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From cytokines, interleukin-2 and interferon-\u03b1 to tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, during the last decade, combinations of immune checkpoint inhibitors have taken over first-line treatment of mccRCC. These combinations are approved based on results from large phase III clinical trials, all of which used sunitinib as the comparator. These trials include CheckMate214 (ipilimumab plus nivolumab), KEYNOTE 426 (pembrolizumab plus axitinib), JAVELIN Renal 101 (avelumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), and the CLEAR study (lenvatinib and pembrolizumab). Results from these studies constitute milestones for newer therapeutic approaches in mccRCC. The broadening spectrum of treatment options for patients with mccRCC with multiple first-line options currently available also means that treating physicians will need to consider each option carefully, balance clinical factors, financial considerations, and weigh toxicity profiles of each drug before deciding the optimal treatment regimen for each individual patient. We describe each frontline treatment option in detail through this review to aid the decision-making process.<\/jats:p>","DOI":"10.1093\/oncolo\/oyab056","type":"journal-article","created":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T05:00:52Z","timestamp":1641013252000},"page":"125-134","source":"Crossref","is-referenced-by-count":29,"title":["First-Line Treatments for Metastatic Clear Cell Renal Cell Carcinoma: An Ever-Enlarging Landscape"],"prefix":"10.1093","volume":"27","author":[{"given":"Shuchi","family":"Gulati","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Labaki","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia Sofia","family":"Karachaliou","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA"},{"name":"Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni K","family":"Choueiri","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA"},{"name":"Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA"},{"name":"Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, 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