A 58-year-old man with stage IV renal cell carcinoma (clear cell type) with pulmonary and bone metastases presents for systemic therapy. He has no prior systemic treatment. What is the drug of choice for first-line treatment?

Explanation

## First-Line Systemic Therapy for Metastatic RCC **Key Point:** Sunitinib is the preferred first-line tyrosine kinase inhibitor (TKI) for treatment-naïve patients with metastatic clear cell renal cell carcinoma. ### Mechanism of Action Sunitinib is a multi-targeted TKI that inhibits: - VEGFR (vascular endothelial growth factor receptor) - PDGFR (platelet-derived growth factor receptor) - c-KIT - RET These targets are critical in RCC pathogenesis, particularly in clear cell histology where VHL inactivation leads to HIF-α accumulation and VEGF overexpression. ### Evidence Base | Feature | Sunitinib | Sorafenib | Pazopanib | |---------|-----------|-----------|----------| | **First-line approval** | Yes (FDA & NCCN) | Second-line | Yes (alternative) | | **Median PFS** | 11 months | 5.5 months | 9.2 months | | **Median OS** | 26.4 months | 17.8 months | 29.3 months | | **Standard dosing** | 50 mg daily (4 weeks on, 2 weeks off) | 400 mg BD daily | 800 mg daily | | **Key advantage** | Superior PFS in treatment-naïve | Better for sorafenib-experienced | Oral bioavailability | **High-Yield:** Sunitinib is the **gold standard first-line TKI** for metastatic clear cell RCC based on the pivotal SUTENT trial (2007), which demonstrated superior progression-free survival compared to interferon-alpha. ### Clinical Pearl Sunitinib's intermittent dosing schedule (4 weeks on, 2 weeks off) allows for dose recovery and tolerability management—a practical advantage in real-world practice. ### Toxicity Profile - Hypertension (30–40%) - Hand-foot skin reaction - Fatigue - Diarrhea - Cardiac dysfunction (rare but serious) **Tip:** Always monitor BP and cardiac function (echocardiography baseline) before starting sunitinib.