First-Line Tislelizumab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Cancer: Three-Year Follow-Up of the Phase 3 RATIONALE-309 Randomized Clinical Trial.

Immunotherapy plus chemotherapy has shown promise, but long-term data are needed to guide first-line treatment.

免疫治疗联合化疗显示出希望，但需要长期数据来指导一线治疗。

Background

To evaluate the 3-year efficacy and safety of tislelizumab plus chemotherapy vs placebo plus chemotherapy in participants with recurrent or metastatic NPC and explore potential biomarkers of treatment response.

评估替雷利珠单抗联合化疗与安慰剂联合化疗在复发或转移性鼻咽癌患者中3年的疗效和安全性，并探索治疗反应的潜在生物标志物。

DESIGN, SETTING, AND PARTICIPANTS: The RATIONALE-309 trial was a double-blind, placebo-controlledphase 3 randomized clinical trial conducted in Asia from April 2019 to December 2023.

设计、地点和参与者：RATIONALE-309试验是一项双盲、安慰剂对照的3期随机临床试验，于2019年4月至2023年12月在亚洲进行。

Treatment-naive adults with histologically or cytologically confirmed recurrent or metastatic NPC were included.

纳入了经组织学或细胞学证实的复发或转移性鼻咽癌（NPC）且未接受过治疗的成年患者。

Data were analyzed from December 2023 to January 2024.

数据从2023年12月至2024年1月进行分析。

Methods

Participants were randomized 1:1 to receive tislelizumab, 200 mg, intravenously or placebo every 3 weeks, both with gemcitabine and cisplatin for 4 to 6 cycles.

参与者被随机分为1:1，接受静脉注射替雷利珠单抗200 mg或安慰剂，每3周一次，均与吉西他滨和顺铂联合使用，持续4至6个周期。

Participants in the placebo arm could cross over to tislelizumab monotherapy at disease progression.

安慰剂组的参与者在疾病进展时可以转为接受替雷利珠单药治疗。

main_outcomes_and_measures

The primary end point was progression-free survival(PFS) assessed by an independent review committee.

主要终点是由独立审查委员会评估的无进展生存期（PFS）。

The primary hypothesis (PFS superiority for tislelizumab vs placebo) was specified in the protocol prior to data collection.

主要假设（替雷利珠单抗与安慰剂相比的无进展生存期优越性）在数据收集之前已在方案中明确指定。

Secondary end points included overall survival(OS), PFS after next-line therapy, and safety.

次要终点包括总生存（OS）、后续治疗后的无进展生存期（PFS）以及安全性。

Results

Of 263 included participants, 206 (78.3%) were male, and the median (range) age was 50 (23-74) years; the median (range) follow-up was 27.5 (0.1-53.0) months.

在纳入的263名参与者中，有206名（78.3%）为男性，中位年龄（范围）为50岁（23-74岁）；中位随访时间（范围）为27.5个月（0.1-53.0个月）。

A total of 131 were randomized to the tislelizumab group and 132 to the placebo group.

共有131名患者被随机分配到替雷利珠单抗组，132名患者被随机分配到安慰剂组。

Tislelizumab plus chemotherapy demonstrated improved PFS vs placebo plus chemotherapy (median PFS, 9.6 months [95% CI, 7.6-11.6] vs 7.4 months [95% CI, 5.6-7.6]; hazard ratio[HR], 0.53; 95% CI, 0.39-0.71).

替雷利珠单抗联合化疗组与安慰剂联合化疗组相比，无进展生存期（PFS）有所改善（中位PFS，9.6个月[95%置信区间，7.6-11.6]对比7.4个月[95%置信区间，5.6-7.6]；风险比[HR]，0.53；95%置信区间，0.39-0.71）。

The median OS was 45.3 months (95% CI, 33.4 to not estimable) vs 31.8 months (95% CI, 25.0 to not estimable), respectively (HR, 0.73; 95% CI, 0.51-1.05).

总生存期的中位数分别为45.3个月（95%置信区间，33.4至无法估计）和31.8个月（95%置信区间，25.0至无法估计），分别对应（风险比，0.73；95%置信区间，0.51-1.05）。

Rank-preserving structural failure time analysis (HR, 0.56; 95% CI, 0.27-1.19) and 2-stage crossover-adjusted analysis (HR, 0.62; 95% CI, 0.40-0.97) showed greater OS benefit.

等级保持结构失效时间分析（风险比，0.56；95%置信区间，0.27-1.19）和两阶段交叉调整分析（风险比，0.62；95%置信区间，0.40-0.97）显示了更大的总生存期获益。

Treatment-emergent adverse events occurred in 133 of 133 participants (100%) in the tislelizumab arm and 129 of 130 participants (99.2%) in the placebo arm, with comparable grade 3 or higher adverse eventrates.

在 tislelizumab 组的 133 名参与者中，有 133 名（100%）出现了治疗相关不良事件，在安慰剂组的 130 名参与者中，有 129 名（99.2%）出现了治疗相关不良事件，两组的3级或更高级别的不良事件发生率相当。

Immune-mediated adverse events were more frequent with tislelizumab (71 [53.4%] vs 49 [37.7%]) but mostly of grades 1 or 2.

tislelizumab 组的免疫介导的不良事件发生率更高（71 [53.4%] vs 49 [37.7%]），但大多数为1级或2级。

High B-cell gene expression was associated with greater OS benefit (HR, 0.41; 95% CI, 0.23-0.74).

高B细胞基因表达与更大的总生存获益相关（HR, 0.41; 95% 置信区间, 0.23-0.74）。

conclusions_and_relevance

In this secondary analysis of the RATIONALE-309 randomized clinical trial, after 3 years of follow-up, tislelizumab plus chemotherapy provided sustained PFS and meaningful OS improvement vs placebo plus chemotherapy in recurrent or metastatic NPC, with an acceptable safety profile.

在这项RATIONALE-309随机临床试验的事后分析中，经过3年的随访，替雷利珠单抗联合化疗与安慰剂联合化疗相比，在复发或转移性鼻咽癌中提供了持续的无进展生存期（PFS）和有意义的总生存期（OS）改善，且具有可接受的安全性。

Greater benefit was observed in participants with activated immune signatures, especially high B-cell expression.

在具有激活免疫标志物的参与者中观察到更大的益处，尤其是高B细胞表达者。

trial_registration

ClinicalTrials.gov Identifier: NCT03924986.

ClinicalTrials.gov注册号：NCT03924986。