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Cited by 751Renal cell carcinoma treatmentCancer Immunotherapy and BiomarkersBladder and Urothelial Cancer Treatments

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

Powles, Thomas, Plimack, Elizabeth R, Soulières, Denis, Waddell, Tom, Stus, Viktor, Gafanov, Rustem, Nosov, Dmitry, Pouliot, Frédéric +12 more·2020·The Lancet Oncology
DOI 10.1016/s1470-2045(20)30436-8
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Abstract

Background The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma.Methods In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331.Findings Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis.Interpretation With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.Funding Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

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  • In 2019, pembrolizumab combined with axitinib was approved by the FDA as the first-line treatment for advanced RCC, based on KEYNOTE-426.

    “In 2019, pembrolizumab combined with axitinib was approved by the FDA as the first-line treatment for advanced RCC, based on the results of KEYNOTE-426 (Table 4) [109].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [109]

  • At a median follow-up time of 30.6 months, the median OS and PFS were longer in the pembrolizumab combined with axitinib arm compared to those in the sunitinib arm.

    “At a median follow-up time of 30.6 months, the median OS and PFS were longer in the pembrolizumab combined with axitinib arm compared to those in the sunitinib arm [109].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [109]

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Authors
Powles, T., Plimack, E. R., Soulières, D., Waddell, T., Stus, V., Gafanov, R., Nosov, D., Pouliot, F., Melichar, B., Vynnychenko, I., Azevedo, S. J., Borchiellini, D., McDermott, R. S., Bedke, J., Tamada, S., Yin, L., Chen, M., Molife, L. R., Atkins, M. B., & Rini, B. I.
Affiliations
  • Queen Mary University of London (GB)
  • Fox Chase Cancer Center (US)
  • Centre Hospitalier de l’Université de Montréal (CA)
  • The Christie NHS Foundation Trust (GB)
  • Ministry of Health (UA)
  • Federal State Budgetary Institution Russian Scientific Center of Roentgenoradiology (RU)
  • Université Laval (CA)
  • Palacký University Olomouc (CZ)
  • Sumy State University (UA)
  • Université Côte d'Azur (FR)
  • University of Tübingen (DE)
  • Osaka City University Hospital (JP)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • MSD (UK) Limited (United Kingdom) (GB)
  • Georgetown Lombardi Comprehensive Cancer Center (US)
  • Cleveland Clinic (US)
Corresponding author
Powles, Thomas
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2020-12
Volume
21
Issue
12
Pages
1563-1573
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(20)30436-8
OpenAlex
W3093923068
Cited by
751
References
20
Citations by year
2026: 61 · 2025: 100 · 2024: 117 · 2023: 180 · 2022: 164 · 2021: 124 · 2020: 5
FWCI
66.57
Type
journal article
Language
en
Update notices
erratum (2020-12-01)
Open access
closed
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Merck Sharp and Dohme
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
Keywords
pembrolizumab, axitinib, sunitinib, advanced renal cell carcinoma, clear cell renal cell carcinoma, first-line therapy, immune checkpoint inhibitors, PD-1 inhibitors, overall survival, progression-free survival, long-term efficacy, safety, treatment-naive patients, long-term follow-up, IMDC risk stratification, tyrosine kinase inhibitors
MeSH terms
Antineoplastic Agents, Immunological, Sunitinib, Axitinib, Progression-Free Survival, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Renal Cell, Female, Humans, Kidney Neoplasms, Male, Middle Aged, Time Factors, Protein Kinase Inhibitors, Antibodies, Monoclonal, Humanized

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