RATIONALE 302: Randomized, phase 3 study of tislelizumab versus chemotherapy as second-line treatment for advanced unresectable/metastatic esophageal squamous cell carcinoma.
Lin Shen, Ken Kato, Sung‐Bae Kim, Jaffer A. Ajani, Kuaile Zhao, Zhiyong He, Xinmin Yu, Yongqian Shu, Qi Luo, Jufeng Wang, Zhendong Chen, Zuoxing Niu, Jong Mu Sun, Chen‐Yuan Lin, Hiroki Hara, Roberto Pazo-Cid, Christophe Borg, Liyun Li, Aiyang Tao, Eric Van Cutsem
Abstract
4012 Background: Tislelizumab (tisle) monotherapy or plus chemotherapy demonstrated antitumor activity in patients (pts) with solid tumors, including esophageal squamous cell carcinoma (ESCC) (NCT03469557 and CTR20160872). Methods: In this global phase 3 study (NCT03430843), adults with histologically confirmed advanced/unresectable or metastatic ESCC whose disease progressed following prior systemic therapy with ≥1 evaluable lesion per RECIST v1.1 and an Eastern Cooperative Oncology Group performance score (ECOG PS) of ≤1 were included. Pts were randomized (1:1) to receive tisle 200 mg intravenously every 3 weeks or investigator-chosen standard chemotherapy ([ICC]; paclitaxel, docetaxel, or irinotecan) and treated until disease progression, unacceptable toxicity, or withdrawal. Stratification factors included ICC option, region, and ECOG PS. The primary endpoint was overall survival (OS) in the intent-to-treat (ITT) population. The key secondary endpoint was OS in the programmed death-ligand 1 (PD-L1)+ population (visually-estimated combined positive score [vCPS] ≥10%, by VENTANA PD-L1 SP263 assay). Other secondary endpoints included (by RECIST v1.1) progression-free survival, overall response rate (ORR), duration of response (DoR), and safety. Results: Overall, 512 pts (median age: 62 years; range 35-86 years) from 132 sites in 10 countries in Asia (404 pts [79%]), Europe, and North America (108 pts [21%]) were randomized to tisle (n=256) or ICC (n=256) (ITT population). Of these, 157 pts (tisle [n=89], ICC [n=68]) had vCPS ≥10% (PD-L1+ population). On 1 Dec 2020 (data cut-off), median follow-up was 8.5 months (m) with tisle and 5.8 m with ICC. The study met its primary endpoint: tisle clinically and significantly improved OS vs ICC in the ITT population (median OS: 8.6 vs 6.3 m; HR 0.70, 95% CI 0.57-0.85, p=0.0001). Tisle also demonstrated significant improvement in OS vs ICC in the PD-L1+ population (median OS: 10.3 vs 6.8 m; HR 0.54, 95% CI: 0.36-0.79, p=0.0006). Survival benefit was consistently observed across pre-defined subgroups, including baseline PD-L1 status and region. Treatment with tisle was also associated with a higher ORR (20.3% vs 9.8%) and more durable response (median DoR: 7.1 vs 4.0 m; HR 0.42, 95% CI 0.23-0.75) than ICC in the ITT population. Fewer pts had ≥Grade 3 (46% vs 68%) treatment-emergent adverse events with tisle vs ICC. Of these, fewer ≥Grade 3 AEs were treatment-related (TR) with tisle vs ICC (19% vs 56%). Fewer pts discontinued tisle vs ICC (7% vs 14%) due to a TRAE. Conclusion: Tisle demonstrated statistically significant and clinically meaningful improvement in OS vs ICC in pts with advanced or metastatic ESCC who had disease progression during or after first-line systemic therapy. Tisle showed a higher and longer response vs ICC. The safety profile of tisle was more favorable than ICC. Clinical trial information: NCT03430843.