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)
Summary
The purpose of this study is to evaluate the efficacy and safety of pembrolizumab (MK-3475) in combination with axitinib versus sunitinib monotherapy as a first-line treatment for participants with advanced/metastatic renal cell carcinoma (mRCC). The primary hypotheses of this study are: 1. The combination therapy of pembrolizumab plus axitinib is superior to sunitinib monotherapy with respect to Progression-Free Survival (PFS) as assessed by blinded independent central imaging review per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) 2. The combination therapy of pembrolizumab plus axitinib is superior to sunitinib monotherapy with respect to Overall Survival (OS).
Timeline
- Start
- 2016-09-16
- Primary completion
- 2018-10-18
- Completion
- 2025-12-26
Outcome
Met primary endpoint
registry analysis (superiority test); Pembrolizumab + Axitinib vs Sunitinib; p = 0.00012; Hazard Ratio (HR) 0.69 (95% CI 0.56 to 0.84); Log Rank NCT02853331 ↗
registry analysis (superiority test); Pembrolizumab + Axitinib vs Sunitinib; p = 0.00005; Hazard Ratio (HR) 0.53 (95% CI 0.38 to 0.74); Log Rank NCT02853331 ↗
paper Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. PMID 33284113 ↗
release “Results from KEYNOTE-426 Studying KEYTRUDA in Combination with Axitinib as First-line Treatment for Advanced or Metastatic Renal Cell Carcinoma Met Primary Endpoints” merck.com ↗
release “Approval Based on Results of KEYNOTE-426, Where KEYTRUDA in Combination With Axitinib Reduced the Risk of Death by Nearly Half Compared to Sunitinib” merck.com ↗
release “The trial demonstrated statistically significant improvements in OS, PFS, and ORR in patients randomized to receive the KEYTRUDA-axitinib combination compared to sunitinib.” merck.com ↗
release “In KEYNOTE-426, KEYTRUDA in combination with axitinib demonstrated a statistically significant improvement in OS, reducing the risk of death by 47% compared with sunitinib” merck.com ↗
release “KEYNOTE-426 trial, in which KEYTRUDA in combination with axitinib demonstrated statistically significant improvements in the dual primary endpoints” merck.com ↗
Publications
- Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, Pouliot F, Alekseev B, Soulieres D, Melichar B, Vynnychenko I, de Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Wu S, Markensohn J, Zhang Y, Loboda A, Vajdi A, Perini RF, Burgents J, Powles T. 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 Oct;31(10):3475-3484. doi: 10.1038/s41591-025-03867-5. Epub 2025 Aug 1.
- Chung HJ, Kondoh C, Bae WK, Tamada S, Matsubara N, Lee HJ, Mizuno R, Anai S, Kimura G, Tomita Y, Chang CH, Chang JW, Lin J, Perini RF, Molife LR, Powles T, Rini BI, Uemura H. First-line pembrolizumab-axitinib versus sunitinib in metastatic RCC: subgroup analysis of patients enrolled in the phase 3 KEYNOTE-426 in Eastern Asia. Jpn J Clin Oncol. 2025 Apr 6;55(4):406-413. doi: 10.1093/jjco/hyae182.
- Rini BI, Atkins MB, Choueiri TK, Teresi RE, Rosbrook B, Thakur M, Hutson TE. Plain language summary looking at how long side effects last after treatment with axitinib is stopped in people with advanced renal cell carcinoma. Future Oncol. 2023 Dec;19(40):2623-2629. doi: 10.2217/fon-2023-0233. Epub 2023 Aug 1.
- Aldin A, Besiroglu B, Adams A, Monsef I, Piechotta V, Tomlinson E, Hornbach C, Dressen N, Goldkuhle M, Maisch P, Dahm P, Heidenreich A, Skoetz N. First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2023 May 4;5(5):CD013798. doi: 10.1002/14651858.CD013798.pub2.
- Bedke J, Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, Pouliot F, Soulieres D, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Tamada S, Nguyen AM, Wan S, Perini RF, Rhoda Molife L, Atkins MB, Powles T. Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma. Eur Urol. 2022 Oct;82(4):427-439. doi: 10.1016/j.eururo.2022.06.009. Epub 2022 Jul 15.
- Rini BI, Atkins MB, Plimack ER, Soulieres D, McDermott RS, Bedke J, Tartas S, Alekseev B, Melichar B, Shparyk Y, Kondoh C, Langiewicz P, Wood LA, Hammers H, Silber CG, Haber B, Jensen E, Chen M, Powles T. Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial. Eur Urol Oncol. 2022 Apr;5(2):225-234. doi: 10.1016/j.euo.2021.05.007. Epub 2021 Jul 6.
- Rini BI, Atkins MB, Choueiri TK, Thomaidou D, Rosbrook B, Thakur M, Hutson TE. Time to Resolution of Axitinib-Related Adverse Events After Treatment Interruption in Patients With Advanced Renal Cell Carcinoma. Clin Genitourin Cancer. 2021 Oct;19(5):e306-e312. doi: 10.1016/j.clgc.2021.03.019. Epub 2021 Apr 5.
- Powles T, Plimack ER, Soulieres D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. 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 Dec;21(12):1563-1573. doi: 10.1016/S1470-2045(20)30436-8. Epub 2020 Oct 23.
- Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulieres D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. doi: 10.1056/NEJMoa1816714. Epub 2019 Feb 16.
- Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, Vaishampayan U, George S, Olencki TE, Tarazi JC, Rosbrook B, Fernandez KC, Lechuga M, Choueiri TK. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018 Mar;19(3):405-415. doi: 10.1016/S1470-2045(18)30081-0. Epub 2018 Feb 10.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Axitinib | Small molecule | 5 mg | Oral |
| Subject | Pembrolizumab | Monoclonal antibody | 200 mg | Intravenous |
| Comparator | Sunitinib | Small molecule | 50 mg | Oral |