The need for new algorithms of treatment sequencing in clear-cell metastatic renal cell carcinoma.

: In recent years, the systemic treatment of patients with metastatic renal-cell carcinoma (mRCC) has undergone profound innovations, offering the availability of new drugs, and raising the bar of the survival expectation in this, previously, almost-always, incurable disease. The likeliness of reaching durable response and long-term survival is still closely linked to good clinical management and smart treatment sequencing, rather than to a single systemic treatment choice.: We review all systemic therapeutic options currently available, describe the evidence behind the current options available for mRCC patient treatment, and provide our personal cues to support clinical decisions.: The IMDC classification is still the only widely validated tool for the choice of primary therapy. Other elements should then be considered for selecting patients who can still receive TKI monotherapy (good-risk patients) or who deserve an 'all-at-once' approach with TKI plus ICI (poor-risk patients with the high metastatic burden and poor-prognosis organ involvement, likely not able to achieve a second chance), identifying these two 'extreme' situations and setting all the other treatment choices on the basis of several nuances. In the second- and further-line settings, ad-hoc prospective trials are awaited.