PD-1 blockade with toripalimab incorporated into induction chemotherapy and radiotherapy with or without concurrent cisplatin in locoregionally advanced nasopharyngeal carcinoma (DIAMOND): A multicenter, non-inferiority, phase 3, randomized controlled trial.

LBA6003 Background: This study aimed to assess the efficacy and safety of toripalimab combined with induction chemotherapy and radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma (LANPC). Methods: Patients with non-metastatic T4N1 or N2–3 (AJCC 8 th edition) NPC were recruited from 13 centers in China from Aug 2021 to Jul 2022 and randomly assigned (1:1) to receive either toripalimab plus gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy ( standard arm) or standard therapy sparing concurrent cisplatin ( cisplatin-free arm). Toripalimab was administered at a dosage of 240 mg once every 3 wks for up to 17 cycles (1.06 year), covering the induction (×3 cycles), radiotherapy (×3), and adjuvant (×11) phases. The trial would be considered positive if both coprimary endpoints, failure-free survival (FFS; non-inferiority) and the incidence of all-grade vomiting (superiority), were significantly met, maintaining a 1-sided type I error of 5% without α splitting. A total of 532 patients were needed to achieve 80% power to detect a HR of 1.74, with non-inferiority defined as the lower limit of the 1-sided 95% CI for the difference in 3-year FFS greater than -8%. Quality of life (QoL) was assessed based on EORTC and FACT systems. Tolerability was measured by PRO-CTCAE questionnaires. Results: After a median follow-up of 36 mo, intention-to-treat analysis in 532 patients (266 vs 266) showed that the estimated 3-year FFS was 88.3% in the cisplatin-free arm and 87.6% in the standard arm, with a difference of 0.7% (1-sided 95% CI, -4.8% to ∞; p non-inferiority = 0.002); the stratified HR was 0.92 (95% CI, 0.66 to 1.79; log-rank p = 0.731). The incidence of all-grade vomiting in safety dataset was 25.6% (68/260) in cisplatin-free arm and 69.0% (156/261) in standard arm (χ 2 p < 0.001); the incidence of grade 3–4 vomiting, 3.8% vs 10.3%. Acute grade 3–4 adverse events (AEs) occurred in 136 (52.3%) and 166 (63.6%) patients, including immune-related AEs in 13 (5.0%) and 22 (8.4%) patients, in the cisplatin-free and standard arms, respectively. No treatment-related death was observed. Compared to standard arm, cisplatin-free arm had significantly better QoL in global health status, physical function, role function, nausea/vomiting, constipation, swallowing, sexuality, and H&N total score, as well as higher tolerability to nausea, vomiting, constipation, and fatigue during radiotherapy. Conclusions: Removing concurrent cisplatin from toripalimab plus chemoradiotherapy provides comparable survival, lower toxicity, and better QoL and tolerability for patients with LANPC. Clinical trial information: NCT04907370 . 3-yr survival (%) Cisplatin-free arm ( n = 266) Standard arm ( n = 266) p non-inferiority OS 96.1 96.5 < 0.001 LRRFS 92.9 93.6 0.001 DMFS 93.2 91.6 < 0.001