What is the role of Toripalimab (generic name not specified, assuming it refers to the monoclonal antibody) in the treatment of Renal Cell Carcinoma (RCC)?

Toripalimab in Renal Cell Carcinoma (RCC)

Toripalimab plus axitinib is an emerging combination therapy for intermediate/poor-risk advanced RCC, showing significant improvement in progression-free survival compared to sunitinib, but is not yet FDA-approved or included in major clinical guidelines as a standard treatment option.

Current Status of Toripalimab in RCC Treatment

Toripalimab is a PD-1 inhibitor that has been investigated for use in RCC, particularly in combination with axitinib (a VEGFR-targeted therapy). While showing promising results in recent clinical trials, it is important to understand its current position in the treatment landscape:

• Toripalimab is not mentioned in the Society for Immunotherapy of Cancer (SITC) consensus guidelines from 2016 1 or 2019 1 for RCC treatment
• It is not included in the FDA-approved immunotherapy options for RCC as of 2024 2
• The 2024 ESMO guidelines mention toripalimab plus axitinib as a potential option for intermediate and poor-risk disease, but note that OS data are still immature 1

Evidence for Toripalimab in RCC

The most recent and highest quality evidence for toripalimab in RCC comes from the phase III RENOTORCH study:

• RENOTORCH trial (2024): Compared toripalimab plus axitinib vs. sunitinib in first-line treatment of intermediate/poor-risk advanced RCC 3:
  • Significantly reduced risk of disease progression or death by 35% (HR 0.65)
  • Median PFS: 18.0 months (toripalimab-axitinib) vs. 9.8 months (sunitinib)
  • ORR: 56.7% (toripalimab-axitinib) vs. 30.8% (sunitinib)
  • Favorable OS trend (HR 0.61) but data still immature
  • Treatment-related grade ≥3 adverse events: 61.5% (toripalimab-axitinib) vs. 58.6% (sunitinib)

Additional supporting evidence includes:

• Neoadjuvant setting: A phase II trial of neoadjuvant toripalimab plus axitinib in locally advanced clear cell RCC showed an ORR of 45% with tumor shrinkage in 95% of patients 4
• Second-line setting: A retrospective multicenter study showed efficacy of toripalimab plus axitinib as second-line therapy after VEGFR-TKI failure, with ORR of 31.6% and median PFS of 11.7 months 5

Current Standard of Care for RCC

According to current guidelines, the standard first-line treatments for advanced RCC include:

1. For intermediate/poor-risk disease:

   • Ipilimumab plus nivolumab 1
   • PD-1 inhibitor plus VEGFR-targeted therapy combinations:
     • Pembrolizumab plus axitinib
     • Nivolumab plus cabozantinib
     • Lenvatinib plus pembrolizumab 1

2. For favorable-risk disease:

   • PD-1 inhibitor plus VEGFR-targeted therapy combinations
   • Ipilimumab plus nivolumab (with weaker recommendation) 1

Clinical Implications and Recommendations

Based on the most recent evidence:

1. For intermediate/poor-risk advanced RCC:

   • Toripalimab plus axitinib shows promising efficacy with significant PFS benefit compared to sunitinib
   • However, until FDA approval and stronger inclusion in guidelines, the established combinations (nivolumab-ipilimumab, pembrolizumab-axitinib, nivolumab-cabozantinib, lenvatinib-pembrolizumab) remain the standard of care

2. Safety considerations:

   • The safety profile of toripalimab plus axitinib appears manageable and comparable to other ICI-TKI combinations
   • Grade ≥3 adverse events occurred in 61.5% of patients on toripalimab-axitinib 3

3. Future directions:

   • Mature OS data from the RENOTORCH trial will be important to determine the long-term benefit
   • Additional studies comparing toripalimab-axitinib to other ICI-TKI combinations would be valuable

Practical Guidance

For clinicians considering treatment options for patients with advanced RCC:

• Use established FDA-approved combinations as first-line therapy
• Consider toripalimab plus axitinib in the context of clinical trials or in regions where it may be approved
• Monitor for emerging data and potential regulatory approvals that may change the treatment landscape

Caveats and Limitations

• The evidence for toripalimab in RCC is still evolving, with limited long-term survival data
• Cross-trial comparisons between toripalimab-axitinib and other ICI-TKI combinations should be avoided due to differences in trial design and patient populations
• Patient selection factors that might predict better response to toripalimab versus other ICIs are not yet established