Background: Tislelizumab is a humanized immunoglobulin G4 anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb). At the interim analysis (median follow-up, 10.0 months), RATIONALE-309 met its primary endpoint, as first-line tislelizumab + chemotherapy significantly improved PFS, as assessed by an independent review committee (IRC), in patients with recurrent/metastatic nasopharyngeal cancer (RM NPC) compared with placebo + chemotherapy. Tislelizumab + chemotherapy had an acceptable safety profile, comparable to placebo + chemotherapy (Yang Y, et al. ESMO-IO Virtual Congress, 2021. Oral presentation 121O). Here, we report an updated analysis of PFS, PFS after next line of treatment (PFS2), and overall survival (OS) with an extended median follow-up of 15.5 months. Methods: A total of 263 eligible patients with RM NPC were randomly assigned 1:1 to receive tislelizumab 200 mg intravenously (IV) or placebo on day 1, plus gemcitabine (1 g/m² IV day 1, day 8), plus cisplatin (80 mg/m² day 1) every 3 weeks for 4–6 cycles, followed by tislelizumab or placebo every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. After IRC-confirmed disease progression, patients in the placebo arm could crossover to receive tislelizumab monotherapy. The primary endpoint was IRC-assessed PFS. Secondary endpoints included IRC-assessed objective response rate and duration of response, investigator-assessed PFS and PFS2, and OS. Biomarker analysis was an exploratory endpoint. Results: At an updated data cut-off (September 30, 2021), IRC-assessed PFS was consistent with the interim data analysis and demonstrated significant improvement for tislelizumab + chemotherapy versus placebo + chemotherapy (median PFS, 9.6 vs. 7.4 months, respectively; hazard ratio [HR], 0.50; 95% CI, 0.37, 0.68). Median PFS2 and OS were not reached for the tislelizumab + chemotherapy arm and were 13.9 months and 23.0 months for the placebo + chemotherapy arm, respectively. The HRs were 0.38 (95% CI, 0.25, 0.58) for PFS2 and 0.60 (95% CI, 0.35, 1.01) for OS. The association of tumor microenvironment features by gene-expression analysis with clinical benefit will be presented. Conclusions: Tislelizumab + chemotherapy showed consistent, clinically meaningful improvement in PFS compared with placebo + chemotherapy in this updated analysis. Clinically meaningful improvements in PFS2 and OS were also observed for the tislelizumab + chemotherapy arm. This is the first report of PFS2 benefit for an anti–PD-1 mAb in combination with chemotherapy in the first-line treatment setting of RM NPC. These results support the use of tislelizumab + chemotherapy as first-line therapy for RM NPC. Clinical trial information: NCT03924986.