Over the past decade, we have witnessed a paradigm shift in the first-line treatment of patients with advanced or metastatic clear cell renal cell carcinoma (RCC). Nowadays, the preferred first-line treatment for these patients consists of a combination of an immune checkpoint inhibitor (ICI) with a tyrosine kinase inhibitor, or dual ICI therapy. With a minimal follow-up of three years, the pivotal CheckMate 9ER trial demonstrated the superior survival and response benefits of combination therapy with cabozantinib and nivolumab over sunitinib as first-line therapy for advanced RCC patients. However, effective management strategies to deal with potential adverse events are key to maintain tolerability with cabozantinib and nivolumab treatment.