Nivolumab combined with chemoradiotherapy sparing concurrent cisplatin in high-risk locoregionally advanced nasopharyngeal carcinoma (PLATINUM): A multicenter, single-arm, phase II clinical trial.

138 Background: Cisplatin-based concurrent chemoradiotherapy has long been regarded as the cornerstone of treatment for patients with locoregionally advanced nasopharyngeal carcinoma (LANPC) over two decades ago. However, the persistent issue of severe acute toxicities (54.0–61.0%) and late sequelae (9.2–11.4%) induced by concurrent cisplatin remains unresolved. Methods: In this single-arm, phase II clinical trial (PLATINUM study), patients with high-risk LANPC (T4N1M0 or T1–4N2–3M0) were recruited from 7 hospitals in China to receive intravenous nivolumab (360 mg once every 3 weeks for 3 cycles [Q3W x 3]) + induction chemotherapy (gemcitabine 1000 mg/m 2 + cisplatin 80 mg/m 2 , 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 overall survival, safety, and health-related quality-of-life (QoL) assessed by cellphone-based EORTC and FACT questionnaires. This trial was registered with ClinicalTrials.gov (NCT03984357). 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 43 months (92.6% alive patients ≥ 36 months), the 3-year FFS was 88.5% (95% CI, 83.4–93.8%) and the 3-year overall survival was 97.9%. 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 skin system (rash, 2.0%; 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, eg. hearing impaired (3.3%) and dry mouth (0.7%). No treatment-related death was observed. Patients had consistent worsening 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 randomized clinical trial assessing PD-1 blockade plus this de-intensified radical chemoradiotherapy is underway (NCT04907370). Clinical trial information: NCT03984357 .