Neoadjuvant Immunotherapy in Head and Neck Cancer
Current evidence does not support routine use of neoadjuvant immunotherapy in head and neck squamous cell carcinoma outside of clinical trials, as no FDA-approved neoadjuvant immunotherapy regimens exist and guideline recommendations focus exclusively on recurrent/metastatic disease. 1, 2
Current Guideline-Based Indications for Immunotherapy
The 2023 ASCO guidelines establish clear recommendations for immunotherapy in HNSCC, but these apply only to recurrent or metastatic disease, not neoadjuvant settings 1:
First-Line Recurrent/Metastatic Disease
- Pembrolizumab combined with platinum and 5-FU should be offered for patients with PD-L1 CPS ≥1 (strong recommendation, high-quality evidence) 1, 3
- Pembrolizumab monotherapy may be offered for patients with CPS ≥20 who do not require rapid tumor reduction, achieving median OS of 14.9 months versus 10.7 months with cetuximab-chemotherapy (HR 0.61, P=0.0007) 1, 3
- For CPS <1, pembrolizumab plus platinum and 5-FU may be offered (moderate evidence quality) 1
Platinum-Refractory Disease
- Pembrolizumab or nivolumab as single agents should be offered regardless of PD-L1 status for patients progressing within 6 months of platinum therapy (strong recommendation, high-quality evidence) 1, 3
Neoadjuvant Setting: Investigational Only
The neoadjuvant use of immunotherapy remains experimental and should only be administered within clinical trials. 1, 4 The 2020 EHNS-ESMO-ESTRO guidelines explicitly state that treatment de-escalation strategies, including neoadjuvant immunotherapy approaches, are investigational 1.
Active Phase 3 Trials (All Cisplatin-Eligible Only)
Three ongoing trials are evaluating neoadjuvant immunotherapy, but all restrict enrollment to cisplatin-eligible patients 1:
- KEYNOTE-689 (NCT03765918): Neoadjuvant pembrolizumab plus standard adjuvant therapy versus standard adjuvant therapy alone, with primary endpoints of event-free survival and major pathological response (estimated completion July 2025) 1
- REDUCTION-I (NCT05582265): Neoadjuvant tislelizumab plus cisplatin and nab-paclitaxel followed by surgery and adjuvant therapy (estimated completion October 2028) 1
- Illuminate-2 (NCT05125055): Neoadjuvant toripalimab plus nab-paclitaxel and cisplatin versus docetaxel, cisplatin, and 5-FU (estimated completion September 2023) 1
Early Phase Data: Promising but Insufficient
Phase II data demonstrate feasibility and safety of neoadjuvant pembrolizumab 4, 5:
- One-year disease-free survival of 97% in intermediate-risk patients (95% CI 71%-90%) and 66% in high-risk patients (95% CI 55%-84%) 5
- Major pathological response rate of 66.7% with pembrolizumab plus cetuximab and chemotherapy in a small retrospective series (n=21) 6
- However, these are single-arm studies without randomized comparisons to standard surgery followed by adjuvant therapy 5
Critical Pitfalls to Avoid
Do Not Use Neoadjuvant Immunotherapy Outside Trials
Standard treatment for resectable locally advanced HNSCC remains surgery followed by risk-adapted adjuvant therapy 1, 7:
- Postoperative radiotherapy for pT3-4 tumors, positive margins (R1/R2), perineural invasion, lymphatic invasion, or >1 positive node 1
- Postoperative chemoradiotherapy with cisplatin 100 mg/m² every 3 weeks for R1 resection or extracapsular extension (strong recommendation) 1, 7
Cisplatin-Ineligible Patients Have No Established Neoadjuvant Options
For cisplatin-ineligible patients with resectable disease, radiotherapy alone remains the reasonable standard of care in the adjuvant setting, as no data support neoadjuvant immunotherapy efficacy in this population 1. All active neoadjuvant trials exclude cisplatin-ineligible patients 1.
FDA Approval Applies Only to Recurrent/Metastatic Disease
The FDA-approved pembrolizumab indications for HNSCC explicitly state: "in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma" 2. No neoadjuvant indication exists.
When Immunotherapy Is Appropriate
Reserve immunotherapy for patients with:
- Recurrent or metastatic disease with PD-L1 CPS ≥1 (first-line pembrolizumab ± chemotherapy) 1, 3
- Platinum-refractory recurrent/metastatic disease regardless of PD-L1 status (pembrolizumab or nivolumab monotherapy) 1, 3
- Enrollment in approved clinical trials evaluating neoadjuvant approaches 1, 4
For resectable locally advanced disease, proceed with standard surgery followed by risk-adapted adjuvant (chemo)radiotherapy 1, 7. Neoadjuvant immunotherapy should not delay definitive surgical management outside of protocol-based care.