托利帕单抗联合化疗作为广泛期小细胞肺癌的一线疗法

IF 22.5 1区医学 Q1 ONCOLOGY

JAMA Oncology Pub Date : 2024-11-14 DOI:10.1001/jamaoncol.2024.5019

Ying Cheng, Wei Zhang, Lin Wu, Caicun Zhou, Donglin Wang, Bing Xia, Minghong Bi, Xiuhua Fu, Chong Li, Dongqing Lv, Yanqiu Zhao, Gongyan Chen, Tienan Yi, Jianan Huang, Min Li, Runxiang Yang, Xiaoping Huang, Ye Wang, Mingjun Zhang, Yueyin Pan, Yilan Sun, Sheng Hu, Xiqin Zhang, Min Zhou, Jian Fang, Faguang Jin, Yunpeng Liu, Yinyin Li, Zhihong Zhang, Jie Hu, Laiyu Liu, Rui Wang, Yan Li, Kangsheng Gu, Cuimin Ding, Qingxia Fan, Guojun Zhang, Yongxing Chen, Liyan Jiang, Wei-E. Zheng, Shaoshui Chen, Cheng Huang, Zhigang Han, Hong Yang, Jianfang Wang, Baocheng Wang, Huita Wu, Yongxing Bao, Manxiang Li, Xianming Luo, Shanshan Gu, Wenbo Yu, Kai Xu, Simo Zhang, Jianjun Yu

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引用次数: 0

摘要

重要性广泛期小细胞肺癌（ES-SCLC）患者预后较差，医疗需求尚未得到满足。目的评估托利帕利单抗联合依托泊苷和铂类化疗（EP）与安慰剂联合EP作为ES-SCLC患者一线治疗的有效性和安全性。设计、设置和参与者这项多中心、双盲、安慰剂对照的3期随机临床试验（EXTENTORCH研究）从2019年9月26日至2021年5月20日在中国的49个地点招募患者。符合条件的患者经组织学或细胞学确诊为ES-SCLC，既往未接受过ES-SCLC的全身抗肿瘤治疗。干预措施患者随机（1:1）接受每3周一次的托瑞帕利单抗（240 mg）或安慰剂加EP治疗，最多4至6个周期，随后接受托瑞帕利单抗或安慰剂维持治疗，直至疾病进展、出现不可耐受的毒性反应或治疗长达2年。主要结果和测量主要终点为研究者评估的无进展生存期（PFS）和总生存期（OS）。全外显子组测序结果确定了临床疗效的相关生物标志物。结果在595名经过筛选的患者中，442名符合条件的患者被随机分组（中位数[范围]年龄为63[30-77]岁；366[82.8%]名男性）；223名患者被随机分组为托利帕利单抗加EP，219名患者被随机分组为安慰剂加EP。截至2023年4月20日，中位（范围）生存随访时间为13.7（0.0-42.7）个月。与安慰剂相比，托瑞帕利单抗改善了研究者评估的 PFS（危险比 [HR]，0.67 [95% CI，0.54-0.82]；P &lt; .001），并显著降低了死亡风险（HR，0.80 [95% CI，0.65-0.98]；P = .03）。托利帕单抗组的中位OS为14.6（95% CI，12.9-16.6）个月，安慰剂组为13.3（95% CI，11.8-14.4）个月。300例患者的全外显子组测序结果显示，肿瘤内异质性低、HLA-A11+ HLA-B62-单倍型、野生型KMT2D和COL4A4或CTNNA2或SCN4A序列变异与托利帕单抗组良好的PFS和OS相关。未观察到新的安全性信号。在这项3期随机临床试验中，在一线化疗中加入托利帕利单抗可显著改善ES-SCLC患者的PFS和OS。该疗法的安全性可接受，支持将这种联合疗法作为 ES-SCLC 患者的一种新的治疗选择：NCT04012606

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Toripalimab Plus Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Lung Cancer

ImportancePatients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs.ObjectiveTo evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC.Design, Setting, and ParticipantsThis multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024.InterventionsPatients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment.Main Outcomes and MeasuresThe primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy.ResultsAmong 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P &lt; .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62− haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively).Conclusions and RelevanceIn this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC.Trial RegistrationClinicalTrials.gov Identifier: NCT04012606

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来源期刊

JAMA Oncology Medicine-Oncology

自引率

1.80%

发文量

423

期刊介绍： JAMA Oncology is an international peer-reviewed journal that serves as the leading publication for scientists, clinicians, and trainees working in the field of oncology. It is part of the JAMA Network, a collection of peer-reviewed medical and specialty publications.