Review Article

Recent progress in the treatment of locally advanced head and neck squamous cell carcinomas

Department of Radiation Oncology, Institute Gustave-Roussy, 114 Rue Edouard Vaillant, Villejuif 94805, France

^* Corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it.

Received: 17 June 2025
Accepted: 17 June 2025

Abstract

Purpose: Concurrent chemoradiotherapy (CRT) has become the standard of care (SOC) for locally advanced (LA) head and neck squamous cell carcinomas (HNSCC) since the French meta-analysis MACH-NC. This review synthesizes recent clinical research progress in LA-HNSCC, focusing on findings from Institut Gustave-Roussy and the French Head and Neck Oncology and Radiotherapy Group (GORTEC). Recent findings: Recent phase 3 trials have explored modifications to CRT protocols with mixed results. The GORTEC 99-02 phase 3 trial demonstrated no additional benefit from combining accelerated radiotherapy (RT) with CRT. Similarly, induction chemotherapy with taxane-platinum-5FU (TPF) followed by RT with cetuximab did not improve outcomes compared to CRT alone in patients with LA-HNSCC (>N2a) in the GORTEC 2007-02 trial. However, in patients with N0-N2a HNSCC, concurrent chemotherapy plus cetuximab-RT outperformed cetuximab-RT in the GORTEC 2007-01 phase 3 trial. Another targeted therapy, the IAP antagonist xevinapant, combined with cisplatin-RT, exhibited promising outcomes in the randomized phase 2 trial Debio1143-201 (GORTEC 2015-03). However, the subsequent phase 3 Trilynx trial failed to confirm xevinapant’s benefit when added to CRT in LA-HNSCC. Immunotherapy integration has been extensively studied. Since 2015, several phase 2/3 trials, including GORTEC 2015-01 (PembroRad), GORTEC 2017-01 (REACH), KEYNOTE-412, and GORTEC 2018-02 (REWRITe), have evaluated immune checkpoint inhibitors (ICIs) combined with RT/CRT in cisplatin-eligible and ineligible patients with unresectable LA-HNSCC. These trials found no clear benefit from concurrent or adjuvant ICI use alongside RT/CRT. In contrast, the KEYNOTE-689 trial, which investigated perioperative pembrolizumab with standard surgery and postoperative RT/CRT for resectable LA-HNSCC, and the GORTEC 2018-01 (NIVOPOSTOP) phase 3 trial, which assessed post-operative nivolumab with cisplatin-RT in resected high-risk LA-HNSCC, have shown preliminary encouraging results with full data expected soon. Summary: Platinum-based CRT remains the SOC for LA-HNSCC. Emerging evidence suggests that perioperative pembrolizumab or postoperative nivolumab may redefine the SOC for resectable or resected HNSCC. Novel combinations, including molecular targeted therapies and ICIs with RT/CRT, require further investigation to establish their efficacy.