Yue Dongsheng, Wang Wenxiang, Liu Hongxu, Chen Qixun, Chen Chun, Liu Lunxu, Zhang Peng, Zhao Guofang, Yang Fan, Han Guang, Cheng Ying, Yu Bentong, Yang Yue, Chen Haiquan, Jiang Jie, Tan Lijie, Xu Shidong, Mao Naiquan, Hu Jian, Zhang Lanjun, Yao Bin, Wang Shengfei, Wang Rui-Hua, Zheng Wenjuan, Wang Changli
Department of Lung Cancer, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
The Second Department of Thoracic Surgery, Hunan Cancer Hospital, Hunan, China.
Lancet Respir Med. 2025 Feb;13(2):119-129. doi: 10.1016/S2213-2600(24)00269-8. Epub 2024 Nov 21.
Treatment guidelines recommend neoadjuvant or adjuvant chemotherapy, with or without immune checkpoint inhibitors, for resectable non-small-cell lung cancer (NSCLC). We report the interim results for the phase 3 RATIONALE-315 study, which aimed to investigate perioperative tislelizumab for the treatment of resectable NSCLC.
RATIONALE-315 is a randomised, double-blind, placebo-controlled phase 3 trial conducted at 50 sites (hospitals or academic research centres) in China. Patients (aged ≥18 years) with untreated stage II-IIIA squamous or non-squamous NSCLC were randomly assigned (1:1) to neoadjuvant tislelizumab 200 mg or placebo intravenously every 3 weeks, plus platinum-based doublet chemotherapy followed by surgery and adjuvant tislelizumab 400 mg or placebo every 6 weeks. Dual primary endpoints were major pathological response rate and event-free survival, analysed by intention to treat. Safety was also assessed in all patients who received at least one dose of study treatment. RATIONALE-315 is registered with ClinicalTrials.gov, NCT04379635, and is active but not recruiting.
Between June 8, 2020, and Aug 31, 2022, 453 patients were assigned to tislelizumab (n=226) or placebo (n=227). The median age of patients was 62·0 years (IQR 56·0-67·0). 410 (91%) of 453 patients were male and 43 (9%) were female. As of Aug 21, 2023 (data cutoff for the interim analysis of event-free survival), median duration of follow-up was 22·0 months (IQR 15·5-28·0). Tislelizumab significantly improved event-free survival versus placebo (stratified hazard ratio 0·56 [95% CI 0·40-0·79]; one-sided p=0·0003). The major pathological response rate was significantly higher in the tislelizumab group (56% [95% CI 50-63]) than in the placebo group (15% [11-20]; difference 41% [33-49]; one-sided p<0·0001). Grade 3 or worse adverse events and serious treatment-related adverse events occurred in 163 (72%) of 226 patients and 35 (15%) of 226 patients, respectively, in the tislelizumab group, and in 150 (66%) and 18 (8%) patients, respectively, in the placebo group. The most common grade 3 or worse treatment-related adverse event was decreased neutrophil count (138 [61%] of 226 in the tislelizumab group vs 134 [59%] of 226 in the placebo group). 31 (14%) of 226 patients in the tislelizumab group and 45 (20%) of 227 patients in the placebo group died during the study.
Perioperative tislelizumab plus neoadjuvant chemotherapy showed a clinically meaningful and statistically significant improvement in efficacy and a manageable safety profile compared with neoadjuvant chemotherapy in patients with resectable stage II-IIIA NSCLC.
BeiGene.
治疗指南推荐对可切除的非小细胞肺癌（NSCLC）进行新辅助或辅助化疗，可联合或不联合免疫检查点抑制剂。我们报告了3期RATIONALE-315研究的中期结果，该研究旨在探讨围手术期使用替雷利珠单抗治疗可切除的NSCLC。
RATIONALE-315是一项在中国50个地点（医院或学术研究中心）进行的随机、双盲、安慰剂对照3期试验。年龄≥18岁、未经治疗的II-IIIA期鳞状或非鳞状NSCLC患者被随机（1:1）分配接受每3周静脉注射200mg替雷利珠单抗或安慰剂，联合铂类双联化疗，随后进行手术，术后每6周接受400mg替雷利珠单抗或安慰剂辅助治疗。双主要终点为主要病理缓解率和无事件生存期，按意向性分析。对所有接受至少一剂研究治疗的患者也进行了安全性评估。RATIONALE-315已在ClinicalTrials.gov注册，编号为NCT04379635，目前处于活性状态但不再招募患者。
2020年6月8日至2022年8月31日期间，453例患者被分配接受替雷利珠单抗治疗（n=226）或安慰剂治疗（n=227）。患者的中位年龄为62.0岁（四分位间距56.0-67.0）。453例患者中410例（91%）为男性，43例（9%）为女性。截至2023年8月21日（无事件生存期中期分析的数据截止日期），中位随访时间为22.0个月（四分位间距15.5-28.0）。与安慰剂相比，替雷利珠单抗显著改善了无事件生存期（分层风险比0.56[95%CI 0.40-0.79]；单侧p=0.0003）。替雷利珠单抗组的主要病理缓解率（56%[95%CI 50-63]）显著高于安慰剂组（15%[11-20]；差值41%[33-49]；单侧p<0.0001）。替雷利珠单抗组226例患者中有163例（72%）发生3级或更严重不良事件，226例患者中有35例（15%）发生严重治疗相关不良事件；安慰剂组分别为150例（66%）和18例（8%）。最常见的3级或更严重治疗相关不良事件是中性粒细胞计数减少（替雷利珠单抗组226例中有138例[61%]，安慰剂组226例中有134例[59%]）。替雷利珠单抗组226例患者中有31例（14%）、安慰剂组227例患者中有45例（20%）在研究期间死亡。
对于可切除的II-IIIA期NSCLC患者，围手术期使用替雷利珠单抗联合新辅助化疗与新辅助化疗相比，在疗效上显示出具有临床意义且统计学显著的改善，安全性也易于管理。
百济神州。
