Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial
Authors: Qiu Miao-Zhen , Oh Do-Youn , Kato Ken , Arkenau Tobias , Tabernero Josep , Correa Marcia Cruz , Zimina Anastasia V , Bai Yuxian , Shi Jianhua , Lee Keun-Wook , Wang Jufeng , Poddubskaya Elena , Pan Hongming , Rha Sun Young , Zhang Ruixing , Hirano Hidekazu , Spigel David , Yamaguchi Kensei , Chao Yee , Wyrwicz Lucjan , Disel Umut , Cid Roberto Pazo , Fornaro Lorenzo , Evesque Ludovic , Wang Hongwei , Xu Yaling , Li Jiang , Sheng Tao , Yang Silu , Li Liyun , Moehler Markus , Xu Rui-Hua 
Published: May 2024

Abstract

Objective
To evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy.

Design
Randomised, double blind, placebo controlled, phase 3 study.

Setting
146 medical centres across Asia, Europe, and North America, between 13 December 2018 and 28 February 2023.

Participants
1657 patients aged ≥18 years with human epidermal growth factor receptor 2 negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, regardless of programmed death-ligand 1 (PD-L1) expression status, who had not received systemic anticancer therapy for advanced disease.

Interventions
Patients were randomly (1:1) assigned to receive either tislelizumab 200 mg or placebo intravenously every three weeks in combination with chemotherapy (investigator’s choice of oxaliplatin and capecitabine, or cisplatin and 5-fluorouracil) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator’s choice of chemotherapy. Treatment continued until disease progression or unacceptable toxicity.

Main outcome measures
The primary endpoint was overall survival, both in patients with a PD-L1 tumour area positivity (TAP) score of ≥5% and in all randomised patients. Safety was assessed in all those who received at least one dose of study treatment.

Results

Of 1657 patients screened between 13 December 2018 and 9 February 2021, 660 were ineligible due to not meeting the eligibility criteria, withdrawal of consent, adverse events, or other reasons. Overall, 997 were randomly assigned to receive tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). Tislelizumab plus chemotherapy showed statistically significant improvements in overall survival versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5% (median 17.2 months
v
12.6 months; hazard ratio 0.74 (95% confidence interval 0.59 to 0.94); P=0.006 (interim analysis)) and in all randomised patients (median 15.0 months
v
12.9 months; hazard ratio 0.80 (0.70 to 0.92); P=0.001 (final analysis)). Grade 3 or worse treatment related adverse events were observed in 54% (268/498) of patients in the tislelizumab plus chemotherapy arm versus 50% (246/494) in the placebo plus chemotherapy arm.

Conclusions
Tislelizumab added to chemotherapy as primary treatment for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5%, and in all randomised patients.

Trial registration

ClinicalTrials.gov
NCT03777657