ASCO GU 2019: Pembrolizumab Plus Axitinib versus Sunitinib as First-line Therapy for Locally Advanced or Metastatic Renal Cell Carcinoma: Phase III KEYNOTE-426 Study

San Francisco, CA ( Previous data has demonstrated that pembrolizumab (anti PD-L1 monoclonal antibody) and axitinib (VEGFR-TKI) have antitumor activity as monotherapies in the advanced RCC setting.  It is hypothesized that these two medications may have synergistic effects, and this is supported by a phase 1b study, where pembrolizumab plus axitinib demonstrated a high overall response rate promising progression free survival and a tolerable safety profile. 

In this presentation, Dr. Powles presented KEYNOTE 426, an international, multi-institutional open label phase III trial evaluating the efficacy and safety of pembrolizumab + axitinib versus sunitinib as first line therapy for metastatic renal cell carcinoma (mRCC).  Of note, the results of this study were published in the New England Journal of Medicine today.  In this study, approximately 430 patients with newly diagnosed or recurrent stage IV clear cell RCC and no previous systemic treatment were randomized to pembrolizumab 200mg IV Q3 weeks plus axitinib 5mg PO BID or sunitinib 50mg PO daily.  At this first interim analysis, patients had a median follow up of 13 months. 

In summary, pembolizumab with axitinib significant improved overall survival, progression free survival, and overall response rate compared to sunitinib [(HR 0.53 [95% CI 0.38-0.74]; P< 0.0001; 12-mo rate 89.9% vs 78.3%), PFS (HR 0.69 [95% CI 0.57-0.84]; P = 0.0001; median 15.1 vs 11.1 mo), and ORR (59.3% vs 35.7%; P< 0.0001)].  Furthermore, duration of response was prolonged in the combination cohort (NR vs 15.2 mo). 

In a subgroup analysis, outcome benefit was demonstrated in the pembolizumab with axitinib cohort in all IMDC risk groups and PD-L1 expression positivity.  Higher grade (3-5) adverse effects were seen in 63% of patients in the pembolizumab with axitinib cohort compared to 58% in the sunitinib arm.  Most common high grade treatment-related adverse events in the combination arm were hypertension, transaminitis, and diarrhea. 

In conclusion, combination PD-L1 and TKI inhibition demonstrated superior tumor activity compared to sunitinib alone in patients with previously untreated, locally advanced or metastatic clear cell kidney cancer.  Benefits were demonstrated amongst all subgroups with acceptable toxicity rates. 

Dr. Powles stated that this randomized data supports pembrolizumab plus axitinib as the new standard of care for first-line treatment previously untreated, locally advanced or metastatic clear cell kidney cancer.

Presented by: Thomas Powles, MD, PhD, FCRP, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom

Written by: David B. Cahn, DO, MBS, @dbcahn, Fox Chase Cancer Center at the Annual ASCO GU meeting 2019, San Francisco, CA, Twitter: @shekabhishek at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA
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