What is the first line therapy for a patient with widespread metastatic renal cell carcinoma (RCC), including metastasis to the brain?

First-Line Therapy for Widespread Metastatic Kidney Cancer Including Brain Metastases

For patients with widespread metastatic renal cell carcinoma including brain metastases, initiate combination immune checkpoint inhibitor therapy with either nivolumab plus ipilimumab (for intermediate/poor-risk patients) or an ICI plus VEGFR-TKI combination (cabozantinib plus nivolumab, axitinib plus pembrolizumab, or lenvatinib plus pembrolizumab), while simultaneously coordinating brain-directed local therapy with radiation oncology. 1, 2

Critical First Step: Address Brain Metastases Immediately

• Brain metastases require urgent brain-directed local therapy with radiation therapy and/or surgery as an essential component of management 1
• Initiate corticosteroids immediately for temporary relief of cerebral symptoms 2
• For patients with a single unresectable brain metastasis and good prognosis, stereotactic radiosurgery (SRS) with or without whole-brain radiotherapy should be considered 2, 3
• For multiple brain metastases, whole-brain radiotherapy 20-30 Gy in 4-10 fractions is recommended for effective symptom control 2, 3

Risk Stratification Determines Systemic Therapy Choice

Before selecting systemic therapy, stratify patients using the International Metastatic RCC Database Consortium (IMDC) criteria into favorable (0 risk factors), intermediate (1-2 risk factors), or poor (3+ risk factors) risk groups 1. Risk factors include: poor performance status, time from diagnosis to treatment <1 year, low hemoglobin, elevated calcium, elevated neutrophils, and elevated platelets 1.

Preferred First-Line Systemic Therapy Options

For Intermediate and Poor-Risk Patients (Most Common with Brain Metastases):

• Nivolumab plus ipilimumab is the recommended first-line treatment for intermediate and poor-risk patients 2, 4, 1

  • This combination demonstrated superior overall survival versus sunitinib with a 9.4% complete response rate 1
  • Level I, A evidence with ESMO-MCBS score of 3 2
  • CheckMate 920 study specifically evaluated this combination in 28 patients with brain metastases, showing acceptable safety (54% grade 3-4 treatment-related adverse events) and 32% overall response rate with median PFS of 9.0 months 2

• Alternative ICI-based combinations are also strongly recommended:

  • Cabozantinib 40 mg daily plus nivolumab 240 mg IV every 2 weeks 1, 5
  • Axitinib plus pembrolizumab 1, 6
  • Lenvatinib plus pembrolizumab 1

For Favorable-Risk Patients:

• VEGFR TKI monotherapy remains acceptable: sunitinib, pazopanib, or cabozantinib 1
• ICI-based combinations may also be used, though data are less robust in this subgroup 1

Special Considerations for Brain Metastases

• The presence of brain metastases does not preclude use of ICI-based combination therapy 1
• Most major trials (CheckMate 214, CheckMate 9ER, KEYNOTE-426, CLEAR) excluded patients with active or symptomatic brain metastases, limiting direct evidence 2
• The GETUG-AFU 26 NIVOREN study showed nivolumab monotherapy had only 12% intracranial response rate in untreated brain metastases, with 72% requiring subsequent brain-directed local therapy 2
• Prior focal brain therapy (surgery or radiation) significantly decreases risk of intracranial progression (HR 0.49; 95% CI 0.26-0.92) 2

Critical Pitfall to Avoid

Do not delay brain-directed local therapy while initiating systemic therapy. The development of brain metastases may be an early sign of systemic therapy failure 7, and radiation therapy is essential for intracranial disease control 1, 3. Coordinate care with radiation oncology from the outset.

Additional Management Considerations

• Cytoreductive nephrectomy is NOT recommended for intermediate and poor-risk patients with widespread metastatic disease requiring immediate systemic therapy 2, 4, 1
• For patients with bone metastases (common in widespread disease), consider bone-directed therapy with zoledronic acid or denosumab to reduce skeletal-related events 1
• Cabozantinib-containing regimens may be particularly beneficial for patients with bone metastases 1

Treatment Duration and Monitoring

• Continue systemic therapy until disease progression or unacceptable toxicity 5
• Monitor with CT scans every 2-4 months during systemic therapy 2, 4
• For brain metastases, coordinate imaging surveillance with radiation oncology to assess intracranial disease control

Evidence Quality Note

The recommendation for ICI-based combination therapy in intermediate/poor-risk patients is based on Level I, A evidence from randomized controlled trials 2, 1. However, specific data for patients with brain metastases comes from smaller prospective studies and expanded access programs 2, making the integration of aggressive brain-directed local therapy particularly critical in this population.