Nivolumab combined with radical chemoradiotherapy sparing concurrent cisplatin in high-risk locoregionally advanced nasopharyngeal carcinoma (PLATINUM): An investigator-initiated, open-label, multicenter, single-arm, phase II clinical trial.
Authors: Xu Cheng , Shen Liangfang , Yang Kun-Yu , Hu Desheng , Chen Xiaozhong , Lin Shaojun , Jin Feng , Zhou Qin , Peng Gang , Huang Jing , Wu Yuan , Tao Changjuan , Li Ji-Bin , Zhao Hongyun , Hong Shu-Bin , Huang Hui-Ling , Li Wen-Fei , Zhou Guan-Qun , Sun Ying , Ma Jun 
Published: June 2024

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Background: The current standard therapy for locoregionally advanced nasopharyngeal carcinoma (LANPC) is radical chemoradiotherapy using induction chemotherapy plus concurrent chemoradiotherapy. However, concurrent cisplatin leads to severe acute (54.0–61.0%) and late (9.2–11.4%) toxicities. We hypothesized that nivolumab combined with radical chemoradiotherapy sparing concurrent cisplatin would obtain promising survival and low toxicity in high-risk LANPC. Methods: In this single-arm, phase II clinical trial (NCT03984357), patients with high-risk LANPC (T4N1M0 or T1–4N2–3M0) were recruited from 7 hospitals in China to receive nivolumab (360 mg once every 3 weeks for 3 cycles [Q3W x 3]) + induction chemotherapy (gemcitabine 1000 mg/m2 + cisplatin 80 mg/m2, Q3W x 3), followed by nivolumab (360 mg, Q3W x 3) + intensity-modulated radiotherapy (PGTVnx, 70Gy/33fx), and thereafter adjuvant nivolumab (480 mg, Q4W x 6). The primary end point was 3-year failure-free survival (FFS), defined as the time from enrollment to any disease failure or death. Secondary end points were safety and quality-of-life (QoL) assessed by cellphone-based EORTC/FACT questionnaires. Results: Between April 2020 and October 2020, 152 patients (median [IQR] age, 49 [39–56] years; 18.4% women) were included. After a median follow-up of 39 months (≥ 36 months, 89.5%), the 3-yr FFS was 88.8% (95% CI, 83.9–94.0%) and the 3-yr overall survival was 98.0%. Sixty (40.2%) patients had grade 3–4 acute treatment-related adverse events (trAEs) throughout treatment; 11 (7.2%) were associated with potential immunologic causes mainly involving hepatic (aspartate aminotransferase increased, 3.3%) and skin toxicities (rash/dermatitis, 2.0%). A total of 123 patients completed all required treatment, including 6 cycles of adjuvant nivolumab, with an overall compliance rate of 80.9%. The incidences of grade 3–4 acute trAEs in the induction, radiotherapy, and adjuvant phases were 30.2%, 16.7%, and 6.0%, respectively; compliance rates, 95.4%, 96.5%, and 91.8%, respectively. Eight (5.2%) patients had grade 3–4 late trAEs, e.g., hearing impaired (3.3%) and dry mouth (0.7%). No treatment-related death was observed. Patients had consistent negative changes in general QoL from baseline between the radiotherapy and induction phases, except for the domains of global health status and physical function/well-being, which were more common during the radiotherapy phase. Conclusions: Nivolumab incorporated into induction chemotherapy followed by radiotherapy has a promising efficacy and low toxicity for high-risk LANPC patients. A phase 3 non-inferior randomized clinical trial assessing PD-1 blockade plus this de-intensified radical chemoradiotherapy is underway (NCT04907370). Clinical trial information: NCT03984357 .