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期刊来源：JAMA

文献发表时间：2023-11-28

原文链接：https://jamanetwork.com/journals/jama/article-abstract/2812324

关键点内容如下：

问题

免疫检查点阻滞剂联合一线化疗能否改善复发或转移性鼻咽癌患者的无进展生存期和总生存期？

调查结果

在最后的无进展生存期分析中，托利帕利单抗治疗的无进展生存期显著长于安慰剂。预先指定的最终总体生存分析显示，与单独化疗相比，在吉西他滨-顺铂基础上加用托利帕利单抗可显著提高生存率，具有统计学意义和临床意义，且安全性可控。

意义

证实的无进展生存期和总生存期获益支持托利帕利单抗联合吉西他滨-顺铂作为复发或转移性鼻咽癌患者的新标准一线治疗。

摘要内容如下：

重要性

目前，美国食品和药物管理局尚未批准治疗鼻咽癌（NPC）的疗法。吉西他滨-顺铂是目前复发或转移性鼻咽癌（RM-NPC）一线治疗的标准治疗方案。

目的

确定与单独使用吉西他滨-顺铂相比，托利帕利单抗联合吉西他滨-顺铂作为RM-NPC的一线治疗是否会显著改善无进展生存期和总生存期。

研究设计和参与者

Jupiter-02是一项国际性、多中心、随机、双盲的3期研究，在包括中国大陆、台湾和新加坡在内的NPC流行地区进行。从2018年11月10日至2019年10月20日，来自35个参与中心的289例RM-NPC患者入选，这些患者既往未接受过RM系统化疗。

干预措施

患者随机（1:1）接受Toripalimab（240 mg[n=146]）或安慰剂（n=143）联合吉西他滨-顺铂治疗最多6个周期，随后使用Toripalimab或安慰剂维持治疗，直至疾病进展、不可耐受的毒性或完成2年治疗。

主要结局

通过盲法独立中心审查评估的无进展生存期。次要终点包括客观缓解率、总生存期、研究者评估的无进展生存期、缓解持续时间和安全性。

结果

在（入选的289名患者中，中位年龄为46[IQR，38-53岁；17%为女性），在最终的无进展生存期分析中，Toripalimab治疗的无进展生存期显著长于安慰剂（中位数分别为21.4个月和8.2个月；HR，0.52[95%CI，0.37-0.73]）。中位生存期随访为36.0个月，与安慰剂相比，Toripalimab显著改善了总生存期（风险比[HR]，0.63[95%CI，0.45-0.89]；双面P=.008）。Toripalimab组未达到中位总生存期，而安慰剂组为33.7个月。在PD-L1（程序性死亡-配体1）高表达和低表达的亚组中发现了对总生存率的一致影响，有利于Toripalimab。两组间所有不良事件、3级或以上不良事件和致命性不良事件的发生率相似。然而，导致停用托利帕利单抗或安慰剂的不良事件（11.6%vs 4.9%）、免疫相关不良事件（54.1%vs 21.7%）和3级或以上免疫相关不良事件（9.6%vs 1.4%）在托利帕利单抗组中更为常见。

结论和相关性

与单独化疗相比，在化疗中加入Toripalimab作为RM-NPC的一线治疗提供了具有统计学意义和临床意义的无进展生存期和总生存期获益，且安全性可控。这些发现支持使用托利帕利单抗联合吉西他滨-顺铂作为该患者人群的新治疗标准。

英文原文如下：

Key Points

Question  Will an immune checkpoint blocker in combination with the first-line chemotherapy improve progression-free survival and overall survival in patients with recurrent or metastatic nasopharyngeal carcinoma?

Findings  At the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo. The prespecified final overall survival analysis revealed that the addition of toripalimab to gemcitabine-cisplatin led to statistically significant and clinically meaningful improvement in survival compared with chemotherapy alone, with a manageable safety profile.

Meaning  The demonstrated progression-free survival and overall survival benefits support the use of toripalimab in combination with gemcitabine-cisplatin as the new standard first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma.

Abstract

Importance  There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC).

Objective  To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone.

Design, Setting, and Participants  JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers.

Interventions  Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment.

Main Outcome  Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety.

Results  Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death–ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group.

Conclusions and Relevance  The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population.

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