RATIONALE-306: Randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC)
Yoon, H. Kato, K. Raymond, E. Hubner, Richard A Shu, Y. Pan, Y. Jiang, Y. Zhang, J. Park, S. Kojima, T.
Yoon, H.
Kato, K.
Raymond, E.
Hubner, Richard A
Shu, Y.
Pan, Y.
Jiang, Y.
Zhang, J.
Park, S.
Kojima, T.
Citations
Altmetric:
Abstract
Background: Tislelizumab, an anti-programmed cell death protein 1 antibody, has
demonstrated a survival benefit as second-line treatment in ESCC. Here, we report
interim analysis (IA) data from the phase 3 RATIONALE-306 study, which evaluated
the efficacy and safety of tislelizumab plus chemotherapy vs placebo plus chemo-
therapy in patients with advanced or metastatic ESCC in the first-line setting.
Methods: In this randomized, double-blind, global study, adults with unresectable
locally advanced or metastatic ESCC, with no prior systemic treatment for advanced
disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression
status. Patients were randomized (1:1) to receive tislelizumab 200 mg (Arm A) or
placebo (Arm B) intravenously once every three weeks, both in combination with
investigator-chosen chemotherapy (ICC; platinum [cisplatin or oxaliplatin] and fluo-
ropyrimidine [capecitabine or 5-FU] or platinum and paclitaxel) until disease pro-
gression per RECIST v1.1, intolerable toxicity, or withdrawal. Randomization was
stratified by geographic region, prior definitive therapy and ICC. The primary endpoint
was overall survival (OS) in the intent-to-treat (ITT) population. Hierarchical
sequentially-tested secondary endpoints were progression-free survival (PFS), objec-
tive response rate (ORR) by the investigator, OS in the PD-L1 score ≥10% subgroup,
and health-related quality of life. Other secondary endpoints included duration of
response (DoR) by the investigator, and safety.
Results: Of 649 patients enrolled from 16 countries/4 regions (74.9% and 25.1% from
Asia and non-Asian countries [Europe, Oceania, and North America]), 326 and 323
patients were randomized to Arms A and B, respectively (ITT population). At data
cutoff (28/02/2022), median follow-up was 16.3 and 9.8 months in Arms A and B,
respectively. The study met its primary endpoint at IA by demonstrating statistically
significant improvement in OS in Arm A vs Arm B (median OS: 17.3 vs 10.6 months;
HR 0.66 [95% CI 0.54, 0.80], p<0.0001). OS improvement was consistently observed
across prespecified subgroups including ICC option, region, and PD-L1 expression
status. In patients with PD-L1 score ≥10%, Arm A also demonstrated significant
improvement in OS vs Arm B (median OS: 16.8 vs 10.0 months, HR 0.61 [95% CI 0.44,
0.85], p=0.0017). A significant improvement in PFS was observed in Arm A vs Arm B
(median PFS: 7.3 vs 5.6 months; HR 0.62 [95% CI 0.52, 0.75], p<0.0001). Arm A was
associated with a higher ORR (63.5% vs 42.4%, odds ratio 2.38 [95% CI 1.73, 3.27],
p<0.0001) and more durable response (median DoR: 7.1 [95% CI 6.1, 8.1] vs 5.7
months [95% CI 4.4, 7.1]) than Arm B. Overall, similar proportions of patients in Arms
A and B had ≥1 treatment-related treatment-emergent adverse event (TRAE; 96.6%
and 96.3%), ≥Grade 3 TRAEs (66.7% vs 64.5%), and TRAEs leading to death (1.9% vs
1.2%), respectively. Serious TRAEs occurred in 28.7% vs 19.3%, and treatment-
emergent AEs leading to discontinuation occurred in 31.8% vs 22.4% in Arms A vs B.
No new safety signal for tislelizumab was observed.
Conclusions: Tislelizumab plus chemotherapy as first-line treatment demonstrated a
statistically significant and clinically meaningful improvement in OS over placebo plus
chemotherapy in patients with advanced or metastatic ESCC, with a manageable
safety profile.
Affiliation
Description
Date
2022
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Yoon H, Kato K, Raymond E, Hubner R, Shu Y, Pan Y, et al. RATIONALE-306: Randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC). Annals of Oncology. 2022 Jun;33:S375-S. PubMed PMID: WOS:000823826500359.