The Study(s): As a reminder, the current preferred agent for low risk disease is still sunitinib (aka Sutent) and for intermediate to high risk disease is combo nivolumab + ipilimumab. This week brings us two large phase 3 trials comparing the VEGF / PD-1 combo with the longtime standard sunitinib. The first is KEYNOTE-426 that randomized 861 patients with advanced clear cell RCC to  oral sunitinib versus  standard-dosing of pembro infusions + oral axitinib. And, alas, the primary endpoint of overall survival was significantly improved at 12 months from 78% to 90% with combo therapy. As was median progression free survival (PFS) from 11 to 15 months. Importantly, these benefits held across expression of PD-L1 and even risk group. Merk tried to outdo itself by enrolling 886 patients in the almost identical JAVELIN Renal 101 trial, but in the end it only muted outcomes by declaring its primary endpoint to be measured only among tumors expressing PD-L1 (n=560). At last median follow-up just shy if a year, 85% were alive with sunitinib and 86% with the combo avelumab + axitinib. However, PFS was doubled from 7 to 14 months with the combo.
Bottom Line: Combo pembro + axitinib is the first systemic therapy regimen to improve survival outcomes across the board in clear cell RCC when compared to sunitinib. | Rini & Motzer, N Engl J Med 2019