Combination therapies in clinical trials for renal cell carcinoma: how could they impact future treatments?

Pharmacological combinations using immune checkpoint inhibition (ICI), tyrosine kinase inhibition (TKIs), and mammalian target of rapamycin inhibitors (mTOR) have improved survival in metastatic clear cell renal cell cancer (mccRCC). Despite improvements in survival, complete durable responses are rare. Molecular pathways involved in mccRCC and drugs targets are highlighted. The background and rationale for combination therapy are covered. Results from combination trials are reviewed and potential approaches with biomarker-stratified treatment and novel experimental agents are examined. PubMed Central and ClinicalTrials.gov were searched. Search terms used to identify clinical trials were '(metastatic renal cell cancer OR renal cell carcinoma OR mccRCC OR mRCC OR RCC OR kidney cancer) AND (combination OR combined).' First-line standard of care has moved to combination therapy with ICI-ICI and TKI-ICI combinations; VEGF-mTORi is available in subsequent lines. Combining targeted treatments without validated biomarkers is imprecise, and combinations may lead to overtreatment of a subset of patients, exposing them to unnecessary toxicity. The aim of combinations must be clear: improvement in overall survival (OS) and complete response (CR). Recent data suggest a role for novel biomarker stratification rather traditional risk groups. Further combination approaches with triplets and quadruplets should be biomarker directed.