Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma

Abstract

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.

Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets

“…Next to sunitinib (mainly vascular endothelial growth factor receptor inhibitor and platelet-derived growth factor receptor inhibitor) and axitinib (mainly vascular endothelial growth factor receptor inhibitor), nivolumab (PD-1) became one of the most frequently applied first-line regimens. The progression-free response rate and overall survival for all three compounds are comparable, except for immune checkpoint inhibitor less side effects have been reported [ 22 ].…”

“…Due to the immunogenicity of ccRCC and good response rate, the FDA has already approved nivolumab in 2015 [ 19 ], an immune checkpoint inhibitor targeting PD-1, to treat RCC, followed by the approval of the combination therapies of nivolumab and ipilimumab [ 20 ], as well as pembrolizumab (anti-PD-1) or avelumab (anti-PD-L1) with axitinib (VEGF receptor tyrosine kinase inhibitor) [ 21 ]. These immunotherapeutic agents have been demonstrated to efficiently reduce tumor growth and prolong the overall survival rate of patients with early and advanced staged tumors [ 22 , 23 ].…”

“…Together with targeted small molecule-based therapeutics, immune checkpoint inhibitors and combinations of such are in use to treat ccRCC [ 22 , 24 ]. Next to sunitinib (mainly vascular endothelial growth factor receptor inhibitor and platelet-derived growth factor receptor inhibitor) and axitinib (mainly vascular endothelial growth factor receptor inhibitor), nivolumab (PD-1) became one of the most frequently applied first-line regimens.…”

Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment

“…Anti-programmed death (PD1)/programmed death-ligand 1 (PD-L1) immunotherapeutic monoclonal antibodies and mammalian target of rapamycin (mTOR) inhibitors are being used for mccRCC treatment as well. These three therapeutic modes complement each other in mRCC management, especially if the patient does not respond to the selected treatment mode [ 6 ].…”

Renal Cell Carcinoma—Lessons in Diversity, Breakthroughs, and Challenges

“…However, multiple TKIs have shown efficacy in pretreated patients with advanced clear cell RCC. 14 Yet, rather than searching for the strongest doublet combination in patients with untreated advanced RCC or the optimal sequencing of therapies, it may be prudent to focus on different treatment concepts or development of agents with novel mechanisms of action. For instance, the COSMIC-313 study (NCT03937219) is assessing the efficacy of a triplet combination with ipilimumab and nivolumab and cabozantinib in untreated patients with advanced clear cell RCC.…”