What tyrosine kinase inhibitor (TKI) can be chosen as a first-line treatment option for a patient with advanced clear cell renal cell carcinoma (RCC)?

TKI Selection for Advanced Clear Cell Renal Cell Carcinoma

For first-line treatment of advanced clear cell RCC, immune checkpoint inhibitor (ICI) combinations with TKIs are now preferred over TKI monotherapy, but if you must choose a TKI alone, select axitinib, cabozantinib, pazopanib, or sunitinib based on your patient's IMDC risk group and comorbidities. 1

First-Line TKI Options by Risk Group

For All Risk Groups (Favorable, Intermediate, and Poor Risk)

When ICI combinations are contraindicated or unavailable:

• Sunitinib 50 mg daily (4 weeks on/2 weeks off) is a category 2A option across all risk groups, with level 1A evidence demonstrating superior progression-free survival and overall survival versus interferon-alpha 1, 2

• Pazopanib 800 mg daily is a category 2A option across all risk groups, with comparable efficacy to sunitinib but superior quality of life profile (less fatigue, hand-foot syndrome, and stomatitis) 1, 3

• Axitinib 5 mg twice daily is FDA-approved as monotherapy only after failure of one prior systemic therapy, not as first-line monotherapy 4

For Intermediate and Poor Risk Specifically

• Cabozantinib is an alternative when ICI therapy cannot be given, with level 2A evidence in this population 1

• Temsirolimus (an mTOR inhibitor, not a TKI) has level 1 evidence for overall survival improvement specifically in poor-risk patients and remains an option when ICI combinations are contraindicated 2

For Favorable Risk Specifically

• Sunitinib, pazopanib, or tivozanib are potential alternatives to ICI-targeted combinations due to lack of clear superiority for ICI combinations over sunitinib in this subgroup 1

Second-Line TKI Selection

After progression on first-line ICI-based therapy:

• Cabozantinib is the preferred agent for second-line treatment with level II, B evidence 1

• Alternative TKIs include: axitinib, lenvatinib plus everolimus, pazopanib, sunitinib, and tivozanib (all level III, B) 1

After progression on first-line VEGFR TKI therapy:

• Nivolumab (if available and not contraindicated) or cabozantinib are recommended, both with level I, A evidence and associated with overall survival benefit 1

• Alternative options include axitinib, everolimus, or lenvatinib plus everolimus (all level II, B) 1

Key Distinguishing Features Between TKIs

Pazopanib vs Sunitinib

The COMPARZ trial demonstrated noninferiority between these agents, but pazopanib showed:

• Superior health-related quality of life 1, 3
• Lower incidence of fatigue, hand-foot syndrome, and stomatitis 3, 5
• Critical caveat: Pazopanib has increased hepatotoxicity risk with ALT elevation in 30% and AST elevation in 21% of patients, requiring liver function monitoring before and during treatment 1, 3

Axitinib Positioning

• Only FDA-approved as monotherapy in second-line setting after one prior systemic therapy 4
• In first-line, only approved in combination with avelumab or pembrolizumab 4
• Preferred second-line option after VEGF-targeted therapy with level IA evidence 2

Cabozantinib Advantages

• Preferred for patients with bone metastases based on expert opinion 2
• Preferred second-line agent after ICI-based first-line therapy 1
• Alternative for intermediate/poor-risk patients who cannot receive ICI therapy 1

Common Pitfalls to Avoid

• Do not use axitinib monotherapy as first-line treatment - it is only FDA-approved for second-line or in combination with ICIs for first-line 4

• Do not ignore hepatotoxicity monitoring with pazopanib - requires baseline liver function tests and regular monitoring with dose interruption/reduction based on severity 1, 3

• Do not use TKI monotherapy as first-line in intermediate/poor-risk patients when ICI combinations are available - ICI combinations have demonstrated superior overall survival 1, 2

• Do not sequence another ICI after progression on first-line ICI therapy - this is not recommended (level I, D evidence); switch to VEGFR TKI therapy instead 1

Practical Treatment Algorithm

Step 1: Determine IMDC risk group (favorable vs intermediate/poor risk) 1, 2

Step 2: Assess whether patient can receive ICI combination therapy 1

Step 3: If ICI contraindicated or unavailable:

• Favorable risk: Sunitinib or pazopanib (choose pazopanib if quality of life is priority; choose sunitinib if hepatic dysfunction present) 1, 3
• Intermediate/poor risk: Cabozantinib preferred, or sunitinib/pazopanib as alternatives 1

Step 4: For second-line after ICI progression: Cabozantinib preferred, then other TKIs not previously used 1

Step 5: For second-line after TKI progression: Nivolumab or cabozantinib (both with OS benefit) 1