What is the first-line treatment choice for a patient with advanced clear cell renal cell carcinoma based on risk scores?

First-Line Treatment Selection for Advanced Clear Cell RCC Based on Risk Scores

For intermediate- and poor-risk patients, immune checkpoint inhibitor (ICI) combinations—specifically nivolumab/cabozantinib, pembrolizumab/axitinib, or pembrolizumab/lenvatinib—are the preferred first-line treatments, while favorable-risk patients have more flexibility with either ICI combinations or single-agent VEGFR TKIs like sunitinib or pazopanib. 1

Intermediate- and Poor-Risk Disease (IMDC)

Preferred regimens (Category 1 or highest level evidence):

• Nivolumab/ipilimumab is a Category 1 preferred option with demonstrated OS benefit (HR 0.70) and should be strongly considered as first-line therapy 1
• Nivolumab/cabozantinib demonstrates superior PFS (16.6 vs 8.4 months) and OS (49.5 vs 35.5 months) compared to sunitinib, with benefits maintained across all IMDC risk groups 1, 2
• Pembrolizumab/axitinib and pembrolizumab/lenvatinib are both recommended with Level 1b evidence and ESMO-MCBS scores of 4, indicating substantial clinical benefit 1

Alternative when ICIs are contraindicated:

• Cabozantinib monotherapy is a Category 2A preferred option for intermediate/poor-risk patients, showing significantly increased PFS and higher ORR versus sunitinib in the CABOSUN trial 1
• Sunitinib or pazopanib remain acceptable alternatives when ICI therapy cannot be administered 1

Favorable-Risk Disease (IMDC)

The treatment landscape differs substantially for favorable-risk patients:

• ICI combinations remain options (nivolumab/cabozantinib, pembrolizumab/axitinib, pembrolizumab/lenvatinib) with Level 1b evidence across all risk groups 1
• Single-agent VEGFR TKIs may be preferred due to lack of clear OS superiority for ICI combinations in this subgroup 1
  • Sunitinib (Category 2A, all risk groups) demonstrated superior PFS and OS trend versus interferon-alpha 1
  • Pazopanib (Category 2A, all risk groups) shows comparable efficacy to sunitinib but with superior quality-of-life profile, particularly less fatigue and hand-foot syndrome 1, 3
  • Tivozanib is listed as a potential alternative 1

Important caveat for favorable-risk patients: Ipilimumab/nivolumab showed inferior outcomes in favorable-risk patients compared to sunitinib in exploratory CheckMate 214 analysis (lower ORR and median PFS), though it remains a Category 2A option with FDA approval limited to intermediate/poor-risk disease 1

Critical Decision Points

When selecting between ICI combinations:

• No single PD-1 inhibitor/VEGFR TKI combination is preferred over others; indirect cross-trial comparisons are not recommended 1
• Consider patient-specific factors including comorbidities, bone metastases (favor cabozantinib), and tolerance for immune-related adverse events 4

Axitinib/avelumab is NOT recommended as it failed to demonstrate OS benefit compared to sunitinib despite PFS improvement, earning an ESMO-MCBS score of only 3 1

Active surveillance is a Category 2A option for select asymptomatic favorable-risk patients, with median time to systemic therapy of 14.9 months in phase II data 1

Safety Monitoring Requirements

• Pazopanib: Monitor liver function before and during treatment due to 30% grade 3 ALT elevation and 21% AST elevation rates 1
• ICI combinations: 35% of patients with immune-mediated adverse events required high-dose steroids; treatment-related discontinuation occurred in 22% with ipilimumab/nivolumab 1
• Nivolumab/cabozantinib: Grade ≥3 treatment-related adverse events occurred in 67% versus 55% with sunitinib 2