FDA Approves Frontline Tislelizumab Plus Chemotherapy in Advanced ESCC
Tislelizumab plus chemotherapy is now FDA-approved for metastatic esophageal squamous cell carcinoma with a tumor PD-L1 expression of 1 or higher.
US FDA
- The FDA approved tislelizumab-jsgr (Tevimbra) and 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.
- Findings from the phase 3 RATIONALE-306 trial (NCT03783442) provide strong evidence supporting the regulatory approval of tislelizumab in combination with chemotherapy.
- The study demonstrated a significant improvement in overall survival (OS) compared to chemotherapy alone.
The FDA approved the combination of tislelizumab and platinum-containing chemotherapy for the frontline treatment of adult patients with unresectable or metastatic ESCC with a tumor PD-L1 expression of 1 or higher.1
Findings from the phase 3 RATIONALE-306 trialsupport this regulatory decision as the tislelizumab combination significantly improved OS vs chemotherapy alone.
At a median follow-up of 16.3 months (interquartile range [IQR], 8.6-21.8) in the tislelizumab plus chemotherapy group (n = 326) and 9.8 months (IQR, 5.8-19.0) in the placebo plus chemotherapy group (n = 323), the median OS was 17.2 months (95% CI, 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.1), respectively. This corresponded to a stratified hazard ratio (HR) of 0.66 (95% CI, 0.54-0.80; 1-sided P < .0001), favoring the tislelizumab combination.2
“The added effect of tislelizumab to chemotherapy was shown in the patients with chemotherapy naïve advanced and recurred ESCC. The magnitude of efficacy was consistent with the former study with chemotherapy plus an immune checkpoint inhibitor [ICI], but tislelizumab showed efficacy even for the patients who were PD-L1 negative,” Ken Kato, MD, PhD, chief of the department of head and neck, and esophageal medical oncology and gastrointestinal medical oncology at the National Cancer Center Hospital in Tokyo, Japan, told Targeted OncologyTM.
Exploratory analyses suggest that the observed OS benefit was largely driven by patients with PD-L1 expression of ≥1%. In this subgroup, patients receiving tislelizumab plus chemotherapy (n = 231) had a median OS of 16.8 months (95% CI, 15.3-20.8) compared with 9.6 months (95% CI, 8.9-11.8) in those receiving chemotherapy alone (n = 250). The corresponding HR was 0.66 (95% CI, 0.53-0.82).
3D Illustration of esophageal cancer in the human male: © Lars Neumann - stock.adobe.com
In the study, the median progression-free survival (PFS) was also significantly prolonged with the tislelizumab combination at 7.3 months (95% CI, 6.9-8.3) 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). At 12 months, these PFS rates were 30.0% (95% CI, 24.6%-35.6%) and 15.7% (95% CI, 11.5%-20.4%) in the tislelizumab and placebo arms.
The objective response rate (ORR), as assessed by investigators, was also significantly higher in the tislelizumab arm at 63%, compared with 42% in the placebo arm (odds ratio, 2.38; 95% CI, 1.73-3.27; P < .0001), indicating a greater likelihood of tumor shrinkage with the immunotherapy combination.
Patients with a PD-L1 tumor area positivity (TAP) score of at least 10% experienced a median OS of 16.6 months (95% CI, 15.3-24.4) in the tislelizumab plus chemotherapy group (n = 116) vs 10.0 months (95% CI, 8.6-13.3) in the placebo plus chemotherapy (n = 107; HR, 0.62; 95% CI, 0.44-0.87; P = .0029) group. At 18 months, the OS rates in these respective arms were 46.9% (95% CI, 37.5%-55.8%) and 34.8% (95% CI, 25.7%-44.0%).
Additionally, patients who had a PD-L1 TAP score of less than 10% had a median OS of 15.8 months (95% CI, 12.3-19.6) in the tislelizumab plus chemotherapy arm (n = 151) vs 10.4 months (95% CI, 9.0-13.6) in the placebo plus chemotherapy arm (n = 168; HR, 0.77; 95% CI, 0.59-1.01). The 18-month OS rates were 45.8% (95% CI, 37.6%-53.6%) and 33.7% (95% CI, 26.5%-41.0%) in these respective arms.
Looking at safety, in the tislelizumab group, 313 (97%) of 324 patients had treatment-emergent adverse events (AEs) vs 309 (96%) of 321 in the placebo group. The most common grade 3 or 4 treatment-related or treatment-emergent AEs included decreased neutrophil count (31% in the tislelizumab group v 33% in the placebo group), decreased white blood cell count (11% v 16%), and anemia (15% v 13%).
Six deaths were observed among patients in the tislelizumab group from gastrointestinal and upper gastrointestinal hemorrhage (n = 2), myocarditis (n = 1), pulmonary tuberculosis (n = 1), electrolyte imbalance (n = 1), and respiratory failure (n = 1]), as well as 4 deaths in the placebo group from pneumonia (n = 1), septic shock (n = 1), and unspecified death (n = 2). These deaths were determined to be treatment-related.
“The approval of [tislelizumab] in combination with chemotherapy for adult patients with ESCC expands first-line treatment options for patients with this disease,” said Nataliya Uboha, MD, PhD, associate professor at the University of Wisconsin, Carbone Cancer Center, in a press release. “There is a critical need for effective treatments of ESCC, and [tislelizumab] has been shown to improve outcomes in this patient population.”
Behind the RATIONALE-306 Trial
RATIONALE-306 was a global, double-blind, parallel-arm trial conducted across 162 centers in Asia, Europe, North America, and Oceana, where patients were randomly assigned 1:1 to receive the tislelizumab combination or placebo.2
Patients received tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet of either cisplatin 60-80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1, plus a fluorouracil at 750-800 mg/m2 intravenously on days 1-5 or capecitabine at 1000 mg/m2 orally twice daily on days 1-14, or paclitaxel at 175 mg/m2 intravenously on day 1. Patients continued treatment until disease progression or unacceptable toxicity.
Patients aged 18 years or older with unresectable, locally advanced, recurrent or metastatic ESCC regardless of PD-L1 expression were eligible for enrollment. Additionally, patients had to have measurable or evaluable disease per RECIST 1.1 criteria and an ECOG performance status of 0 or 1.
The primary end point of the study was OS, and secondary end points were PFS, ORR, OS in the subgroup of patients with a PD-L1 TAP score of at least 10%, duration of response, safety, and health-related quality of life.
A total of 869 patients were screened, and 649 were randomly assigned to the tislelizumab plus chemotherapy arm (n = 326) or placebo plus chemotherapy (n = 323) between December 12, 2018, and November 24, 2020.1 The median age among patients enrolled were 64 years old (interquartile range [IQR] 59.0-69.0), 87% of patients were male, 13% were female, 75% were Asian, and 24% were White. For those given tislelizumab, 99% received at least 1 dose of the study drug, as well as 99% in the placebo group.
At the data cutoff date of February 28, 2022, the median follow-up was 16.3 months (IQR, 8.6-21.8) for patients given tislelizumab and 9.8 months (IQR, 5.8-19.0) with placebo. Sixty percent vs 70% of patients in the tislelizumab vs placebo group had died.
REFERENCES
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://tinyurl.com/bdzy9e59
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
