The Current and Evolving Landscape of First-Line Treatments for Advanced Renal Cell Carcinoma.

Agents targeting the vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), as well as the mammalian target of rapamycin (mTOR) and immune checkpoint receptor programmed death 1 (PD-1) signaling pathway have improved clinical outcomes for patients with advanced renal cell carcinoma (RCC). The VEGFR tyrosine kinase inhibitors (TKIs) pazopanib and sunitinib are FDA-approved first-line treatment options for advanced RCC; however, other treatment options in this setting are available, including the recently approved combination of nivolumab (anti-PD-1) and ipilimumab (anti-cytotoxic T-lymphocyte-associated protein-4 [CTLA-4]) for patients with intermediate or poor risk. Unfortunately, treatment guideline recommendations provide little guidance to aid first-line treatment choice. In addition, several ongoing randomized phase III trials of investigational first-line regimens may complicate the RCC treatment paradigm if these agents gain approval. This article reviews clinical trial and real-world evidence for currently approved and investigational first-line treatment regimens for advanced RCC and provides clinical evidence to aid first-line treatment selection. IMPLICATIONS FOR PRACTICE: Vascular endothelial growth factor receptor tyrosine kinase inhibitors are approved by the U.S. Food and Drug Administration as first-line treatment options for advanced renal cell carcinoma; however, the treatment paradigm is rapidly evolving. The combination of nivolumab plus ipilimumab was recently approved for intermediate- and poor-risk patients, and other combination strategies and novel first-line agents will likely be introduced soon.

Soluble forms of PD-L1 and PD-1 as prognostic and predictive markers of sunitinib efficacy in patients with metastatic clear cell renal cell carcinoma.

Metastatic clear cell renal cell carcinoma (mccRCC) benefits from several treatment options in the first-line setting with VEGFR inhibitors and/or immunotherapy including anti-PD-L1 or anti-PD1 agents. Identification of predictive biomarkers is highly needed to optimize patient care. Circulating markers could reflect the biology of metastatic disease. Therefore, we evaluated soluble forms of PD-L1 (sPD-L1) and PD-1 (sPD-1) in mccRCC patients. The levels of sPD-L1 and sPD-1 were evaluated from plasma samples of mccRCC patients before they received a first-line treatment (T0) by the VEGFR inhibitor sunitinib (50 patients) or by the anti-VEGF bevacizumab (37 patients). The levels of sPD-L1 and sPD-1 were correlated to clinical parameters and progression-free survival (PFS). High levels of sPD-1 or sPDL1 were not correlated to PFS under bevacizumab while they were independent prognostic factors of PFS in the sunitinib group. Patients with high T0 plasmatic levels of sPD-L1 had a shorter PFS (11.3 vs 22.5 months, p = .011) in the sunitinib group. Equivalent shorter PFS was found with high levels of sPD-1 (8.6 vs 14.1 months, p = .009). mccRCC patients with high plasmatic levels of sPD-L1 or sPD-1 are poor responders to sunitinib. sPD-L1 or sPD-1 could be a valuable tool to guide the optimal treatment strategy including VEGFR inhibitor.