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. 2025 Sep 14.
doi: 10.1007/s40487-025-00378-8. Online ahead of print.

First-Line Tislelizumab Plus Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer: PD-L1 ≥ 50% Subgroup Analysis from the RATIONALE-304 Trial

Shun Lu  1 , Jie Wang  2 , Yan Yu  3 , Xinmin Yu  4 , Yanping Hu  5 , Liao Wangjun  6 , Xingya Li  7 , Yuepeng Liu  8 , Weidong Li  9 , Xiaofei Qu  10 , Yuanyuan Bao  11 , Mengzhao Wang  12
Affiliations
Free article

First-Line Tislelizumab Plus Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer: PD-L1 ≥ 50% Subgroup Analysis from the RATIONALE-304 Trial

Shun Lu et al. Oncol Ther. .
Free article

Abstract

Introduction: RATIONALE-304 compared first-line tislelizumab (a programmed cell death protein 1 inhibitor) plus chemotherapy versus chemotherapy in advanced non-squamous non-small cell lung cancer (nsq-NSCLC). This exploratory analysis focused on patients with tumor cell programmed death ligand 1 (PD-L1) expression ≥ 50%.

Methods: Patients with stage IIIB/IV nsq-NSCLC were randomized (2:1) to tislelizumab plus platinum-based chemotherapy and pemetrexed every 3 weeks, followed by maintenance tislelizumab and pemetrexed, or platinum-based chemotherapy and pemetrexed followed by maintenance pemetrexed. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS); secondary endpoints included overall survival (OS), IRC-assessed objective response rates, and safety.

Results: The PD-L1 ≥ 50% population included 110 patients (tislelizumab plus chemotherapy, n = 74; chemotherapy, n = 36); 71.8% (n = 79) were male and 28.2% (n = 31) were female. Consistent with the final analysis (median follow-up 16.5 months), the 4-year follow-up data (median follow-up 23.4 months) continued to show an improvement in median PFS (17.2 vs. 4.6 months; stratified HR 0.29, 95% CI 0.17-0.50) and median OS (41.9 vs. 13.1 months; stratified HR 0.38, 95% CI 0.23-0.62) for patients who received tislelizumab plus chemotherapy versus chemotherapy. An additional post hoc analysis showed no significant differences in PFS or OS between PD-L1 50-89% and ≥ 90% subgroups in the tislelizumab plus chemotherapy arm. The safety profile of tislelizumab plus chemotherapy was manageable and consistent with previous analyses.

Conclusions: In patients with advanced nsq-NSCLC and PD-L1 tumor cell expression ≥ 50%, first-line tislelizumab plus chemotherapy demonstrated clinically meaningful improvement in PFS and OS versus chemotherapy. Efficacy was consistent across subgroups of patients with high PD-L1 tumor cell expression levels (50-89% and ≥ 90%).

Trial registration: Clinical Trials.gov NCT03663205.

Keywords: Anti-PD-1 antibody; First line; Non-small cell lung cancer; Stage IIIB-IV; Tislelizumab.

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Conflict of interest statement

Declarations. Conflicts of Interest: Shun Lu reports fees from AstraZeneca, BeOne Medicines, Bristol Myers Squibb, GenomiCare Hansoh, Hengrui, Hutchison MediPharma, Menarini, Mirati Therapeutics Inc, Novartis, Pfizer, Roche, Yuhan Corporation, and ZaiLab. Xiaofei Qu was an employee of BeOne Medicines, Ltd. during the time this study was conducted and manuscript developed. Yuanyuan Bao is an employee of BeOne Medicines, Ltd. Jie Wang, Yan Yu, Xinmin Yu, Yanping Hu, Liao Wangjun, Xingya Li, Yuepeng Liu, Weidong Li, and Mengzhao Wang declare no conflicts of interest. Ethical Approval: RATIONALE-304 was conducted in conformance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and its amendments, and was approved by the relevant institutional review board/independent ethics committee for each study site (Supplementary Table S1). Written informed consent from each patient was obtained before study participation.

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