Therapeutic sequencing in advanced renal cell carcinoma: How to choose considering clinical and biological factors

In the last fifteen years a better understanding of the biological processes promoting tumour growth and pro-gression led to an impressive revolution in metastatic renal cell carcinoma (mRCC) treatment landscape. Angiogenesis plays a critical role in the pathogenesis of RCC. These biological evidences led to targeted therapies interfering with vascular endothelial growth factor and mammalian target of rapamycin pathway. Another big step in the RCC therapeutic landscape was recently made because of the understanding of the interplay between angiogenesis and immune cells. Dual immune checkpoint inhibitors (ICIs) and ICIs plus tyrosine kinase inhibitors (TKI) combinations have been approved considering overall survival benefit compared to targeted therapies as first line treatment. We summarize the activity and the biological rationale of ICIs combinations as mRCC first line therapy. Additionally, we review the clinical and biological criteria useful to guide clinicians in the choice of treatment sequencing focusing on ICIs combinations resistance mechanisms.

Automated summary

In the past fifteen years, there has been a significant revolution in the treatment of metastatic renal cell carcinoma (mRCC) due to a better understanding of the biological processes promoting tumor growth and progression. Angiogenesis, as a critical factor in RCC pathogenesis, has led to the development of targeted therapies that interfere with vascular endothelial growth factor and mammalian target of rapamycin pathway. The understanding of the interplay between angiogenesis and immune cells has also led to the approval of dual immune checkpoint inhibitors (ICIs) and ICIs plus tyrosine kinase inhibitors (TKI) combinations as first line treatment, showing overall survival benefit compared to targeted therapies. This article summarizes the activity and biological rationale of ICIs combinations as mRCC first line therapy, as well as reviewing the clinical and biological criteria useful for treatment sequencing, focusing on ICIs combinations resistance mechanisms.