ASCO 2019: Pembrolizumab Plus Axitinib versus Sunitinib as First-Line Therapy for mRCC: Outcomes in the Combined IMDC Intermediate/Poor Risk and Sarcomatoid Subgroups of the Phase 3 KEYNOTE-426 Study

Chicago, IL ( In KEYNOTE-426, pembrolizumab plus axitinib significantly improved overall survival (OS) (HR 0.53, 95% CI 0.38-0.74, p < 0.0001), progression-free survival (PFS) (HR 0.69, 95% CI 0.57-0.84, p = 0.0001), and objective response rate (ORR) (59.3% vs 35.7%, p < 0.0001) vs sunitinib.1 This combination therapy also had manageable toxicity as first-line therapy for mRCC. Furthermore, the pembrolizumab plus axitinib benefit was observed across all IMDC risk groups and regardless of PD-L1 expression.  

Brian Rini and KEYNOTE-426 investigators presented outcomes for the combined intermediate/poor risk group and for patients with sarcomatoid features. Their objectives for the current analysis included evaluating different thresholds of the percentage of tumor shrinkage and to assess OS, PFS, and ORR in the aforementioned subgroups. 

KEYNOTE-426 evaluated 861 eligible patients with clear-cell mRCC, no prior systemic therapy for mRCC, and KPS ≥70 that were randomized 1:1 to pembrolizumab 200 mg IV every 3 weeks for a maximum of 35 cycles plus axitinib 5 mg orally BID (n = 432) or sunitinib 50 mg orally daily (4-weeks on/2-weeks off) (n = 429). The primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review). ORR (RECIST v1.1 by blinded, independent central review) was the key secondary endpoint. The intermediate/poor risk group was prespecified and the sarcomatoid group was exploratory. 

In their assessment of change from baseline in target lesions in the intention to treat population, Dr. Rini noted that in the pembrolizumab plus axitinib arm: 94% had any decrease, 77% had decrease >=30%, 42% had decrease >=60%, 17% had decrease >=80%, and 9% had complete response of the target lesions. In the sunitinib arm: 85% had any decrease, 50% had decrease >=30%, 16% had decrease >=60%, 6% had decrease >=80%, and 3% had complete response of the target lesions.

There were 592 (68.8%) of all randomized patients that were of IMDC intermediate/poor risk — 294 in the pembrolizumab plus axitinib arm and 298 in the sunitinib arm. Pembrolizumab plus axitinib improved OS (HR 0.52, 95% CI 0.37-0.74; 12-month rate 87.3% vs 71.3%), PFS (HR 0.67, 95% CI 0.53-0.85; median 12.6 vs 8.2 months), and ORR (55.8% vs 29.5%) in patients with intermediate/poor risk. 
Of the 578 patients with known status, 105 (18.2%) had sarcomatoid features — 51 in the pembrolizumab plus axitinib arm and 54 in the sunitinib arm. Pembrolizumab plus axitinib favored OS (HR 0.58, 95% CI 0.21-1.59; 12-month rate 83.4% vs 79.5%), PFS (HR 0.54, 95% CI 0.29-1.00; median not reached vs 8.4 months), and ORR (58.8% vs 31.5%) in patients with sarcomatoid features. 
Dr. Rini also presented results of patients with favorable risk disease (n=138 pembrolizumab plus axitinib; n=131 sunitinib), noting that OS favored pembrolizumab plus axitinib (HR 0.64, 95 %CI 0.24-1.68; OS data still maturing in this subset), as well as PFS (HR 0.81, 95%CI 0.53-1.24). ORR was 66.7% for pembrolizumab plus axitinib and 49.6% for sunitinib. 
Dr. Rini concluded with several take-home messages:
  • The percentage of tumor shrinkage was substantially greater with pembrolizumab plus axitinib than with sunitinib
  • OS, PFS and ORR benefit of pembrolizumab plus axitinib vs sunitinib was observed across key subgroups
  • Pembrolizumab plus axitinib is a new standard of care for first-line treatment of advanced clear-cell RCC, with OS, PFS, and ORR benefit in all IMDC risk categories and substantial activity in participants with sarcomatoid RCC
Clinical trial information: NCT02853331

Presented by: Brian I. Rini, MD, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

Co-Authors: Elizabeth R. Plimack, Viktor Stus, Rustem Gafanov, Robert Hawkins, Dmitry Nosov, Frederic Pouliot, Denis Soulieres, Bohuslav Melichar, Ihor Vynnychenko, Sergio Jobim Azevedo, Delphine Borchiellini, Raymond S. McDermott, Jens Bedke, Satoshi Tamada, Shuyan Wan, Rodolfo F. Perini, Mei Chen, Michael B. Atkins, Thomas Powles; Fox Chase Cancer Center, Philadelphia, PA; Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine, Dnipro, Ukraine; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; The Christie NHS Foundation Trust, Manchester, United Kingdom; Central Clinical Hospital with Outpatient Clinic, Moscow, Russian Federation; CHU de Québec and Université Laval, Quebec City, QC, Canada; Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada; Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic; Sumy State University, Sumy Regional Oncology Center, Sumy, Ukraine; Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Centre Antoine Lacassagne, Université Côte d’Azu, Nice, France; Adelaide and Meath Hospital and University College Dublin, Dublin, Ireland; Department of Urology, Eberhard-Karls University Tübingen, Tübingen, Germany; Osaka City University Hospital, Osaka, Japan; Merck & Co., Inc., Kenilworth, NJ; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

  1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-1127