The U.S. Food and Drug Administration (FDA) has granted approval to tislelizumab-jsgr (Tevimbra) in combination with platinum and fluoropyrimidine-based chemotherapy for the first-line treatment of adult patients with unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJ) whose tumors express PD-L1.
This approval marks a significant advancement in the treatment landscape for gastric and GEJ cancers, which are among the most common and deadly cancers worldwide. The decision was primarily based on the results of the Phase 3 RATIONALE-305 trial, demonstrating a statistically significant and clinically meaningful improvement in overall survival (OS) for patients receiving Tevimbra in combination with chemotherapy.
RATIONALE-305 Trial Results
The RATIONALE-305 trial (NCT03777657) was a randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of Tevimbra in combination with chemotherapy as a first-line treatment for patients with advanced G/GEJ cancer. The trial enrolled 997 patients who were randomized to receive either Tevimbra with investigator-selected chemotherapy or placebo with chemotherapy.
The study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in overall survival (OS). Patients treated with Tevimbra and chemotherapy achieved a median OS of 15.0 months compared to 12.9 months for the placebo group (HR, 0.80; 95% CI, 0.70-0.92; P = .0011), representing a 20% reduction in the risk of death.
Safety and Tolerability
Safety data pooled from 1,972 patients across multiple studies revealed that common grade 3 or 4 adverse reactions when Tevimbra was combined with chemotherapy included neutropenia, thrombocytopenia, anemia, fatigue, rash, pneumonia, pneumonitis, hypokalemia, hyponatremia, decreased appetite, hepatitis, and elevated liver enzymes. The findings highlighted Tevimbra’s potential as a valuable first-line treatment option, providing significant survival benefits for patients with advanced G/GEJ cancers while maintaining a manageable safety profile.
Impact on Gastric and GEJ Cancer Treatment
Gastric cancer is the fifth most common cancer globally and ranks fifth in cancer-related deaths, with nearly 1 million new cases and 660,000 deaths reported in 2022. In the US, approximately 27,000 new cases and 11,000 deaths were estimated in 2024, with a 5-year survival rate of 36%. GEJ cancer, which occurs where the esophagus meets the stomach beneath the diaphragm, represents a distinct and challenging subset of these cancers.
According to a study published in Annals of Surgery, patients with GEJ cancer have worse disease-specific survival and a higher recurrence rate than those with gastric cancer, with hematogenous recurrence being more common in GEJ cancer (60.1% vs 31.4%) and peritoneal recurrence more frequent in gastric cancer (52.9% vs. 12.5%). Together, esophageal and gastric cancers account for 1.6 million new cases and 1.3 million deaths annually. GEJ cancer incidence has risen significantly, with a 2.5-fold increase in 2 decades, and non-cardia gastric adenocarcinoma is increasing in younger individuals. Surgery remains central to treatment, but perioperative therapies play a key role in advanced cases.
Mechanism of Action
Tevimbra is a uniquely designed humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping the body’s immune cells detect and fight tumors.
Clinical Perspective
“Today’s FDA approval of Tevimbra for the treatment of gastric or gastroesophageal junction cancers in patients who are PD-L1 positive marks a significant step forward in our mission to deliver transformative therapies to patients with cancer,” said Mark Lanasa, MD, PhD, chief medical officer of Solid Tumors at BeiGene. “This is the second US approval for Tevimbra this year, underscoring its potential to address critical needs in oncology. We remain deeply grateful to the patients, clinicians, and researchers whose commitment and courage have made this progress possible—and we look forward to building on this momentum in 2025.”
This approval offers a new and effective treatment option for patients with advanced gastric and GEJ adenocarcinoma, providing hope for improved outcomes and quality of life.
