Dr Cruz-Correa on the FDA Approval of Tislelizumab Plus Chemotherapy for Metastatic Gastric/GEJ Cancer

“I think the combination of a longer time of connectivity [between tislelizumab and] the receptor [and] the fact that [this agent] avoids the other macrophages…could have been partly responsible for the efficacy that we saw.”

Marcia Cruz-Correa, MD, PhD, AGAF, FASGE, gastroenterologist, professor, medicine, director, University of Puerto Rico Comprehensive Cancer Center, discusses the December 2024 FDA approval of frontline tislelizumab-jsgr (Tevimbra) in combination with platinum- and fluoropyrimidine-based chemotherapy for the treatment of patients with unresectable or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1.

The regulatory decision was supported by data from the phase 3 RATIONALE 305 trial (NCT03777657), which showed that treatment with tislelizumab plus chemotherapy led to a statistically significant and clinically meaningful improvement in overall survival (OS) compared with placebo plus chemotherapy (HR, 0.80; 95% CI, 0.70-0.92; P = .0011) in this patient population. Patients treated with tislelizumab plus chemotherapy experienced a median OS of 15.0 months vs 12.9 months for those treated with placebo plus chemotherapy.

The trial also demonstrated significant OS improvements with tislelizumab plus chemotherapy compared with chemotherapy alone in patients with PD-L1–positive disease. The benefit with the combination also extended to secondary end points, including PFS and ORR.

Cruz-Correa explains that tislelizumab is a monoclonal antibody targeting the PD-1 receptor, distinguishing it from other agents within the anti–PD-1 therapy class. Preclinical data revealed unique pharmacologic features of tislelizumab, including its prolonged receptor binding duration and its ability to bypass Fc-gamma receptor engagement on macrophages, according to Cruz-Correa. These attributes may reduce macrophage-mediated antibody degradation and contribute to the enhanced efficacy and reduced toxicity of the agent, she notes.

Safety findings from the study showed that tislelizumab has a favorable toxicity profile. Fewer immune-related adverse effects (AEs) were observed with tislelizumab compared with other anti–PD-1 agents, likely due to tislelizumab’s reduced macrophage engagement. The most common treatment-related AEs included fatigue, rash, and diarrhea, with hematologic toxicities attributed to the chemotherapy component of the regimen. These results further underscore the potential for tislelizumab as a safe treatment alternative for patients with advanced gastric or GEJ cancer.

Tislelizumab’s FDA approval represents a significant advancement in the treatment paradigm for advanced gastric/GEJ cancer both in the United States and globally, Cruz-Correa concludes.