Efficacy and safety of toripalimab in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): a phase 1b/2 study

Signal Transduction and Targeted Therapy ARTICLE www.nature.com/sigtrans OPEN Efficacy and safety of toripalimab in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): a phase 1b/ 2 study 1234567890();,: Ye Guo 1 ✉, Zhendong Li2, Liqiong Xue1, Jinguan Lin3, Song Qu4, Chuanzheng Sun5, Meiyu Fang6, Youhua Zhu7, Jingfeng Zong8, Wantao Chen9, Guochun Cao10, Jin Wu11, Minghua Ge12, Zhiming Li13, Siyang Wang14, Xudong Wang15, Hao Jiang16, Desheng Hu17, Liangfang Shen18, Yumei Wei19, Chuan Jin20, Hong Zhang21, Xiaoming Huang22, Yan Sun23, Jianhua Shi24, Mo Wang25, Xianming Luo25, Shijuan Kuang25, Shuanghui Wei25, Rong Deng25 and Yuteng Shen25 This open-label, multicenter, phase 1b/2 trial assessed the safety and efficacy of toripalimab plus cetuximab in patients with platinum-refractory (Cohort A) or previously untreated programmed cell death-ligand 1 (PD-L1)-positive (Cohort B) recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Patients received toripalimab 240 mg intravenously (IV) every 3 weeks and cetuximab (400 mg/m² loading, then 250 mg/m² weekly maintenance). Primary endpoints were safety in phase 1b and objective response rate (ORR) as assessed by the Independent Review Committee (Cohort A) and investigator (Cohort B) in phase 2. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). By October 25, 2024, 88 patients were enrolled (Cohort A: 45; cohort B: 43). In Cohort A, confirmed ORR was 60.0% (95% confidence interval [CI]: 44.3%, 74.3%), median PFS was 9.9 months (95% CI: 4.2, 19.4), and median OS was 14.1 months (95% CI: 8.5, 17.7). PD-L1-positive (combined positive score [CPS] ≥1) patients appeared to benefit more than PD-L1-negative (CPS < 1) patients (ORR: 64.5% vs. 40.0%, median PFS: 10.4 vs. 4.0 months, median OS: 15.4 vs. 13.3 months). In Cohort B, confirmed ORR was 44.2% (95% CI: 29.1%, 60.1%), median PFS was 8.2 months (95% CI: 4.2, 17.1), and median OS was 18.1 months (95% CI: 10.6, inestimable). Grade ≥3 treatment-emergent adverse events occurred in 53.3% (Cohort A) and 51.2% (Cohort B) of the patients in phase 2. No novel safety signals were identified. Toripalimab combined with cetuximab demonstrated manageable safety and promising efficacy for R/M HNSCC, warranting further investigation. Clinical trial number: NCT04856631. Signal Transduction and Targeted Therapy (2026)11:223 INTRODUCTION Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of malignancies that arise from the mucosal surfaces of the oral cavity, pharynx, larynx, and sinonasal tract. The ; https://doi.org/10.1038/s41392-026-02707-3 major risk factors are tobacco use, alcohol consumption, and human papillomavirus (HPV) infection1,2. In 2022, China reported an estimated 94,600 new cases and 52,100 deaths, excluding nasopharyngeal carcinoma.3 Globally, the disease burden 1 Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; 2Department of Head and Neck Surgery, Liaoning Cancer Hospital & Institute, Shenyang, China; 3Department of Comprehensive Chemotherapy/Daytime Chemotherapy, Hunan Cancer Hospital, Changsha, China; 4Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, China; 5Department of Head and Neck Surgery Section II, Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China; 6Department of Rare Cancer & Head and Neck Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China; 7Department of Otolaryngology-Head and Neck Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 8Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fuzhou, China; 9Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 10Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China; 11Department of Head and Neck Genitourinary Medicine, Harbin Medical University Cancer Hospital, Harbin, China; 12Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, China; 13Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; 14Department of Head and Neck Oncology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China; 15Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China; 16 Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China; 17Department of Radiotherapy, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 18Department of Oncology, Xiangya Hospital, Central South University, Changsha, China; 19 Department of Head and Neck Radiotherapy, Shandong Provincial ENT Hospital, Shandong University, Jinan, China; 20Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China; 21Department of Head & Neck Oncology, West China Hospital, Sichuan University, Chengdu, China; 22 Department of Otorhinolaryngology-Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; 23Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China; 24Department of Oncology, Linyi Cancer Hospital, Linyi, China and 25Shanghai Junshi Biosciences, Shanghai, China Correspondence: Ye Guo () These authors contributed equally: Ye Guo, Zhendong Li, Liqiong Xue. Received: 20 June 2025 Revised: 9 February 2026 Accepted: 23 March 2026 © The Author(s) 2026 Efficacy and safety of toripalimab in combination with cetuximab in. . . Guo et al. 2 accounted for 771,000 new cases and 385,000 deaths.4 While early-stage HNSCC is often curable with surgery and/or radiation, a proportion of patients (10–50%) experience locoregional recurrence or distant metastasis.5 Recurrent or metastatic (R/M) HNSCC carries a poor prognosis, with a median overall survival (OS) of only 10.1 months for patients treated with the EXTREME regimen (cetuximab combined with chemotherapy) as a first-line therapy and less than 6 months for patients treated with cetuximab monotherapy as a later-line therapy.6,7 The advent of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape for R/M HNSCC. Programmed death-1 (PD-1) inhibitors as monotherapy or in combination with chemotherapy have been established as standard first- or second-line options for the treatment of R/M HNSCC in multiple clinical guidelines.8–10 Monotherapy with nivolumab and pembrolizumab has demonstrated median OS improvements of 8.4 months and 7.5 months compared to standard therapy, respectively, in patients with platinum-resistant or plat (...truncated)