Guiding treatment selection with immunotherapy compared to targeted therapy agents in patients with metastatic kidney cancer

ABSTRACT Introduction Kidney cancer treatment has been first revolutionized by the advent of targeted therapies (TKIs and mTOR inhibitors) and then by the approval of immunotherapy and immunocombinations. Whereas immunocombinations represent the most used first-line therapy in intermediate/poor risk patients with clear-cell tumors, cabozantinib and nivolumab are both effective compounds at progression, and till today it is not totally clear what to prefer. No standard treatments are approved in post-second-line setting and in non-clear carcinoma. Areas covered The aim of this review is to summarize the main evidence supporting the use of targeted therapies and immunotherapy, in every setting of clear-cell and non-clear cell renal cell carcinoma, while also providing an insight into promising ongoing and upcoming trials. Expert opinion We speculate on what could help physicians in guiding the therapeutic decision-making process in advanced kidney cancer. International mRCC Database Consortium criteria are still recommended for the choice of primary treatments, despite presenting several limitations in the current immunotherapy-era. Multiple predictors of response to immunotherapy or targeted therapies are emerging but validated biomarkers are awaited. Furthermore, we discuss therapeutic sequences in kidney cancer, guessing how physicians may prefer immunotherapy or TKI as later-line strategies on the basis of previous treatments. Summary The therapeutic armamentarium for advanced clear cell RCC has been revolutionized by the approval of novel immune-based combinations in the last decade. Anti-VEGF TKI as a first-line treatment still represents a valid choice in good risk patients or in subjects who are not able to receive immunocombinations. Several compounds are available in second-line after TKI monotherapy, but no specific indications are available after immunocombinations. Cabozantinib seems to be the option with the strongest rationale and the most widely investigated, but the issue is still open. No standard therapy is approved for non-clear cell patients, although cabozantinib is emerging as the most promising option. Data regarding immunotherapy are still awaited. Prospective and molecular-driven trials enrolling non-clear patients are required. No predictive biomarkers have been validated to guide physician’s treatment choice, toward TKIs or either immunotherapic compounds. Future efforts are necessary to improve the predictive role of novel emerging biomarkers in both clear cell and non-clear cell histologies, such as gene expression profiling and tumor microenvironment features.