Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study

Abstract

Purpose: Patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) have poor prognosis. For these patients, treatment options are limited after first-line systemic therapy.

Patients and methods: In this open-label phase III clinical study, patients with advanced or metastatic ESCC, whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive intravenous tislelizumab, an anti-programmed cell death protein 1 antibody, 200 mg every 3 weeks or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). The primary end point was overall survival (OS) in all patients. The key secondary end point was OS in patients with programmed death-ligand 1 tumor area positivity (TAP) score ≥ 10%.

Results: In total, 512 patients across 11 countries/regions were randomly assigned. At final analysis, conducted after 410 death events occurred, OS was significantly longer with tislelizumab versus chemotherapy in all patients (median, 8.6 v 6.3 months; hazard ratio [HR], 0.70 [95% CI, 0.57 to 0.85]; one-sided P = .0001), and in patients with TAP ≥ 10% (median, 10.3 months v 6.8 months; HR, 0.54 [95% CI, 0.36 to 0.79]; one-sided P = .0006). Survival benefit was consistently observed across all predefined subgroups, including those defined by baseline TAP score, region, and race. Treatment with tislelizumab was associated with higher objective response rate (20.3% v 9.8%) and a more durable antitumor response (median, 7.1 months v 4.0 months) versus chemotherapy in all patients. Fewer patients experienced ≥ grade 3 treatment-related adverse events (18.8% v 55.8%) with tislelizumab versus chemotherapy.

Conclusion: Tislelizumab significantly improved OS compared with chemotherapy as second-line therapy in patients with advanced or metastatic ESCC, with a tolerable safety profile. Patients with programmed death-ligand 1 TAP ≥ 10% also demonstrated statistically significant survival benefit with tislelizumab versus chemotherapy.

Trial registration: ClinicalTrials.gov NCT03430843.

FIG 1.

CONSORT diagram. ^aOne patient died before random assignment and was inadvertently randomly assigned into the study. Data cutoff: December 1, 2020. AE, adverse event; ITT, intent-to-treat.

FIG 2.

Kaplan-Meier plot of OS in the (A) intent-to-treat population, (B) PD-L1 TAP ≥ 10%, (C) PD-L1 TAP < 10%, and (D) TAP unknown populations. One-sided P value was estimated from a log-rank test stratified by ECOG PS and chemotherapy option. HR was based on a Cox regression model including treatment as a covariate and ECOG PS and chemotherapy option as strata. ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1; TAP, tumor area positivity.

FIG 3.

Subgroup analysis of overall survival in the intent-to-treat population. HR was based on an unstratified Cox regression model including treatment as a covariate. The race subcategory other includes Black or African American, not reported, unknown, and other. ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PD-L1, programmed death-ligand 1; TAP, tumor area positivity.

FIG 4.

Kaplan-Meier plot of (A) PFS and (B) DoR in the intent-to-treat population. HR was based on a Cox regression model including treatment as a covariate and Eastern Cooperative Oncology Group performance status and chemotherapy option as strata. DoR, duration of response; HR, hazard ratio; PFS, progression-free survival.