Recent advances in the frontline treatment of metastatic renal cell carcinoma

We aim to describe the most recent advances in the upfront treatment of metastatic renal cell carcinoma, and to provide criteria though often subjective which could be used for treatment selection, by means of a critical review of the results of novel trials of immune-based combinations, coupled with personal considerations and experiences. To date, 5 immune-based combinations have been tested within large phase III trials; four of them yielded a significant overall survival benefit (Ipilimumab + Nivolumab, Pembrolizumab + Axitinib, Nivolumab + Cabozantinib and Pembrolizumab + Lenvatinib), while the combination of Avelumab + Axitinib, although reaching study primary endpoint, determined just a significant progression-free survival benefit. In terms of safety, the excess of adverse events is overall counterbalanced to the higher activity of the combinations. Overall, all the discussed immune-based combinations were ultimately approved by different regulatory authorities, and are indeed included in the most important international guidelines. Waiting for longer follow-ups and more mature trial data, as well as for real-world experiences, in the absence of validated biomarkers, our 1st line treatment choice cannot but rely on methodologically incorrect treatment comparisons, personal preferences, and experience.