FDA Approves First-Line Tislelizumab Plus Chemotherapy for Unresectable or Metastatic ESCC

The FDA has approved tislelizumab-jsgr (Tevimbra) plus platinum-containing chemotherapy for the frontline treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) with a tumor PD-L1 expression of 1 or higher.1

This regulatory decision was supported by findings from the phase 3 RATIONALE-306 trial (NCT03783442). The tislelizumab combination led to a significant improvement in overall survival (OS) vs chemotherapy alone. At a median follow-up of 16.3 months (interquartile range [IQR], 8.6-21.8) in patients who received tislelizumab plus chemotherapy (n = 326) and 9.8 months (IQR, 5.8-19.0) in those who received placebo plus chemotherapy (n = 323), the median OS was 17.2 months (95% CI, 15.8-20.1) in the tislelizumab arm vs 10.6 months (95% CI, 9.3-12.1) in the placebo arm (stratified HR, 0.66; 95% CI, 0.54-0.80; 1-sided P < .0001).2

Data from exploratory analyses indicated that the improvement observed in the intention-to-treat population was primarily attributed to data observed in the subset of patients with PD-L1 expression of 1 or higher.1 In patients with PD-L1 expression of 1% or higher on tumor and tumor-associated immune cells (TAP), the median OS with tislelizumab plus chemotherapy (n = 231) was 16.8 months (95% CI, 15.3-20.8) vs 9.6 months (95% CI, 8.9-11.8) with chemotherapy alone (n = 250; HR, 0.66; 95% CI, 0.53-0.82).

“The approval of [tislelizumab] in combination with chemotherapy for adult patients with ESCC expands first-line treatment options for patients with this disease,” Nataliya Uboha, MD, PhD, associate professor at the University of Wisconsin, Carbone Cancer Center, stated in a news release. “There is a critical need for effective treatments of ESCC, and [tislelizumab] has been shown to improve outcomes in this patient population.”

About RATIONALE-306

The global, double-blind, parallel-arm RATIONALE-306 trial was conducted across 162 centers in Asia, Europe, North America, and Oceana. The trial enrolled patients at least 18 years of age with unresectable, locally advanced, recurrent or metastatic ESCC regardless of PD-L1 expression.2 Patients needed to have an ECOG performance status of 0 or 1 and measurable disease per RECIST 1.1 criteria.

Patients were randomly assigned 1:1 to receive tislelizumab at 200 mg or placebo intravenously every 3 weeks on day 1 of each 21-day cycle in combination with a chemotherapy doublet of investigator's choice that consisted of a platinum agent plus a fluoropyrimidine or capecitabine or paclitaxel. Treatment continued until disease progression or unacceptable toxicity.

OS served as the primary endpoint. Key secondary end points included progression-free survival (PFS), overall response rate (ORR), OS in the subgroup of patients with a PD-L1 tumor area positivity (TAP) score of at least 10%, duration of response, safety, and health-related quality of life.

Additional Efficacy Data

The median PFS was 7.3 months (95% CI, 6.9-8.3) in the tislelizumab arm vs 5.6 months (95% CI, 4.9-6.0) in the placebo arm (HR, 0.62; 95% CI, 0.52-0.75; P < .0001). The 12-month PFS rates in these respective arms were 30.0% (95% CI, 24.6%-35.6%) and 15.7% (95% CI, 11.5%-20.4%).

The investigator-assessed ORR was 63% in the tislelizumab arm vs 42% in the placebo arm (odds ratio, 2.38; 95% CI, 1.73-3.27; P < .0001).

Among patients with a PD-L1 TAP score of at least 10%, the median OS was 16.6 months (95% CI, 15.3-24.4) with tislelizumab plus chemotherapy (n = 116) vs 10.0 months (95% CI, 8.6-13.3) with placebo plus chemotherapy (n = 107; HR, 0.62; 95% CI, 0.44-0.87; P = .0029). The 18-month OS rates in these respective populations were 46.9% (95% CI, 37.5%-55.8%) and 34.8% (95% CI, 25.7%-44.0%).

Among patients with a PD-L1 TAP score of less than 10%, the median OS was 15.8 months (95% CI, 12.3-19.6) with tislelizumab plus chemotherapy (n = 151) vs 10.4 months (95% CI, 9.0-13.6) with placebo plus chemotherapy (n = 168; HR, 0.77; 95% CI, 0.59-1.01). The 18-month OS rates in these respective populations were 45.8% (95% CI, 37.6%-53.6%) and 33.7% (95% CI, 26.5%-41.0%).

Safety Insights

The most common grade 3/4 treatment-related adverse effects in the tislelizumab arm included decreased neutrophil counts (31%), decreased white blood cell counts (11%), and anemia (15%). Six deaths in the tislelizumab arm were attributed to treatment and included GI and upper GI hemorrhage (n = 2), electrolyte imbalance (n = 1), pulmonary tuberculosis (n = 1), respiratory failure (n = 1), and myocarditis (n = 1).

References

1. Tevimbra approved in US for first-line treatment of advanced esophageal squamous cell carcinoma in combination with chemotherapy. News release. BeiGene, Ltd. March 4, 2025. Accessed March 4, 2025. https://hkexir.beigene.com/news/tevimbra-approved-in-u-s-for-first-line-treatment-of-advanced-esophageal-squamous-cell-carcinoma-in-combination/8379a7c3-35ce-45af-82d3-164c64ecf37c/
2. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023;24(5):483-495. doi:10.1016/S1470-2045(23)00108-0