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

Abstract

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.

Keywords: Clinical trial; Gastric cancer; Gastroesophageal junction cancer; Immunotherapy; PD-1 inhibitor; Tislelizumab.

Fig. 1

Kaplan–Meier curve of OS by baseline PD-L1 TAP score of ≥ 1% at the final analysis (A) and 3-year follow-up (B). PD-L1 TAP score was determined with an investigational use-only version of the VENTANA PD-L1 (SP263) CDx Assay. Unstratified hazard ratios were based on a Cox regression model. The red circles and gray triangles represent censored patients. A The data cutoff was February 28, 2023. B The data cutoff was February 28, 2024. ^aOne patient in the placebo plus ICC arm had an updated PD-L1 reading after final analysis. Overall survival rates were estimated by Kaplan–Meier method, with 95% CIs estimated using Greenwood's formula. CI confidence interval, ICC investigator-chosen chemotherapy, (m)OS (median) overall survival, PD-L1 programmed death-ligand 1, TAP Tumor Area Positivity

Fig. 2

Subgroup analysis of OS by baseline PD-L1 TAP score ≥ 1% at the final analysis (efficacy-evaluable population). The data cutoff was February 28, 2023. Medians were estimated by Kaplan–Meier method, with 95% CIs estimated using the method of Brookmeyer and Crowley using log–log transformation. The HR and its 95% CI were estimated from an unstratified Cox regression model including treatment as a covariate. The race subcategory Other includes not reported, unknown, and other. The range of the x-axis for HR is (0–3) and some extreme 95% CI values > 3 are not shown in the plot. Patients were permitted to have received prior neoadjuvant or adjuvant therapy for earlier stage GC/GEJC as long as this was completed and patients had experienced no recurrence or disease progression for at least 6 months. CI confidence interval, dMMR mismatch repair deficient, HR hazard ratio, ICC investigator-chosen chemotherapy, MSI-H/L microsatellite instability high/low, MSS microsatellite stable, PD-L1 programmed death-ligand 1, pMMR mismatch repair proficient, TAP Tumor Area Positivity

Fig. 3

Kaplan–Meier curve of PFS by baseline PD-L1 TAP score ≥ 1% at the final analysis (A) and 3-year follow-up (B). PD-L1 TAP score was determined with an investigational use-only version of the VENTANA PD-L1 (SP263) CDx Assay. Unstratified hazard ratios were based on a Cox regression model. The red circles and gray triangles represent censored patients. A The data cutoff was February 28, 2023. B The data cutoff was February 28, 2024. ^aOne patient in the placebo plus ICC arm had an updated PD-L1 reading after final analysis. Progression free survival rates were estimated by Kaplan-Meier method, with 95% CIs estimated using Greenwood's formula. CI confidence interval, ICC investigator-chosen chemotherapy, (m)PFS (median) progression-free survival, PD-L1 programmed death-ligand 1, TAP Tumor Area Positivity

Fig. 4

Subgroup analysis of PFS by baseline PD-L1 TAP score ≥ 1% at the final analysis (efficacy-evaluable population). The data cutoff was February 28, 2023. Medians were estimated by Kaplan–Meier method, with 95% CIs estimated using the method of Brookmeyer and Crowley using log–log transformation. The HR and its 95% CI were estimated from an unstratified Cox regression model including treatment as a covariate. The race subcategory 'Other' includes not reported, unknown, and other. The range of the x-axis for HR is (0–3), some extreme values greater than three are not shown in the plot. CI confidence interval, dMMR mismatch repair deficient, ECOG Eastern Cooperative Oncology Group, HR hazard ratio, ICC investigator-chosen chemotherapy, MSI-H/L microsatellite instability high/low, MSS microsatellite stable, PD-L1 programmed death-ligand 1, pMMR mismatch repair proficient, TAP Tumor Area Positivity