What is the best treatment for metastatic Renal Cell Carcinoma (mRCC)?

From the Guidelines

The best treatment for metastatic Renal Cell Carcinoma (mRCC) is a combination approach with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) as the backbone, with lenvatinib plus pembrolizumab, axitinib plus pembrolizumab, or cabozantinib plus nivolumab being recommended for first-line treatment, irrespective of IMDC risk group, as stated in the most recent guideline 1.

Treatment Approach

The treatment approach for mRCC involves a combination of systemic therapies, with the goal of improving survival outcomes and quality of life.

• First-line treatment generally consists of ICIs either alone or in combination with TKIs.
• For favorable-risk patients, lenvatinib plus pembrolizumab or axitinib plus pembrolizumab are preferred regimens.
• For intermediate or poor-risk patients, ipilimumab plus nivolumab or pembrolizumab plus axitinib are recommended.

Dosing and Treatment Duration

Dosing typically involves:

• Pembrolizumab 200mg IV every 3 weeks with axitinib 5mg orally twice daily.
• Nivolumab 240mg IV every 2 weeks with cabozantinib 40mg orally daily.
• Ipilimumab 1mg/kg with nivolumab 3mg/kg IV every 3 weeks for 4 doses, followed by nivolumab monotherapy. Treatment continues until disease progression or unacceptable toxicity.

Second-Line Options

For patients who progress on first-line therapy, second-line options include:

• Cabozantinib.
• Lenvatinib plus everolimus.
• Other TKIs like sunitinib or pazopanib.

Surgical Approaches

Surgical approaches, including cytoreductive nephrectomy and metastasectomy, may benefit selected patients.

Treatment Selection

Treatment selection should be individualized based on patient risk category (using IMDC criteria), comorbidities, and toxicity profiles, as recommended by the European Society for Medical Oncology (ESMO) guideline 1 and the American Society of Clinical Oncology (ASCO) guideline 1. These therapies work by either enhancing the immune system's ability to recognize and attack cancer cells or by blocking growth signals in tumor cells, effectively slowing disease progression and improving survival outcomes, as supported by the European Association of Urology (EAU) guideline 1.

From the FDA Drug Label

(1.15) Renal Cell Carcinoma (RCC) in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. (1.16) in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC.

The best treatment for metastatic Renal Cell Carcinoma (mRCC) is pembrolizumab in combination with axitinib or lenvatinib for the first-line treatment of adult patients with advanced RCC, as stated in the drug label 2.

From the Research

Treatment Options for Metastatic Renal Cell Carcinoma (mRCC)

The treatment of mRCC has undergone significant changes with the introduction of immune-checkpoint inhibitors (ICI) and combination therapies. Several studies have compared the efficacy and safety of different treatment options, including:

• Ipilimumab and nivolumab as first-line treatment for intermediate to poor risk mRCC 3
• Pembrolizumab plus axitinib, nivolumab plus ipilimumab, and avelumab plus axitinib as first-line treatments for mRCC 4, 5
• Lenvatinib plus pembrolizumab and nivolumab plus cabozantinib as newly introduced ICI-TKI combinations 6

Efficacy and Safety of Treatment Options

The studies have reported the following efficacy and safety results:

• Pembrolizumab plus axitinib and nivolumab plus ipilimumab were significantly more effective than sunitinib in terms of overall survival (OS) and progression-free survival (PFS) 4
• Avelumab plus axitinib was statistically superior to sunitinib in terms of PFS 4
• Nivolumab plus ipilimumab had significantly lower rates of serious adverse events than sunitinib 4
• Pembrolizumab plus axitinib seemed to be the most efficacious first-line agent, while nivolumab plus ipilimumab had the most favorable efficacy-tolerability equilibrium 4
• Lenvatinib plus pembrolizumab demonstrated the highest likelihood of PFS and objective response rate (ORR) 6
• Nivolumab plus cabozantinib had the highest likelihood of providing the maximal OS 6

Biomarkers and Treatment Selection

The studies have also discussed the role of biomarkers in treatment selection, including:

• Programmed death ligand 1 (PD-L1) expression status, which could help guide physicians and patients to select the appropriate treatment strategy 6
• The lack of a specific and ideal biomarker to select the ideal patient for the appropriate first-line treatment 7