Neoadjuvant and adjuvant toripalimab for high-risk locoregionally advanced nasopharyngeal carcinoma: A randomized, double-blind, placebo-controlled phase 2 trial.
Authors: Liu Sai Lan , Mai Hai-Qiang , Wen Dongxiang , Yang Jin-Hao , Guo Shan-Shan , Liu Li-Ting , Luo Mei-Juan , Liang YuJing , Sun Xue-Song , Li Xiao-Yun , Luo Dong-Hua , Li Ji-Bin , Wang Pan , Guo Ling , Mo Hao-Yuan , Sun Rui , Zhao Chong , Xu Rui-Hua , Tang Lin-Quan , Chen Qiu-Yan 
Published: June 2024

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Background: Patients with locoregionally advanced nasopharyngeal carcinoma with high pretreatment plasma Epstein–Barr virus (EBV) DNA levels remain at high risk for recurrence after platinum-based concurrent chemoradiotherapy. We aimed to assess whether the addition of neoadjuvant and adjuvant toripalimab (anti-PD-1) to chemoradiotherapy could improve treatment outcomes in this patient population. Methods: We conducted a single-center, randomized, double-blind phase 2 trial to evaluate neoadjuvant and adjuvant toripalimab treatment for high-risk locoregionally advanced nasopharyngeal carcinoma. Participants with nasopharyngeal carcinoma (stage III-IVA, AJCC 8th Staging System, pretreatment plasma EBV DNA ≥1500 copies/ml) were assigned in a 2:1 ratio to receive neoadjuvant toripalimab (240 mg) or placebo once every 2 weeks for 2 cycles, followed by concurrent chemoradiotherapy and adjuvant toripalimab (240 mg) or placebo once every 3 weeks for up to 8 cycles. The primary endpoint was progression-free survival at 2 years in the intention-to-treat population. The secondary endpoints included overall survival, locoregional relapse-free survival, distant metastasis-free survival at 2 years, a major pathological response in nasopharynx biospy, overall response, treatment adherence, quality-of-Life and safety. Results: From December 2019 through December 2021,100 patients were assigned to the neoadjuvant-adjuvant toripalimab group, and 50 to the placebo group. At a median follow-up of 26.9 months, progression-free survival at 2 years was 91.8% in the toripalimab group and 73.9% in the placebo group (hazard ratio for disease progression or death = 0.33; 95% confidence interval [CI], 0.15 to 0.76; P = 0.006). Overall survival was longer in the toripalimab group than in the placebo group (100% vs. 94.0% of patients alive at 2 years; hazard ratio for death, 0.10; 95% CI, 0.01 to 0.82). Distant metastasis–free survival at 2 years was 92.8% and 80.0% (hazard ratio for distant metastasis or death, 0.39; 95% CI, 0.16 to 0.96); locoregional recurrence–free survival at 2 years was 99.0% and 82.0% (hazard ratio for locoregional recurrence or death, 0.09; 95% CI, 0.02 to 0.41). Across all treatment phases, 73.7% of toripalimab group participants and 68.0% of placebo group participants had grade 3 or higher treatment-related adverse events. No deaths related to toripalimab therapy occurred. Conclusions: In patients with high-risk locoregionally advanced nasopharyngeal carcinoma, compared with concurrent chemoradiotherapy, neoadjuvant toripalimab combined with concurrent chemoradiotherapy and adjuvant toripalimab significantly improved progression-free survival, overall survival, locoregional recurrence–free survival, and distant metastasis–free survival. Clinical trial information: NCT03925090 .