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.

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.

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, NCT02853331.

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.

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.

Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

The Lancet. Oncology. 2020 Oct 23 [Epub ahead of print]

Thomas Powles, Elizabeth R Plimack, Denis Soulières, Tom Waddell, Viktor Stus, Rustem Gafanov, Dmitry Nosov, Frédéric Pouliot, Bohuslav Melichar, Ihor Vynnychenko, Sergio J Azevedo, Delphine Borchiellini, Raymond S McDermott, Jens Bedke, Satoshi Tamada, Lina Yin, Mei Chen, L Rhoda Molife, Michael B Atkins, Brian I Rini

Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute, and Queen Mary University of London, London UK. Electronic address: ., Fox Chase Cancer Center, Philadelphia, PA, USA., Centre Hospitalier de l'Universitaire de Montréal, Montréal, QC, Canada., The Christie NHS Foundation Trust, Manchester, UK., Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine, Dnipro, Ukraine., Russian Scientific Center of Roentgenoradiology, Moscow, Russia., Central Clinical Hospital With Outpatient Clinic, Moscow, Russia., CHU of Québec and Laval University, Québec, QC, Canada., Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic., Sumy State University, Sumy Regional Oncology Center, Sumy Oblast, Ukraine., Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Centre Antoine Lacassagne, Université Côte d'Azur, Nice, France., Adelaide and Meath Hospital, Dublin, Ireland; University College Dublin, Dublin, Ireland., University Hospital, Eberhard Karls University Tübingen, Tübingen, Germany., Osaka City University Hospital, Osaka, Japan., Merck & Co, Kenilworth, NJ, USA., Merck Sharp & Dohme UK, London, UK., Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA., Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.