Two is company, is three a crowd? Triplet therapy, novel molecular targets, and updates on the management of advanced renal cell carcinoma

Abstract

Purpose of reviewThe purpose of this review is to highlight the most recent changes in the management of advanced renal cell carcinoma, a complicated and ever-changing field of research. Recent findingsA recent meta-analysis examining combination therapy favors nivolumab plus cabozantinib as the overall survival leader in doublet therapy. Initial results on the first ever trial of triplet therapy have demonstrated improved progression-free survival over current standard of care. The hypoxia-inducible factor-2a (HIF-2a) inhibitor belzutifan is FDA approved for patients with von Hippel-Lindau disease and is currently being investigated in patients with nonhereditary renal cell carcinoma. The new glutamate synthesis inhibitor, telaglenastat, perhaps confers synergistic benefit when combined with everolimus, but combination with cabozantinib was not so effective. Dual mammalian target of rapamycin (mTOR) inhibition with sapanisertib does not appear to be an effective therapeutic option. New biomarkers and targets are actively being investigated. Four recent trials examining alternative agents to pembrolizumab in the adjuvant setting did not demonstrate an improvement in recurrence-free survival. Cytoreductive nephrectomy in the combination therapy era is supported by retrospective data; clinical trials are recruiting patients.

Special populations in metastatic renal cell carcinoma

“…Innovations in metastatic renal cell carcinoma (mRCC) occur against the greater backdrop of precision oncology [1]. We have come a long way since the cytokine era, with an ever-expanding arsenal of targeted and immunotherapies to tailor treatment for each individual patient (Table 1) [2,3]. But as therapies increase in precision, so too does the risk that we neglect our outliers: those patients whose characteristics, or the characteristics of their cancer, do not fit neatly into the design of our clinical trials and are thus poorly represented.…”