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Background Immune checkpoint inhibitor (ICI) rechallenge in recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) is a promising therapeutic strategy. We aim to evaluate the efficacy and establish prognostic models in RM-NPC patients who received ICI rechallenge.Methods R/M NPC patients who failed prior anti-PD-1 immunotherapy and got ICI rechallenge were enrolled. Clinical features were recorded, and univariate and multivariate analysis were conducted to evaluate prognostic factors. Prognostic models were developed and validated to predict progression-free survival (PFS) and overall survival (OS), respectively.Results A total of 243 patients were enrolled between January, 2019 and December, 2023. The ORR and DCR for the whole cohort were 24.3% and 75.7%, respectively. After 10.5 months median follow-up, the median PFS was 6.3 months, with the median duration of response (DOR) was 9.8 months and the median OS was 19.8 months. Multivariate Cox analysis shown that recently efficacy of anti-PD-1 therapy (HR 0.587, 95%CI 0.357-0.963, p=0.035), EBV DNA level (HR 1.743, 95%CI 1.252-2.426, p=0.001), locoregional therapy (HR 0.467, 95%CI 0.268-0.812, p=0.007), and rechallenge with anti-PD-1 inhibitor (HR 1.548, 95%CI 1.005-2.385, p=0.047), were independent statistically prognostic factors for PFS. Additionally, age (HR 2.044, 95%CI 1.297-3.222, p=0.002), bone metastatic (HR 1.642, 95%CI 1.055-2.555, p=0.028), and EBV DNA level (HR 1.673, 95%CI 1.034-2.706, p=0.036) were independent significantly associated with OS. Prognostic models based on risk factors were developed. Patients were classified using prognostic scores obtained from the model, and low-risk patients expressed a significantly improved PFS and OS, respectively.Conclusions This study provided a detailed exploration of the efficacy and prognostic factors of ICI rechallenge in RM-NPC patients who failed prior anti-PD-1 immunotherapy, and established a prognostic model which could identify candidates for ICI rechallenge. Further prospective trials are warranted to confirm and expand these findings.Acknowledgements The authors have no conflicts of interest to disclose.This study is supported by Clinical Research Training Project of The First Affiliated Hospital of Nanchang University (No. YFYLCYJPY202444) and Science and Technology Project of Health Commission of Jiangxi Provincial (No. 202510240).Ethics Approval The study was approval by the Sun Yat-sen University Cancer Center Institutional Review Board, and informed consent was obtained from all patients or their guardians.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.