KEYNOTE-426
Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426)
Phase 3N = 861NCT02853331
- Population
- Adults with previously untreated advanced clear-cell renal cell carcinoma
- Design
- Open-label, randomised (1:1) phase 3 trial in previously untreated advanced clear-cell renal cell carcinoma, stratified by IMDC risk status and geographical region. The primary end points were overall survival and progression-free survival in the intention-to-treat population; the key secondary end point was objective response rate. The primary report is the protocol-specified first interim analysis; later reports are exploratory with nominal p values.
- Primary endpoint
- OS, PFS
- Arms
- Pembrolizumab plus axitinib (experimental, n = 432): Pembrolizumab 200 mg intravenously every 3 weeks (up to 35 cycles) plus axitinib 5 mg orally twice daily
- Sunitinib (control, n = 429): Sunitinib 50 mg orally once daily for the first 4 weeks of each 6-week cycle
- People
- Rini BI, KEYNOTE-426 Investigators
OSHR 0.53 (95% CI 0.38–0.74)Δ 12-month OS+11.6 pointsPFSHR 0.69 (95% CI 0.57–0.84)Δ median PFS+4 monthsΔ ORR+23.6 pointsOSHR 0.68 (95% CI 0.55–0.85)
Show the numbers
| Endpoint | Analysis | Pembrolizumab plus axitinib | Sunitinib | Effect |
|---|---|---|---|---|
| OS | interimmedian follow-up 12.8 monthsRini 2019 | 89.9% at 12 mo | 78.3% at 12 mo | HR 0.53 (95% CI 0.38–0.74)P<0.0001First interim analysis. |
| PFS | interimmedian follow-up 12.8 monthsRini 2019 | median 15.1 months | median 11.1 months | HR 0.69 (95% CI 0.57–0.84)P<0.001First interim analysis. |
| ORR | interimmedian follow-up 12.8 monthsRini 2019 | 59.3% (54.5–63.9%) | 35.7% (31.1–40.4%) | P<0.001Key secondary end point, first interim analysis. |
| OS | long term-updatemedian follow-up 30.6 monthsPowles 2020 | — | median 35.7 months | HR 0.68 (95% CI 0.55–0.85)P=0.0003Exploratory analysis with nominal p values. Median overall survival was not reached with pembrolizumab plus axitinib; the sunitinib median had a 95% CI of 33.3 to not reached. |
| PFS | long term-updatemedian follow-up 30.6 monthsPowles 2020 | median 15.4 months (12.7–18.9) | median 11.1 months (9.1–12.5) | HR 0.71 (95% CI 0.60–0.84)P<0.0001Exploratory analysis with nominal p values. |
| OS | long term-updatemedian follow-up 67.2 monthsRini 2025 | median 47.2 months | median 40.8 months | HR 0.84 (95% CI 0.71–0.99)Analysis with at least 5 years of follow-up (median follow-up 67.2 months, range 60.0 to 75.0). Exploratory: no formal hypothesis testing; the primary end points were met at the first interim analysis. The text gives no confidence intervals for the medians. |
| PFS | long term-updatemedian follow-up 67.2 monthsRini 2025 | median 15.7 months | median 11.1 months | HR 0.69 (95% CI 0.59–0.81)Analysis with at least 5 years of follow-up (median follow-up 67.2 months). Exploratory; the text gives no confidence intervals for the medians. |
| ORR | long term-updatemedian follow-up 67.2 monthsRini 2025 | 60.6% | 39.6% | Confirmed objective response by blinded independent central review at the 5-year analysis (median follow-up 67.2 months): complete responses 11.6% (50 participants) with pembrolizumab plus axitinib and 4.0% (17 participants) with sunitinib. Exploratory. |
| Endpoint | Analysis | Pembrolizumab plus axitinib | Sunitinib | Effect |
|---|---|---|---|---|
| OS | interimmedian follow-up 12.8 monthsRini 2019 | 89.9% at 12 mo | 78.3% at 12 mo | HR 0.53 (95% CI 0.38–0.74)P<0.0001First interim analysis. |
| PFS | interimmedian follow-up 12.8 monthsRini 2019 | median 15.1 months | median 11.1 months | HR 0.69 (95% CI 0.57–0.84)P<0.001First interim analysis. |
| ORR | interimmedian follow-up 12.8 monthsRini 2019 | 59.3% (54.5–63.9%) | 35.7% (31.1–40.4%) | P<0.001Key secondary end point, first interim analysis. |
| OS | long term-updatemedian follow-up 30.6 monthsPowles 2020 | — | median 35.7 months | HR 0.68 (95% CI 0.55–0.85)P=0.0003Exploratory analysis with nominal p values. Median overall survival was not reached with pembrolizumab plus axitinib; the sunitinib median had a 95% CI of 33.3 to not reached. |
| PFS | long term-updatemedian follow-up 30.6 monthsPowles 2020 | median 15.4 months (12.7–18.9) | median 11.1 months (9.1–12.5) | HR 0.71 (95% CI 0.60–0.84)P<0.0001Exploratory analysis with nominal p values. |
| OS | long term-updatemedian follow-up 67.2 monthsRini 2025 | median 47.2 months | median 40.8 months | HR 0.84 (95% CI 0.71–0.99)Analysis with at least 5 years of follow-up (median follow-up 67.2 months, range 60.0 to 75.0). Exploratory: no formal hypothesis testing; the primary end points were met at the first interim analysis. The text gives no confidence intervals for the medians. |
| PFS | long term-updatemedian follow-up 67.2 monthsRini 2025 | median 15.7 months | median 11.1 months | HR 0.69 (95% CI 0.59–0.81)Analysis with at least 5 years of follow-up (median follow-up 67.2 months). Exploratory; the text gives no confidence intervals for the medians. |
| ORR | long term-updatemedian follow-up 67.2 monthsRini 2025 | 60.6% | 39.6% | Confirmed objective response by blinded independent central review at the 5-year analysis (median follow-up 67.2 months): complete responses 11.6% (50 participants) with pembrolizumab plus axitinib and 4.0% (17 participants) with sunitinib. Exploratory. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.53 | 0.38–0.74 |
| PFS | 0.69 | 0.57–0.84 |
| OS | 0.68 | 0.55–0.85 |
| PFS | 0.71 | 0.6–0.84 |
| OS | 0.84 | 0.71–0.99 |
| PFS | 0.69 | 0.59–0.81 |
- Pembrolizumab plus axitinib (experimental)
- Sunitinib (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 axitinib | Sunitinib |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 9 | 66.2% | 57.0% |
| 19 | 41.8% | 30.5% |
| 28 | 27.7% | 17.4% |
| 38 | 17.5% | 9.3% |
- Sunitinib (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Sunitinib |
|---|---|
| 0 | 100.0% |
| 22 | 65.2% |
| 45 | 41.7% |
| 67 | 27.2% |
| 89 | 17.8% |
Appears in
Sources
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127.
Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573.
Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial. Nat Med. 2025;31(10):3475-3484.