PD-L1为50%或以上晚期非小细胞肺癌一线塞米单抗单药治疗和进展后继续使用塞米单抗加化疗： 多中心、开放标签、随机3期试验随访

SCI

28 August 2023

First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial

(Lancet Oncol IF: 41.32)

Özgüroğlu M, Kilickap S, Sezer A, et al. First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial [published online ahead of print, 2023 Aug 14]. Lancet Oncol. 2023;S1470-2045(23)00329-7. doi:10.1016/S1470-2045(23)00329-7

Background 研究背景

Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months’ follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression.

塞米普利姆单抗为晚期非小细胞肺癌患者带来了显著的生存获益，这些患者的PD-L1肿瘤表达至少为50%，且随访1年时无可操作的生物标记物。在这项探索性分析中，我们提供了 35 个月随访后的结果，以及在疾病进展时在塞米单抗基础上加用化疗的效果。

Methods 研究方法

EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator’s choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540.

EMPOWER-Lung 1 是一项多中心、开放标签、随机的 3 期试验。我们招募了组织学确诊为鳞状或非鳞状晚期非小细胞肺癌、PD-L1肿瘤表达达50%或以上的患者（年龄≥18岁）。我们将患者随机分配（1:1）至静脉注射塞米单抗 350 毫克，每 3 周一次，最长 108 周，或直至疾病进展，或由研究者选择化疗。由交互式网络响应系统生成的中央随机方案管理随机分配过程，并按组织学和地理区域进行分层。主要终点是总生存期和无进展生存期，由盲人独立中央审查（BICR）根据《实体瘤反应评估标准》1.1版进行评估。使用赛米普利单抗后病情进展的患者可继续使用赛米普利单抗，但最多只能接受四个周期的化疗。我们以化疗开始前的最后一次扫描为新基线，通过BICR评估这些患者的反应。我们对所有随机分配的参与者（即意向治疗人群）以及PD-L1表达至少为50%的患者进行了主要终点评估。我们对所有接受了至少一剂指定治疗的患者进行了不良事件评估。该试验已在 ClinicalTrials.gov 登记，编号为 NCT03088540。

Findings 研究结果

Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months’ follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1–31·8; 149 [52%] of 284 died) versus 13·3 months (10·5–16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46–0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2–8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3–6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42–0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1–9·3) and overall survival of 15·1 months (11·3–18·7). The most common grade 3–4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment- related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals.

2017 年 5 月 29 日至 2020 年 3 月 4 日期间，我们招募了 712 名患者（其中 607 名[85%]为男性，105 名[15%]为女性）。我们随机分配了 357 名患者（50%）接受赛米普利单抗治疗，355 名患者（50%）接受化疗。284名（50%）被分配使用赛米普利单抗的患者和281名（50%）被分配使用化疗的患者经证实PD-L1表达至少达到50%。在35个月的随访中，经证实PD-L1表达至少为50%的患者中，cemiplimab组的中位总生存期为26-1个月（95% CI 22-1-31-8；284人中有149人[52%]死亡），而化疗组为13-3个月（10-5-16-2；281人中有188人[67%]死亡）（危险比[HR] 0-57，95% CI 0-46-0-71； p＜0-0001），cemiplimab组的中位无进展生存期为8-1个月（95% CI 6-2-8-8；发生214例），而化疗组为5-3个月（4-3-6-1；发生236例）（HR 0-51，95% CI 0-42-0-62；p＜0-0001）。继续使用塞米单抗加化疗作为二线疗法（n=64），中位无进展生存期为6-6个月（6-1-9-3），总生存期为15-1个月（11-3-18-7）。最常见的3-4级治疗突发不良事件是贫血（赛米普利单抗组356名患者中15人[4%]，对照组343人中60人[17%]）、中性粒细胞减少（3人[1%]，对照组35人[10%]）和肺炎（18人[5%]，对照组13人[4%]）。在接受赛米普利单抗治疗的 356 名患者中，有 10 人（3%）发生了与治疗相关的死亡（原因包括自身免疫性心肌炎、心力衰竭、心肺功能骤停、脓毒性休克、肿瘤过度进展、肾炎、呼吸衰竭，[n=1]）、 呼吸衰竭[各1例]和全身失调或不明原因[各2例]），以及343例接受化疗的患者中的7例（2%）（肺炎和肺栓塞[各2例]，以及心脏骤停、肺脓肿和心肌梗死[各1例]）。在35个月内使用赛米普利单抗以及继续使用赛米普利单抗加化疗的安全性概况与之前观察到的这些疗法的安全性概况基本一致，没有出现新的安全性信号。

Interpretation 解读

At 35 months’ follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. 

在35个月的随访中，塞米普利单抗为晚期非小细胞肺癌患者带来的生存获益至少与1年时的获益相同，这肯定了塞米普利单抗作为一线单药疗法在这一人群中的应用。晚期非小细胞肺癌患者在化疗的基础上加用舍米普利单抗，可能会成为一种新的二线治疗方法。

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