What is the role of Toripalimab (toripalimab) in treating advanced esophageal squamous cell carcinoma (ESCC)?

Role of Toripalimab in Advanced Esophageal Squamous Cell Carcinoma (ESCC)

Toripalimab plus chemotherapy is an effective first-line treatment option for advanced ESCC, demonstrating significant improvement in overall survival and progression-free survival compared to chemotherapy alone. 1

First-line Treatment Options for Advanced ESCC

Current Standard Recommendations

The ESMO Clinical Practice Guidelines (2022) recommend several first-line treatment options for advanced ESCC:

1. Platinum-fluoropyrimidine chemotherapy

   • Standard first-line treatment for advanced untreated ESCC [II, A] 2
   • Dose-reduced oxaliplatin-capecitabine for patients unsuitable for full-dose chemotherapy [I, A] 2

2. Immune checkpoint inhibitors (ICIs) plus chemotherapy

   • Pembrolizumab plus chemotherapy (greatest benefit in PD-L1 CPS ≥10) [I, A] 2
   • Nivolumab plus chemotherapy (recommended for tumors with PD-L1 TPS ≥1%) [I, A] 2
   • Nivolumab plus ipilimumab (with caution due to lower response rate and risk of early progression) [I, B] 2

Evidence for Toripalimab in Advanced ESCC

Toripalimab, a PD-1 inhibitor, has shown promising results in advanced ESCC:

• The JUPITER-06 phase 3 trial (514 patients) demonstrated:

  • Significant improvement in progression-free survival (HR = 0.58; 95% CI, 0.46-0.74; p < 0.0001) 1
  • Significant improvement in overall survival (HR = 0.58; 95% CI, 0.43-0.78; p = 0.0004) 1
  • Manageable safety profile with similar incidence of grade ≥3 adverse events compared to chemotherapy alone 1

• A network meta-analysis comparing different PD-1 inhibitors combined with chemotherapy found:

  • Toripalimab plus chemotherapy achieved the best overall survival benefit (HR: 0.58,95% CI: 0.43-0.78) compared to other immunotherapy combinations 3

Second-line Treatment Options for Advanced ESCC

For patients who progress after first-line therapy, the following options are recommended:

1. Nivolumab monotherapy

   • Recommended for ESCC previously treated with platinum-fluoropyrimidine chemotherapy [I, A] 2
   • Based on ATTRACTION-3 trial showing improved OS compared to chemotherapy (HR 0.77,95% CI 0.62-0.96) 2

2. Pembrolizumab monotherapy

   • Option for previously treated SCC with PD-L1 CPS ≥10 who have not received first-line ICIs [I, A] 2
   • Based on KEYNOTE-181 trial 2

3. Chemotherapy with taxane or irinotecan

   • For fit patients previously treated with platinum-fluoropyrimidine and/or ICIs [II, B] 2

Emerging Applications of Toripalimab

Locally Advanced ESCC

• A phase 2 trial (EC-CRT-001) combining toripalimab with definitive chemoradiotherapy in unresectable locally advanced ESCC showed:
  • Complete response rate of 62% (95% CI 46-76) 4
  • 1-year overall survival of 78.4% (95% CI 66.9-92.0) 4
  • Acceptable toxicity profile, though lymphopenia was common (86%) 4

Toripalimab with Chemoradiotherapy

• A recent phase 2 trial combining toripalimab with chemotherapy and radiotherapy for treatment-naive advanced ESCC showed:
  • Median progression-free survival of 9.8 months 5
  • Objective response rate of 45.5% 5
  • 1-year overall survival rate of 69.7% 5
  • Manageable safety profile, though lymphopenia was common (82%) 5

Practical Considerations and Caveats

Patient Selection

• PD-L1 expression testing is important for optimal patient selection
• The ASCO guideline notes that data from toripalimab trials (JUPITER-06) support its use, though it is not yet FDA-approved 2

Safety Considerations

• Most common severe adverse events with toripalimab plus chemotherapy are similar to other PD-1 inhibitors
• Immune-mediated adverse events require monitoring and prompt management
• When combined with radiotherapy, lymphopenia is very common (>80%) 4, 5

Treatment Algorithm for Advanced ESCC

1. First-line therapy:

   • For PD-L1 positive patients: Consider PD-1 inhibitor (including toripalimab where approved) plus platinum-fluoropyrimidine chemotherapy
   • For PD-L1 negative patients: Standard platinum-fluoropyrimidine chemotherapy
   • For frail patients: Consider dose-reduced chemotherapy regimens

2. Second-line therapy:

   • If no prior immunotherapy: Nivolumab monotherapy or pembrolizumab (if PD-L1 CPS ≥10)
   • If prior immunotherapy: Taxane or irinotecan-based chemotherapy

Conclusion

Toripalimab represents an important addition to the treatment landscape for advanced ESCC, with phase 3 data showing significant survival benefits when combined with chemotherapy. While not yet included in all major guidelines, the evidence supports its efficacy as a first-line treatment option for advanced ESCC, with a safety profile comparable to other PD-1 inhibitors.