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)

NCT02853331 | Completed Phase 3 Results DMC FDA Drug

• 7 other identifiers: 3475-426163460MK-3475-426KEYNOTE-4262023-507294-18-00U1111-1295-68362016-000588-17
• Study Type: interventional
• Target: 861
• Locations: 0 countries
• Sites: N/A

Brief 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. 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. 2.The combination therapy of pembrolizumab plus axitinib is superior to sunitinib monotherapy with respect to Overall Survival (OS).

Conditions

Renal Cell Carcinoma

Keywords

PD1; PD-1; PDL1; PD-L1; PDL2; PD-L2; VEGFR TKI

Outcome Measures

Primary Outcomes (2)

• Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review

  PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The PFS for participants is presented.

  Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)

• Overall Survival (OS)

  OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. The OS for participants is presented.

  Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)

Secondary Outcomes (13)

• Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review

  Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)

• Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review

  Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)

• Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review

  Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)

• Number of Participants Who Experienced an Adverse Event (AE)

  Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)

• Number of Participants Who Discontinued Study Drug Due to an AE

  Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)

Other Outcomes (1)

• Mean Baseline EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Score

  Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days])

Study Arms (2)

Pembrolizumab+Axitinib Combination Therapy

EXPERIMENTAL

Participants receive pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily.

Biological: Pembrolizumab; Drug: Axitinib

Sunitinib Monotherapy

ACTIVE COMPARATOR

Participants receive sunitinib 50 mg orally once daily for 4 weeks and then are off treatment for 2 weeks.

Drug: Sunitinib

Interventions

Pembrolizumab BIOLOGICAL

Intravenous infusion

Also known as: MK-3475, KEYTRUDA®

Pembrolizumab+Axitinib Combination Therapy

Axitinib DRUG

Oral tablet

Also known as: INLYTA®

Pembrolizumab+Axitinib Combination Therapy

Sunitinib DRUG

Oral capsule

Also known as: SUTENT®

Sunitinib Monotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features
• Has locally advanced/metastatic disease (i.e., newly diagnosed Stage IV RCC per American Joint Committee on Cancer) or has recurrent disease
• Has measurable disease per RECIST 1.1 as assessed by the investigator/site radiologist
• Has received no prior systemic therapy for advanced RCC.
• Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
• Has Karnofsky performance status (KPS) ≥ 70% as assessed within 10 days prior to randomization.
• If receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have therapy initiated at least 2 weeks prior to randomization.
• Demonstrates adequate organ function.
• Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug.
• Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug.

You may not qualify if:

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization.
• Has had major surgery within 4 weeks, received radiation therapy within 2 weeks prior to randomization, or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to prior treatment.
• Has had prior treatment with any anti-programmed cell death (anti-PD-1), or programmed cell death ligand 1 (PD-L1), or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms.
• Has received prior systemic anti-cancer therapy for RCC with vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) or mechanistic target of rapamycin (mTOR) targeting agents.
• Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to axitinib or sunitinib.
• Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapy exceeding physiologic corticosteroid dose or any other form of immunosuppressive therapy within 7 days prior to randomization, except in the case of central nervous system (CNS) metastases.
• Has an active autoimmune disease requiring systemic treatment with in the past 2 years OR a documented history of clinically severe autoimmune disease. Note: Participants with vitiligo, Sjøgren's syndrome, Type 1 diabetes, resolved childhood asthma/atopy, hypothyroidism or adrenal or pituitary insufficiency who are stable on hormone replacement, are not excluded.
• Has a known additional malignancy that has progressed or has required active treatment in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ such as breast cancer in situ are acceptable if they have undergone potentially curative therapy.
• Has known active CNS metastases and/or carcinomatous meningitis.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV).
• Has known active Hepatitis B or Hepatitis C infection.
• Has received a live virus vaccine within 30 days of randomization.
• Has a clinically significant gastrointestinal (GI) abnormality including:

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (10)

• 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.

  PMID: 40750932 DERIVED

• 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.

  PMID: 39815637 DERIVED

• 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.

  PMID: 37526095 DERIVED

• 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.

  PMID: 37146227 DERIVED

• 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.

  PMID: 35843776 DERIVED

• 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.

  PMID: 34244116 DERIVED

• 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.

  PMID: 33947608 DERIVED

• 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.

  PMID: 33284113 DERIVED

• 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.

  PMID: 30779529 DERIVED

• 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.

  PMID: 29439857 DERIVED

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

pembrolizumab; Axitinib; Sunitinib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrroles; Indoles

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2016
• First Posted: August 2, 2016
• Study Start: September 16, 2016
• Primary Completion: October 18, 2018
• Study Completion: December 26, 2025
• Last Updated: February 2, 2026
• Results First Posted: November 8, 2019

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share