Manuela Schmidinger, MD

“TARGETED AGENTS were a breakthrough in the treatment of renal cell carcinoma, and immunotherapy also works well, improving survival. In the past 2 years, combining a checkpoint inhibitor with targeted agents appears to work even better, and multiple combination trials are underway. The outcomes vary, but some patients do well on sunitinib [Sutent]. We need better biomarkers, because programmed cell death ligand 1 (PD-L1) expression alone is unreliable,” explained formal discussant Manuela Schmidinger, MD, of the Medical University of Vienna, Austria.

“Gene-expression signatures are important to study,” she continued. “They are not only relative to the disease and tumor biology, but to the mechanism of action of the different strategies.”

“The gene-expression profiles that have been identified and validated in Dr. Rini’s presentation show differential effects across treatment arms and different subgroups. They tell us that sunitinib should be given to those with high but not low expression of angiogenesis-related genes and that atezolizumab (Tecentriq) plus bevacizumab (Avastin) is superior to sunitinib in those with low expression of angiogenesis-related genes. Sarcomatoid tumors are more frequently associated with low expression of angiogenesis-related genes and more frequently with high expression of T-effector cells/PD-L1 positivity,” she told listeners.

Selecting Patients for Treatment

“BASED ON THESE findings and considering the era of checkpoint inhibitors, which patients should receive sunitinib? The answer is those with favorable-risk disease, most likely high expression of angiogenesis-related genes, less commonly high expression of T-effector cells, and most likely nonsarcomatoid disease,” she said. “Checkpoint inhibitors should most likely be given to intermediate/poor-risk patients who have a higher chance of low expression of angiogenesis-related genes and high expression of T-effector cells. In patients with tumors that have sarcomatoid features, checkpoint inhibitors may benefit those with high expression of T-effector cells and PD-L1–positive tumors,” she noted.

“These profiles are part of the puzzle to address the heterogeneity of the population,” Dr. Schmidinger continued. “Biomarkers need to be assessed individually in clinical practice, and you can’t assume clinical profile based on risk group.”

She added: “This is the first identification of useful biomarkers in renal cell carcinoma, and clinical application of these findings is feasible. You need to obtain tumor tissue from metastases, because gene expression may be dynamic and influenced by pretreatment. ■

DISCLOSURE: Dr. Schmidinger has received honoraria for lectures and advisory boards from Pfizer, Roche, BMS, Novartis, Ipsen, Exelixis, Eisai, Eusa Pharma, and Astellas.