The European Commission has granted approval to tislelizumab (Tevimbra) in combination with chemotherapy for the first-line treatment of adult patients with esophageal squamous cell carcinoma (ESCC) and gastric or gastroesophageal junction (GEJ) adenocarcinoma. This decision marks a significant advancement in the treatment landscape for these aggressive cancers, where survival times are often measured in months.
The approval is based on data from two pivotal Phase 3 trials: RATIONALE-306 (NCT03783442) in ESCC and RATIONALE-305 (NCT03777657) in gastric/GEJ adenocarcinoma. These trials evaluated the efficacy and safety of tislelizumab in combination with chemotherapy compared to placebo plus chemotherapy.
RATIONALE-306: Tislelizumab in Esophageal Squamous Cell Carcinoma
The RATIONALE-306 trial, a randomized, placebo-controlled, double-blind study, enrolled 649 patients with unresectable, locally advanced recurrent, or metastatic ESCC across North America, Asia-Pacific, and Europe. Patients were randomized 1:1 to receive either tislelizumab 200 mg intravenously every 3 weeks plus chemotherapy or placebo plus chemotherapy. The primary endpoint was overall survival (OS).
The results demonstrated a statistically significant and clinically meaningful improvement in OS for the tislelizumab arm compared to the placebo arm (HR, 0.66; 95% CI, 0.54-0.80; 1-sided P < .0001). The median OS was 17.2 months in the tislelizumab group compared to 10.6 months in the placebo group. In patients with PD-L1 expression of 5% or greater, the median OS was 19.1 months for the tislelizumab group and 10.0 months for the placebo group (HR, 0.62; 95% CI, 0.49-0.79).
RATIONALE-305: Tislelizumab in Gastric/Gastroesophageal Junction Adenocarcinoma
The RATIONALE-305 trial was a randomized, double-blind, placebo-controlled study that enrolled 997 patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Patients were randomized 1:1 to receive either tislelizumab 200 mg intravenously every 3 weeks plus chemotherapy or placebo plus chemotherapy. The primary endpoint was OS.
The trial met its primary endpoint, demonstrating a statistically significant improvement in OS for the tislelizumab plus chemotherapy arm compared with the placebo plus chemotherapy arm (HR, 0.80; 95% CI, 0.70-0.92; P = .0011). The median OS was 15.0 months in the tislelizumab group versus 12.9 months in the placebo group. In patients with PD-L1 expression of 5% or greater, the median OS was 16.4 months in the tislelizumab group and 12.8 months in the placebo group (HR, 0.71; 95% CI, 0.58-0.86).
Safety Profile
The safety data submitted to the European Commission included data from over 2800 patients, with 1534 receiving tislelizumab as monotherapy and 1319 receiving it in combination with chemotherapy. Common grade 3 or 4 adverse events associated with tislelizumab plus chemotherapy included neutropenia, thrombocytopenia, anemia, fatigue, hypokalemia, hyponatremia, pneumonia, decreased appetite, rash, and lymphopenia.
"Patients diagnosed with advanced gastric and esophageal cancers confront median survival times in months, not years—highlighting the urgent need for more effective treatment options," said Florian Lordick, MD, PhD, professor of oncology and director of the University Cancer Center in Leipzig, Germany. "The compelling data from the RATIONALE-305 and 306 trials underscore the unique clinical profile of tislelizumab and its potential to deliver meaningful improvements in outcomes for eligible patients, offering new hope where it’s needed most."
