Checkmate-025 was the seminal trial that showed the survival benefit of nivolumab in patients with vascular endothelial growth factor refractory disease compared with everolimus (standard of care). Not only was nivolumab more efficacious, but it was better tolerated than everolimus. Although there was an increase in survival with nivolumab, a proportional tumor response rate was not seen, with only 1% of patients achieving a complete tumor response.
Several theories have been proposed for the lack of tumor response with PD-1 blockade therapy, which include inhibition of tumor antigen presentation, secretion of immunosuppressive factors by the tumor, alternative pathway for immune system inhibition, and recruitment of immunosuppressive cell types. This has led to the use of combination therapy to counteract some of these mechanisms.
The addition of vascular endothelial growth factor inhibitors has shown synergy with PD-1 blockade therapy by reducing immunosuppressive cell population and increasing T-cell infiltration into the tumors. A phase 2 study adding bevacizumab to atezolizumab versus sunitinib showed initial promise with an objective response rate of 41%. In the phase 2 study, the effect was blunted in newcomers, but it did show some benefit in patients with high PD-1 tumor expression. Another phase 2 trial assessed the effect of adding axitinib to pembrolizumab, which showed promising results with an overall response rate of 70%, with 94% of patients showing some type of tumor shrinkage. No new toxicities were noted in the study, and very few patients were terminated because of hepatotoxicity, which had been a concern.
There are numerous combination trials on the horizon, with the most exciting being the combination of cabozantinib and nivolumab. There are future trials that may include costimulator agents such as varlilumab (a CD27 agonist). Treatment with varlilumab has been linked to increase PD-L1/L2-ligand expression in cold tumors.
In conclusion, PD-1 blockade therapy has revolutionized the treatment of advanced RCC. Even with PD-1 blockade therapy, 30% of patients remain refractory to the treatment, likely from a variety of alternate mechanisms. A tremendous volume of clinical innovation is in progress assessing combination treatments and improving agent tolerability.
Presented by: Lauren Marshman, MD, Brigham and Women's Hospital and Dana-Farber Cancer Institute
Written By: Andres F. Correa, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia, PA
at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA