What is the role of immunotherapy, including checkpoint inhibitors like pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in the treatment of nasopharyngeal cancer?

Role of Immunotherapy in Nasopharyngeal Cancer

Immunotherapy with PD-1 inhibitors combined with gemcitabine and cisplatin should be offered as first-line treatment for patients with recurrent or metastatic nasopharyngeal cancer, with toripalimab, camrelizumab, or tislelizumab being the preferred agents. 1

First-Line Treatment for Recurrent/Metastatic Disease

Preferred Regimens

• First-line therapy: PD-1 inhibitor + gemcitabine + cisplatin
  • Preferred agents: toripalimab, camrelizumab, or tislelizumab 1
  • Alternative agents (if preferred agents unavailable): pembrolizumab or nivolumab with gemcitabine and cisplatin 1

This recommendation is based on high-quality evidence showing significant benefits in terms of mortality and morbidity outcomes, with a strong recommendation strength according to the ASCO guidelines 1.

Alternative First-Line Option

• For patients who cannot receive immunotherapy: Cisplatin + gemcitabine is the standard first-line chemotherapy choice 1

Second-Line Treatment Options

For patients who progress after platinum-based therapy:

• PD-1 inhibitors (nivolumab, pembrolizumab, camrelizumab) may be offered as monotherapy 1
  • Response rates: camrelizumab (34.1%), pembrolizumab (26.3%), nivolumab (19.0%) 2
  • Strength of recommendation: Weak (based on low-quality evidence) 1

Biomarker Testing

• PD-L1 testing: PD-L1 combined positive score (CPS) ≥1 correlates with better response to PD-1 inhibitors
  • Pooled objective response rate: 28.4% for PD-L1-positive vs. 17.4% for PD-L1-negative patients 2
• TMB testing: May be performed when CPS is not available 1
  • TMB ≥10 should be interpreted as high and correlates with clinical benefit to PD-1 inhibitors 1

Special Clinical Scenarios

Oligometastatic Disease

• For patients with limited metastatic burden:
  • Consider aggressive treatment including chemotherapy, surgery, or definitive radiation therapy to metastatic sites 1
  • Radiation therapy is safe to give concurrently with immunotherapy for palliation or local control 1
  • In newly diagnosed metastatic NPC, adding locoregional RT to systemic therapy improves locoregional control and overall survival 1

Locally Recurrent Disease

• For local recurrences not invading the carotid artery or extending intracranially:
  • Consider nasopharyngectomy (especially for rT1-rT3) 1
  • Endoscopic nasopharyngectomy may be superior to IMRT for selected cases 1
  • For lymphatic recurrences in the neck: neck dissection is recommended 1

Safety Considerations

• Toxicity profiles of PD-1 inhibitors:
  • Nivolumab and pembrolizumab have shown optimal safety regarding overall adverse events 2
  • Camrelizumab and nivolumab demonstrated better safety profiles regarding grade 3-5 adverse events 2
  • Combination therapy (immunotherapy + chemotherapy) has higher rates of adverse events than monotherapy 2

Rationale for Immunotherapy in NPC

Nasopharyngeal carcinoma is particularly suitable for immunotherapy due to:

1. Strong association with Epstein-Barr virus (EBV) infection 3, 4
2. Dense lymphocytic infiltration in tumor stroma 5
3. Positive PD-L1 expression in tumor cells 5

Clinical Pearls and Pitfalls

• Patient selection is crucial for re-irradiation due to high incidence of major late complications, even with modern RT techniques 1
• Pre-treatment circulating EBV DNA is a prognostic factor for distant metastasis in candidates for surgery and for patients treated with first-line chemotherapy 1
• Combination therapy (immunotherapy + chemotherapy) achieves dramatically higher response rates than chemotherapy alone (90.9% vs. 64.1%) but with increased toxicity 2
• For patients with high burden of distant metastases (more than two distant sites, mainly visceral involvement), systemic treatment should be prioritized over locoregional treatment unless symptoms occur 1

By incorporating immunotherapy into treatment algorithms for nasopharyngeal cancer, particularly for recurrent or metastatic disease, clinicians can significantly improve patient outcomes in terms of response rates and potentially survival.