Improving Outcomes in Metastatic Clear Cell Renal Cell Carcinoma by Sequencing Therapy

Abstract

Targeted agents have substantially improved outcomes in metastatic clear cell renal cell carcinoma. However, due to multiple mechanisms of evasive resistance, almost all patients progress at some point and may require subsequent therapies. Various agents have been explored after failure of first-line treatment in randomized clinical trials. However, so far few questions about the optimal sequence have been answered. Both everolimus and axitinib have been considered standard of care after failure of first-line VEGF-TKI; sorafenib has been proposed as an additional option. In clinical practice, several factors may influence the choice of subsequent treatment: these include considerations on appropriate drug exposure in first-line, gained insights on prognostic and predictive factors as well as mechanisms of resistance. Once the decision in second-line has been made and treatment has been initiated, treating physicians may already be challenged by the question of what to offer in third- and later lines. Treatment beyond second-line treatment isn't supported by strong evidence, and at this stage of disease, retrospective reports on rechallenge may help to guide decisions. In addition, local treatment approaches including metastasectomy and stereotactic radiosurgery may help to optimize outcomes in all treatment lines.KEY POINTSPhase III evidence supports the sequential use of targeted agents in clear cell mRCC; axitinib, everolimus (and sorafenib) are considered standard options.Treatment decisions in second- or later lines remain difficult because few questions about the optimal sequence of drugs have been answered.Identified mechanisms of resistance may influence treatment decisions toward change or maintenance of mode of action.Local treatment approaches (e.g., metastasectomy and stereotactic radiosurgery) may offer additional benefits and improve outcomes.Patients may require a personalized treatment approach: there might be no standard paradigm for the optimal sequence.