0.66)P<0.001 |
| OSAll randomised patients (N = 827, intention to treat) | interimMakker 2022 | median 18.3 months (15.2–20.5) | median 11.4 months (10.5–12.9) | HR 0.62 (95% CI 0.51–0.75)P<0.001First interim analysis of overall survival. |
| ORRpMMR population (697 of 827 randomised)Confirmed objective response by blinded independent central review according to RECIST 1.1 (secondary endpoint) | primaryMakker 2022 | 30.3% | 15.1% | Objective response was a secondary endpoint; confidence intervals were not adjusted for multiplicity. |
| ORRAll randomised patients (N = 827, intention to treat)Confirmed objective response by blinded independent central review according to RECIST 1.1 (secondary endpoint) | primaryMakker 2022 | 31.9% | 14.7% | Secondary endpoint. |
| OSpMMR population (697 of 827 randomised) | finalmedian follow-up 14.7 monthsMakker 2023 | median 18 months (14.9–20.5) | median 12.2 months (11.0–14.1) | HR 0.70 (95% CI 0.58–0.83)Final prespecified analysis of overall survival; median follow-up was 18.7 months in the lenvatinib-pembrolizumab arm and 12.2 months in the chemotherapy arm. In the chemotherapy arm, 10.0% of pMMR patients received subsequent lenvatinib plus pembrolizumab. |
| OSAll randomised patients (N = 827, intention to treat) | finalmedian follow-up 14.7 monthsMakker 2023 | median 18.7 months (15.6–21.3) | median 11.9 months (10.7–13.3) | HR 0.65 (95% CI 0.55–0.77)Final prespecified analysis of overall survival. In the chemotherapy arm, 8.7% of all-comers received subsequent lenvatinib plus pembrolizumab. |
| OSpMMR population (697 of 827 randomised) | long term-updatemedian follow-up 68.8 monthsMakker 2026 | median 18 months (14.9–20.5); 16.7% at 5 y | median 12.2 months (11.0–14.1); 7.3% at 5 y | HR 0.70 (95% CI 0.60–0.83)Five-year follow-up. Crossover to lenvatinib plus pembrolizumab or poststudy exposure occurred in the chemotherapy group (9 of 41 alive pMMR patients). |
| OSAll randomised patients (N = 827, intention to treat) | long term-updatemedian follow-up 68.8 monthsMakker 2026 | 19.9% at 5 y | 7.7% at 5 y | HR 0.66 (95% CI 0.57–0.77)Five-year follow-up. |
| OSdMMR population (130 of 827 randomised) | long term-updatemedian follow-up 68.8 monthsMakker 2026 | median 31.9 months (15.6–47.7); 36.5% at 5 y | median 8.6 months (5.5–13.4); 9.8% at 5 y | HR 0.44 (95% CI 0.29–0.67)Five-year follow-up; the trial was not designed to compare the arms in the dMMR population. |
| Endpoint | Analysis | Lenvatinib plus pembrolizumab | Chemotherapy of physician's choice | Effect |
|---|---|---|---|---|
| PFSpMMR population (697 of 827 randomised)Progression-free survival by blinded independent central review according to RECIST 1.1 | primaryMakker 2022 | median 6.6 months (5.6–7.4) | median 3.8 months (3.6–5.0) | HR 0.60 (95% CI 0.50–0.72)P<0.001Final analysis of PFS and first interim analysis of OS. Median follow-up 12.2 months (lenvatinib plus pembrolizumab) and 10.7 months (chemotherapy). |
| OSpMMR population (697 of 827 randomised) | interimMakker 2022 | median 17.4 months (14.2–19.9) | median 12 months (10.8–13.3) | HR 0.68 (95% CI 0.56–0.84)P<0.001First interim analysis of overall survival. |
| PFSAll randomised patients (N = 827, intention to treat)Progression-free survival by blinded independent central review according to RECIST 1.1 | primaryMakker 2022 | median 7.2 months (5.7–7.6) | median 3.8 months (3.6–4.2) | HR 0.56 (95% CI 0.47–0.66)P<0.001 |
| OSAll randomised patients (N = 827, intention to treat) | interimMakker 2022 | median 18.3 months (15.2–20.5) | median 11.4 months (10.5–12.9) | HR 0.62 (95% CI 0.51–0.75)P<0.001First interim analysis of overall survival. |
| ORRpMMR population (697 of 827 randomised)Confirmed objective response by blinded independent central review according to RECIST 1.1 (secondary endpoint) | primaryMakker 2022 | 30.3% | 15.1% | Objective response was a secondary endpoint; confidence intervals were not adjusted for multiplicity. |
| ORRAll randomised patients (N = 827, intention to treat)Confirmed objective response by blinded independent central review according to RECIST 1.1 (secondary endpoint) | primaryMakker 2022 | 31.9% | 14.7% | Secondary endpoint. |
| OSpMMR population (697 of 827 randomised) | finalmedian follow-up 14.7 monthsMakker 2023 | median 18 months (14.9–20.5) | median 12.2 months (11.0–14.1) | HR 0.70 (95% CI 0.58–0.83)Final prespecified analysis of overall survival; median follow-up was 18.7 months in the lenvatinib-pembrolizumab arm and 12.2 months in the chemotherapy arm. In the chemotherapy arm, 10.0% of pMMR patients received subsequent lenvatinib plus pembrolizumab. |
| OSAll randomised patients (N = 827, intention to treat) | finalmedian follow-up 14.7 monthsMakker 2023 | median 18.7 months (15.6–21.3) | median 11.9 months (10.7–13.3) | HR 0.65 (95% CI 0.55–0.77)Final prespecified analysis of overall survival. In the chemotherapy arm, 8.7% of all-comers received subsequent lenvatinib plus pembrolizumab. |
| OSpMMR population (697 of 827 randomised) | long term-updatemedian follow-up 68.8 monthsMakker 2026 | median 18 months (14.9–20.5); 16.7% at 5 y | median 12.2 months (11.0–14.1); 7.3% at 5 y | HR 0.70 (95% CI 0.60–0.83)Five-year follow-up. Crossover to lenvatinib plus pembrolizumab or poststudy exposure occurred in the chemotherapy group (9 of 41 alive pMMR patients). |
| OSAll randomised patients (N = 827, intention to treat) | long term-updatemedian follow-up 68.8 monthsMakker 2026 | 19.9% at 5 y | 7.7% at 5 y | HR 0.66 (95% CI 0.57–0.77)Five-year follow-up. |
| OSdMMR population (130 of 827 randomised) | long term-updatemedian follow-up 68.8 monthsMakker 2026 | median 31.9 months (15.6–47.7); 36.5% at 5 y | median 8.6 months (5.5–13.4); 9.8% at 5 y | HR 0.44 (95% CI 0.29–0.67)Five-year follow-up; the trial was not designed to compare the arms in the dMMR population. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.6 | 0.5–0.72 |
| OS | 0.68 | 0.56–0.84 |
| PFS | 0.56 | 0.47–0.66 |
| OS | 0.62 | 0.51–0.75 |
| OS | 0.7 | 0.58–0.83 |
| OS | 0.65 | 0.55–0.77 |
| OS | 0.7 | 0.6–0.83 |
| OS | 0.66 | 0.57–0.77 |
| OS | 0.44 | 0.29–0.67 |
- Lenvatinib plus pembrolizumab (experimental)
- Chemotherapy of physician's choice (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Lenvatinib plus pembrolizumab | Chemotherapy of physician's choice |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 4 | 65.7% | 48.2% |
| 8 | 43.2% | 23.2% |
| 12 | 28.4% | 11.2% |
| 17 | 16.8% | 4.5% |
- Lenvatinib plus pembrolizumab (experimental)
- Chemotherapy of physician's choice (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Lenvatinib plus pembrolizumab | Chemotherapy of physician's choice |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 11 | 64.5% | 53.0% |
| 22 | 41.6% | 28.1% |
| 33 | 26.9% | 14.9% |
| 44 | 17.3% | 7.9% |
Appears in
Sources
Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022;386(5):437-448.
Makker V, Colombo N, Casado Herráez A, Monk BJ, Mackay H, Santin AD, et al. Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775. J Clin Oncol. 2023;41(16):2904-2910.
Makker V, Colombo N, Casado A, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: 5-year outcomes from the randomized, phase 3 Study 309/KEYNOTE-775. J Immunother Cancer. 2026;14(2).