RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
Authors: Li Zhang, Yunpeng Yang, Jian-ji Pan, Xiaozhong Chen, Yan Sun, Hui Wang, Shenhong Qu, Nianyong Chen, Lizhu Lin, Siyang Wang, Qitao Yu, Guihua Wang, Feng Lei, Jiyu Wen, Chenqi Chen, Yanjie Wu, Shiangjiin Leaw, Wenfeng Fang
Journal: Journal of Clinical Oncology (2022)

384950 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/m 2 IV day 1, day 8), plus cisplatin (80 mg/m 2 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.