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Introduction <p>Tislelizumab plus investigator-chosen chemotherapy (ICC) demonstrated a statistically significant&#xa0;improvement in overall survival (OS) versus placebo plus ICC in RATIONALE-305 in patients with locally&#xa0;advanced&#xa0;unresectable&#xa0;or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric cancer/gastroesophageal junction cancer (GC/GEJC) in the intent-to-treat population and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score&#xa0;≥&#xa0;5%. The United States Food and Drug Administration Oncologic Drugs Advisory Committee voted (September 2024) against first-line treatment with programmed cell death protein-1 inhibitors in this setting in patients with a PD-L1 combined positive score&#xa0;&lt;&#xa0;1 or TAP score&#xa0;&lt;&#xa0;1%, due to an unfavorable benefit–risk profile. Thus, we retrospectively analyzed data from RATIONALE-305 in patients with a PD-L1 TAP score&#xa0;≥&#xa0;1%.</p> Methods <p>Adult patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC were randomized to tislelizumab 200 mg or placebo with ICC every 3 weeks. Efficacy and safety outcomes of tislelizumab plus ICC versus placebo plus ICC were retrospectively assessed in those with a PD-L1 TAP score&#xa0;≥&#xa0;1%.</p> Results <p>At the final analysis cutoff (February 28, 2023), 432 patients received tislelizumab plus ICC and 453 received placebo plus ICC, and had a PD-L1 TAP score&#xa0;≥&#xa0;1%. Clinically meaningful improvements to OS were observed with tislelizumab plus ICC compared with placebo plus ICC [15.0&#xa0;months (95% confidence interval&#xa0;[CI] 13.3–16.7) vs. 12.8 months&#xa0;(95% CI&#xa0;12.1–14.1), respectively; stratified hazard ratio 0.77 (95% CI 0.67–0.90)]. Progression-free survival, overall response rate, duration of response, and disease control rate, were also improved. OS improvements were maintained at a 3-year data cutoff (February 28, 2024). Tislelizumab plus ICC had an acceptable safety profile with no new safety signals.</p> Conclusions <p>Tislelizumab plus ICC is an effective and tolerable first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC with a PD-L1 TAP score&#xa0;≥&#xa0;1%.</p> Trial registration number <p>NCT03777657.</p>

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First-Line Tislelizumab Plus Chemotherapy for Advanced Gastric Cancer with Programmed Death-Ligand 1 Expression ≥ 1%: A Retrospective Analysis of RATIONALE-305

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  • 发表日期：

    2025年3月13日

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  • Markus Moehler,
  • Do-Youn Oh,
  • Ken Kato,
  • Tobias Arkenau,
  • Josep Tabernero,
  • Keun-Wook Lee,
  • Sun Young Rha,
  • Hidekazu Hirano,
  • David Spigel,
  • Kensei Yamaguchi,
  • Lucjan Wyrwicz,
  • Umut Disel,
  • Roberto A. Pazo-Cid,
  • Lorenzo Fornaro,
  • Yaling Xu,
  • Tao Sheng,
  • Silu Yang,
  • Alysha Kadva,
  • Marcia Cruz-Correa,
  • Rui-Hua Xu

摘要

Introduction

Tislelizumab plus investigator-chosen chemotherapy (ICC) demonstrated a statistically significant improvement in overall survival (OS) versus placebo plus ICC in RATIONALE-305 in patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric cancer/gastroesophageal junction cancer (GC/GEJC) in the intent-to-treat population and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 5%. The United States Food and Drug Administration Oncologic Drugs Advisory Committee voted (September 2024) against first-line treatment with programmed cell death protein-1 inhibitors in this setting in patients with a PD-L1 combined positive score < 1 or TAP score < 1%, due to an unfavorable benefit–risk profile. Thus, we retrospectively analyzed data from RATIONALE-305 in patients with a PD-L1 TAP score ≥ 1%.

Methods

Adult patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC were randomized to tislelizumab 200 mg or placebo with ICC every 3 weeks. Efficacy and safety outcomes of tislelizumab plus ICC versus placebo plus ICC were retrospectively assessed in those with a PD-L1 TAP score ≥ 1%.

Results

At the final analysis cutoff (February 28, 2023), 432 patients received tislelizumab plus ICC and 453 received placebo plus ICC, and had a PD-L1 TAP score ≥ 1%. Clinically meaningful improvements to OS were observed with tislelizumab plus ICC compared with placebo plus ICC [15.0 months (95% confidence interval [CI] 13.3–16.7) vs. 12.8 months (95% CI 12.1–14.1), respectively; stratified hazard ratio 0.77 (95% CI 0.67–0.90)]. Progression-free survival, overall response rate, duration of response, and disease control rate, were also improved. OS improvements were maintained at a 3-year data cutoff (February 28, 2024). Tislelizumab plus ICC had an acceptable safety profile with no new safety signals.

Conclusions

Tislelizumab plus ICC is an effective and tolerable first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC with a PD-L1 TAP score ≥ 1%.

Trial registration number

NCT03777657.