First-Line Tislelizumab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Cancer: Three-Year Follow-Up of the Phase 3 RATIONALE-309 Randomized Clinical Trial.

Importance: Nasopharyngeal carcinoma (NPC) is a major health concern in Asia, and treatment options for recurrent or metastatic disease are limited. Immunotherapy plus chemotherapy has shown promise, but long-term data are needed to guide first-line treatment. Objective: To evaluate the 3-year efficacy and safety of tislelizumab plus chemotherapy vs placebo plus chemotherapy in participants with recurrent or metastatic NPC and explore potential biomarkers of treatment response. Design, Setting, and Participants: The RATIONALE-309 trial was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted in Asia from April 2019 to December 2023. Treatment-naive adults with histologically or cytologically confirmed recurrent or metastatic NPC were included. Data were analyzed from December 2023 to January 2024. Interventions: Participants were randomized 1:1 to receive tislelizumab, 200 mg, intravenously or placebo every 3 weeks, both with gemcitabine and cisplatin for 4 to 6 cycles. Participants in the placebo arm could cross over to tislelizumab monotherapy at disease progression. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by an independent review committee. The primary hypothesis (PFS superiority for tislelizumab vs placebo) was specified in the protocol prior to data collection. Secondary end points included overall survival (OS), PFS after next-line therapy, and safety. Results: Of 263 included participants, 206 (78.3%) were male, and the median (range) age was 50 (23-74) years; the median (range) follow-up was 27.5 (0.1-53.0) months. A total of 131 were randomized to the tislelizumab group and 132 to the placebo group. Tislelizumab plus chemotherapy demonstrated improved PFS vs placebo plus chemotherapy (median PFS, 9.6 months [95% CI, 7.6-11.6] vs 7.4 months [95% CI, 5.6-7.6]; hazard ratio [HR], 0.53; 95% CI, 0.39-0.71). The median OS was 45.3 months (95% CI, 33.4 to not estimable) vs 31.8 months (95% CI, 25.0 to not estimable), respectively (HR, 0.73; 95% CI, 0.51-1.05). Rank-preserving structural failure time analysis (HR, 0.56; 95% CI, 0.27-1.19) and 2-stage crossover-adjusted analysis (HR, 0.62; 95% CI, 0.40-0.97) showed greater OS benefit. Treatment-emergent adverse events occurred in 133 of 133 participants (100%) in the tislelizumab arm and 129 of 130 participants (99.2%) in the placebo arm, with comparable grade 3 or higher adverse event rates. Immune-mediated adverse events were more frequent with tislelizumab (71 [53.4%] vs 49 [37.7%]) but mostly of grades 1 or 2. High B-cell gene expression was associated with greater OS benefit (HR, 0.41; 95% CI, 0.23-0.74). Conclusions and Relevance: In this secondary analysis of the RATIONALE-309 randomized clinical trial, after 3 years of follow-up, tislelizumab plus chemotherapy provided sustained PFS and meaningful OS improvement vs placebo plus chemotherapy in recurrent or metastatic NPC, with an acceptable safety profile. Greater benefit was observed in participants with activated immune signatures, especially high B-cell expression. Trial Registration: ClinicalTrials.gov Identifier: NCT03924986.