What is the role of neoadjuvant immunotherapy (e.g., PD‑1 inhibitors such as pembrolizumab or nivolumab) in the management of oral cavity squamous cell carcinoma?

Neoadjuvant Immunotherapy in Oral Cavity Squamous Cell Carcinoma

Neoadjuvant immunotherapy is NOT currently recommended as standard treatment for oral cavity squamous cell carcinoma outside of clinical trials. The established standard of care remains primary surgical resection followed by risk-adapted adjuvant therapy (radiation or chemoradiation) for locally advanced disease 1.

Current Standard of Care

For oral cavity squamous cell carcinoma, the evidence-based treatment algorithm is:

• T3/T4 oral cavity cancers: Primary surgical treatment followed by RT or CRT is the preferred approach 1
• Locally advanced disease: Standard options are surgery plus adjuvant (C)RT or primary concomitant CRT 1
• Early disease: Single-modality treatment (surgery alone) when feasible 1

Induction chemotherapy is explicitly NOT routinely recommended outside of larynx preservation protocols 1.

Role of Immunotherapy: Approved Indications Only

Current FDA and guideline-supported uses of PD-1 inhibitors in head and neck cancer are restricted to:

Recurrent/Metastatic Disease

• Pembrolizumab + platinum/5-FU: First-line for PD-L1 expressing tumors (CPS ≥1) 1
• Pembrolizumab monotherapy: First-line for PD-L1 CPS ≥1 tumors 1
• Nivolumab: For progression within 6 months of platinum therapy 1

These are the only validated, guideline-endorsed applications 1, 2, 3.

Neoadjuvant Immunotherapy: Investigational Status

While emerging research shows promise, neoadjuvant immunotherapy remains experimental:

Evidence from Clinical Trials

Most recent high-quality data 4 from 2025 demonstrates:

• Camrelizumab + TPF chemotherapy achieved 76.4% major pathological response (MPR) in locally advanced OSCC
• 2-year event-free survival of 91.2% with immunochemotherapy
• Camrelizumab alone showed only 14.7% MPR and 52.9% EFS at 2 years

Earlier phase 2 trials 5, 6 showed:

• Nivolumab ± ipilimumab: 50-53% volumetric response, 54-73% pathologic response
• No surgical delays, acceptable safety profile
• 1-year progression-free survival 85%

Critical Limitations

These are all phase 2 trials without regulatory approval or guideline endorsement 7. The Society for Immunotherapy of Cancer consensus 7 acknowledges multiple ongoing neoadjuvant trials but provides no recommendation for routine use.

Clinical Decision Algorithm

For Resectable Oral Cavity Cancer

1. Proceed directly to surgery followed by risk-adapted adjuvant therapy 1
2. Consider clinical trial enrollment if available 7
3. Do NOT delay definitive surgery for neoadjuvant immunotherapy outside trials

For Borderline Resectable Disease

Recent data 8 suggests low-dose nivolumab with chemotherapy and oral metronomic therapy achieved 90.3% R0 resection conversion, but this remains investigational. Standard approach:

1. Multidisciplinary tumor board evaluation
2. Consider neoadjuvant chemotherapy (though not routinely recommended per guidelines 1)
3. Clinical trial enrollment preferred over off-label immunotherapy

For Unresectable/Metastatic Disease

1. Test PD-L1 expression (FDA-approved IHC test) 1
2. If PD-L1 CPS ≥1: Pembrolizumab + platinum/5-FU or pembrolizumab monotherapy 1, 2
3. If PD-L1 negative: Platinum/5-FU/cetuximab 1

Common Pitfalls to Avoid

• Do not use neoadjuvant immunotherapy as standard care - it lacks regulatory approval and guideline support for oral cavity cancer
• Do not delay surgery - primary surgical resection remains the cornerstone for resectable disease 1
• Do not extrapolate from recurrent/metastatic data - neoadjuvant efficacy requires separate validation
• Monitor for immune-related adverse events if immunotherapy is used - bilateral ophthalmoplegia and other severe toxicities have been reported 9

Future Considerations

Multiple phase 2 trials are ongoing 7, investigating combinations of PD-1 inhibitors with chemotherapy, radiation, and other agents. Until phase 3 data demonstrates survival benefit and regulatory approval is obtained, neoadjuvant immunotherapy should be restricted to clinical trials 7.

The 2020 EHNS-ESMO-ESTRO guidelines 1 make no mention of neoadjuvant immunotherapy for oral cavity cancer, reinforcing that this approach remains investigational despite promising early signals 4, 5, 6, 8, 10.