ASCO 2021: Pembrolizumab (Pembro) plus Axitinib (Axi) Versus Sunitinib as First-Line Therapy for Advanced Clear Cell Renal Cell Carcinoma (ccRCC): Results from 42-Month Follow-up of KEYNOTE-426

( In this presentation, Dr. Brian Rini presented 42-month follow-up data from the KEYNOTE-426 trial of pembrolizumab in combination with axitinib as first-line therapy for clear cell renal cell carcinoma (ccRCC). The first interim analysis of this combination, published in 20191 showed a statistically significant improvement in overall survival and progression-free survival relative to sunitinib. Subsequent follow-up at a median of 30.6 months confirmed these findings. For this presentation, Dr. Rini presented data from a median follow-up of 42.8 months, with a minimum follow-up of 35.6 months.

The study design of KEYNOTE-426 is shown below. Patients with newly diagnosed metastatic ccRCC who were treatment naïve and had measurable disease were randomized 1:1 to either the combination of pembrolizumab (for up to 2 years) and daily axitinib or daily sunitinib for four weeks on and two weeks off. The dual primary endpoints of the study were overall survival and progression-free survival in the intention to treat population.


Of the 861 patients randomized on the study, 62 patients (14.5%) continue to receive pembrolizumab and axitinib, whereas 40 patients (9.4%) continue to receive sunitinib. The reasons for treatment discontinuation are shown below.


The baseline characteristics of the patients, including region of enrollment, IMDC risk breakdown, sarcomatoid differentiation rates, and other parameters are shown below.


Most patients in both arms went on to receive subsequent anti-cancer therapy. Most patients in the pembro/axitinib treatment arm went on to receive a different tyrosine kinase inhibitor, whereas most patients in the sunitinib arm received immune checkpoint blockade.

At the longer follow-up time point, the overall survival and progression-free survival advantage for combination therapy relative to sunitinib was confirmed. The median overall survival for pembrolizumab and axitinib-treated patients was 45.7 months, relative to 40.1 months for sunitinib.


The median progression-free survival for pembro/axitinib was 15.7 months relative to 11.1 months with sunitinib (HR for progression 0.68, 95% CI 0.58-0.80, p < 0.0001). Pembrolizumab and axitinib resulted in an objective response rate of 60.4%, including 10% of patients having a complete response. Sunitinib resulted in a 39.6% response rate, including 3.5% complete responses. 11.3% of patients treated with pembo/axi had progressive disease as best response, relative to 17% in the sunitinib arm.

Duration of response data is summarized below. Each arm had a similar median time to response, though pembro/axi was associated with a longer median duration of response.


The advantage of pembrolizumab and axitinib relative to sunitinib was generally confirmed across IMDC subgroups. Of note, the overall survival advantage did not favor combination therapy, but this analysis is more limited given the low number of survival events in that subgroup, as evidence by the wide confidence interval.


A summary of the treatment-related adverse events and rates of specific events of interest is shown below.



Dr. Rini concluded that with a median follow-up of over 42 months, this data from KEYNOTE-426 confirms the overall survival, progression-free survival, and response rate benefit for combination pembrolizumab and axitinib relative to sunitinib. This dataset represents the longest follow-up to date of combination immune checkpoint inhibition and tyrosine kinase inhibitor as first-line therapy for ccRCC. Long-term follow-up did not reveal any new safety signals from the original report. These data support pembro/axi as a standard of care option for treatment-naïve metastatic ccRCC.

Presented by: Brian I. Rini, MD, Professor of Medicine and chief of Clinical Trials at Vanderbilt University Medical Center, Nashville, TN

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021


  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.
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