What is the management of stage 4 renal cell carcinoma (RCC)?

From the Guidelines

Management of stage 4 renal cell carcinoma (RCC) requires a multidisciplinary approach focused on systemic therapy, with first-line treatment typically involving targeted therapy with tyrosine kinase inhibitors (TKIs) or immunotherapy combinations, as recommended by the most recent guidelines 1. The treatment approach depends on patient factors, including performance status, comorbidities, and tumor characteristics.

• For patients with favorable risk factors, TKIs such as sunitinib (50mg daily for 4 weeks on, 2 weeks off) or pazopanib (800mg daily) remain standard.
• Intermediate or poor-risk patients benefit more from immunotherapy combinations like nivolumab (240mg every 2 weeks) plus ipilimumab (1mg/kg every 3 weeks for 4 doses) 1.
• Cytoreductive nephrectomy may be considered in select patients with good performance status and limited metastatic burden, as suggested by the Society for Immunotherapy of Cancer consensus statement 1.
• Metastasectomy can be appropriate for isolated or oligometastatic disease.
• Palliative radiation therapy helps manage painful bone metastases or brain lesions. Throughout treatment, supportive care addressing pain, nutrition, and psychological support is essential, with regular imaging every 2-3 months needed to assess treatment response, and subsequent lines of therapy introduced as resistance develops, as outlined in the ASCO guideline 1. Despite advanced disease, modern therapies have significantly improved survival outcomes for stage 4 RCC patients, with the most recent studies indicating improved overall survival and quality of life 1.

From the FDA Drug Label

1. 4 Recommended Dosage for Renal Cell Carcinoma (RCC) First-Line Treatment of Patients with Advanced RCC The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity. Previously Treated RCC The recommended dosage of LENVIMA is 18 mg in combination with 5 mg everolimus orally once daily until disease progression or until unacceptable toxicity.

For Stage 4 renal cell carcinoma management, the recommended dosage of lenvatinib is:

• 20 mg orally once daily in combination with pembrolizumab for first-line treatment of advanced RCC
• 18 mg orally once daily in combination with everolimus for previously treated RCC 2

From the Research

Stage 4 Renal Cell Carcinoma Management

• The management of stage 4 renal cell carcinoma has undergone significant changes with the introduction of targeted agents and immunotherapies 3.
• Current first-line treatment options include tyrosine kinase inhibitors (TKIs) such as cabozantinib, and immunotherapy combinations like nivolumab and ipilimumab 3, 4.
• The combination of ipilimumab and nivolumab has been shown to be effective in treating intermediate to poor risk metastatic renal cell carcinoma 4.
• Other combination therapies, such as pembrolizumab and lenvatinib, or axitinib and pembrolizumab, have also demonstrated promising results in clinical trials 5, 6.
• A systematic review and network meta-analysis found that pembrolizumab plus axitinib, and nivolumab plus ipilimumab, probably improve overall survival compared to sunitinib 7.
• The same review found that lenvatinib plus pembrolizumab may also improve overall survival, but the evidence is of low certainty 7.
• The risk of serious adverse events varies between treatments, with some combinations, such as lenvatinib plus pembrolizumab, and nivolumab plus ipilimumab, probably increasing the risk of serious adverse events compared to sunitinib 7.

Treatment Options

• Tyrosine kinase inhibitors (TKIs):
  • Cabozantinib
  • Axitinib
  • Lenvatinib
• Immunotherapy combinations:
  • Nivolumab and ipilimumab
  • Pembrolizumab and axitinib
  • Lenvatinib and pembrolizumab
• Other treatments:
  • Sunitinib
  • Pazopanib

Efficacy and Safety

• Overall survival:
  • Pembrolizumab plus axitinib: probably improves overall survival compared to sunitinib 7
  • Nivolumab plus ipilimumab: probably improves overall survival compared to sunitinib 7
  • Lenvatinib plus pembrolizumab: may improve overall survival, but evidence is of low certainty 7
• Serious adverse events:
  • Lenvatinib plus pembrolizumab: probably increases the risk of serious adverse events compared to sunitinib 7
  • Nivolumab plus ipilimumab: probably increases the risk of serious adverse events compared to sunitinib 7
  • Pembrolizumab plus axitinib: probably increases the risk of serious adverse events compared to sunitinib 7