The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued positive opinions recommending the approval of tislelizumab (Tevimbra) in combination with chemotherapy for the first-line treatment of certain patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma and esophageal squamous cell carcinoma (ESCC). These recommendations are based on data from the phase 3 RATIONALE-305 and RATIONALE-306 trials, respectively, and mark a significant step forward in addressing the unmet needs in these aggressive cancers.
RATIONALE-305: Gastric/GEJ Adenocarcinoma
The CHMP's positive opinion for gastric/GEJ adenocarcinoma specifically covers the use of tislelizumab in combination with platinum- and fluoropyrimidine-based chemotherapy for adult patients with HER2-negative, locally advanced unresectable or metastatic gastric/GEJ cancer whose tumors express PD-L1 with a tumor area positivity (TAP) score of at least 5%.
The RATIONALE-305 trial, a randomized, double-blind, placebo-controlled, global Phase 3 study, enrolled 997 patients. Results demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit. Patients treated with tislelizumab plus chemotherapy achieved a median OS of 15.0 months (95% CI, 13.6-16.5) compared to 12.9 months (95% CI, 12.1-14.1) for those treated with placebo plus chemotherapy (HR: 0.80; 95% CI: 0.70, 0.92; P=0.0011), representing a 20% reduction in the risk of death. In the PD-L1 ≥ 5% subgroup, the median OS was 16.4 months with tislelizumab plus chemotherapy versus 12.8 months with placebo plus chemotherapy (HR: 0.71; 95% CI, 0.58-0.86), a 29% reduction in the risk of death.
RATIONALE-306: Esophageal Squamous Cell Carcinoma
The CHMP also recommended tislelizumab in combination with platinum-based chemotherapy for the first-line treatment of adult patients with unresectable, locally advanced or metastatic ESCC whose tumors express PD-L1 with a TAP score of at least 5%. This recommendation stems from the RATIONALE-306 trial.
The RATIONALE-306 trial, another randomized, placebo-controlled, double-blind, global Phase 3 study, enrolled 649 patients. The study met its primary endpoint, demonstrating a statistically significant and clinically meaningful OS benefit with the tislelizumab combination. The median OS was 17.2 months for tislelizumab with chemotherapy versus 10.6 months for placebo plus chemotherapy (HR: 0.66; 95% CI, 0.54-0.80; 1-sided p-value of < 0.0001), reflecting a 34% reduction in the risk of death. Three-year OS data in the PD-L1 ≥ 5% population showed a substantial improvement in the tislelizumab arm (median 19.1 months versus 10.0 months; HR: 0.62; 95% CI, 0.49-0.79), a 38% reduction in the risk of death.
Safety Profile
The safety data considered in the applications included 1,534 patients who received tislelizumab monotherapy and 1,319 patients with G/GEJ cancer, ESCC, or NSCLC who received tislelizumab in combination with various chemotherapies. Common Grade 3 or 4 adverse reactions for tislelizumab plus chemotherapy included neutropenia, thrombocytopenia, anemia, fatigue, hypokalemia, hyponatremia, pneumonia, decreased appetite, rash, lymphopenia, increased alanine aminotransferase, increased aspartate aminotransferase, diarrhea, pneumonitis, and hepatitis.
Addressing Unmet Needs
Professor Florian Lordick, Director and Professor of Oncology at the University Cancer Center Leipzig, Germany, emphasized the importance of these findings: “Survival rates in the advanced stages of gastric/gastroesophageal and esophageal cancers are among the lowest of all cancer types despite recent advances, and new treatment options are needed. The RATIONALE-305 and 306 trials showed that tislelizumab plus chemotherapy improved survival compared to treatment with placebo plus chemotherapy, highlighting its potential to deliver better outcomes for eligible patients.”
With these positive CHMP opinions, tislelizumab is one step closer to becoming a valuable new treatment option for patients with previously untreated G/GEJ cancer and ESCC, offering hope for improved outcomes in these challenging diseases.
