Enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (EV-302): patient-reported outcomes from an open-label, randomised, controlled, phase 3 study.

Patient-reported outcomes (PROs) from EV-302 are reported here.

EV-302试验的患者报告结果（PROs）在此报告。

Methods

EV-302 was a phase 3, open-label, two-group, randomised global study to evaluate the combination of enfortumab vedotin plus pembrolizumab versus standard-of-care platinum-based chemotherapy (gemcitabine with cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial cancer.

EV-302 是一项第三阶段、开放标签、两组、随机的全球研究，旨在评估恩福他滨维多汀联合派姆单抗与标准护理铂类化疗（吉西他滨联合顺铂或卡铂）在先前未接受治疗的局部晚期或转移性尿路上皮癌患者中的效果。

The study was done at 185 clinical sites in 25 countries.

该研究在25个国家的185个临床地点进行。

Eligible patients were aged 18 years and older with unresectable untreated locally advanced or metastatic urothelial cancer, were eligible for platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less.

符合条件的患者年龄在18岁及以上，患有不可切除的未治疗的局部晚期或转移性尿路上皮癌，适合接受铂类为基础的化疗，并且东部肿瘤协作组（ECOG）表现状态为2或更好。

Patients were randomly assigned (1:1) to receive either enfortumab vedotin (1·25 mg/kg, intravenously) on days 1 and 8 of 3-week cycles plus pembrolizumab (200 mg, intravenously) on day 1 of each cycle; or platinum-based chemotherapy consisting of gemcitabine (1000 mg/m2, intravenously) on days 1 and 8 of each cycle plus either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC] 4·5 or 5·0 according to local guidelines) on day 1 of each 3-week cycle for up to six cycles using interactive response technology.

患者按1:1的比例随机分配接受以下治疗：在3周为一个周期的第1天和第8天静脉注射enfortumab vedotin（1.25 mg/kg），以及每个周期的第1天静脉注射pembrolizumab（200 mg）；或者接受以铂类为基础的化疗，包括每个周期的第1天和第8天静脉注射吉西他滨（1000 mg/m2），以及每个3周周期的第1天静脉注射顺铂（70 mg/m2）或根据当地指南卡铂（AUC 4.5或5.0），最多六个周期，使用交互式响应技术。

Randomisation was stratified by cisplatin eligibility, PD-L1 expression status, and presence or absence of liver metastases.

随机分组根据顺铂适应性、PD-L1表达状态以及是否存在肝转移进行了分层。

The dual primary endpoints of progression-free survivaland overall survivalin patients with locally advanced or metastatic urothelial cancer have been reported previously.

之前已经报告了局部晚期或转移性尿路上皮癌患者无进展生存和总生存的双重主要终点。

Here, we report additional, protocol-prespecified secondary endpoint data, and statistical analysis plan-prespecified descriptive endpoints assessing patient quality of life (QOL).

在此，我们报告了额外的、协议预定的次要终点数据，以及统计分析计划预定的描述性终点，这些终点用于评估患者的生活质量（QOL）。

These endpoints related to patient functioning and symptoms and were assessed using two PRO questionnaires: the Brief Pain Inventory-Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).

这些终点与患者的机能和症状相关，并使用两种患者报告结果问卷进行评估：简短疼痛调查表-短表（BPI-SF）和欧洲癌症研究与治疗组织生活质量问卷核心30（EORTC QLQ-C30）。

The PRO full analysis set comprised patients who received study treatment and completed at least one baseline PRO questionnaire.

PRO 完整分析集包括接受研究治疗并至少完成一次基线 PRO 问卷的患者。

The BPI-SF and the EORTC QLQ-C30 were completed at baseline, weekly for 12 weeks, at week 14, then every 3 weeks during follow-up.

BPI-SF 和 EORTC QLQ-C30 在基线时、每周连续12周、第14周以及随访期间每3周完成一次。

Time to pain progression and mean change from baseline in BPI-SF worst pain at week 26 were protocol-prespecified secondary endpoints tested by the hierarchical gatekeeping strategy.

疼痛进展时间和第26周基线时BPI-SF最差疼痛评分的平均变化是预先设定的次要终点，通过层次化门控策略进行测试。

Mean change from baseline to week 26 in EORTC QLQ-C30 and BPI-SF scale scores were analysed descriptively.

从基线到第26周EORTC QLQ-C30和BPI-SF量表评分的平均变化被描述性分析。

The trial is registered with ClinicalTrials.gov, NCT04223856.

该试验已在ClinicalTrials.gov注册，注册号为NCT04223856。

Results

At data cutoff on Aug 8, 2023, 886 patients were enrolled in the study, with a median duration of follow-up for survival of 17·2 months (IQR 12·5-21·7). 731 (83%) of 886 patients completed at least one PRO questionnaire at baseline and were included in the PRO full analysis set, with 376 patients treated with enfortumab vedotin plus pembrolizumab and 355 with platinum-based chemotherapy. 570 (78%) of 731 patients were male, 161 (22%) were female, and 479 (66%) patients were White.

截至2023年8月8日的数据截止时，共有886名患者参与了该研究，生存随访的中位持续时间为17.2个月（四分位数间距12.5-21.7）。

There was no significant difference in time to pain progression between treatments; hence differences in least squares mean change in BPI-SF worst pain score from baseline to week 26 with enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy were not formally tested.

治疗之间在疼痛进展时间上没有显著差异；因此，对于enfortumab vedotin联合pembrolizumab与基于铂的化疗相比，从基线到第26周BPI-SF最差疼痛评分的最小二乘均值变化差异没有进行正式测试。

However, a numerical improvement from baseline up to week 26 was observed (least squares mean -0·74, SE 0·12 vs -0·36, 0·12; least squares mean difference -0·38, SE 0·13; 95% CI -0·64 to -0·12; nominal two-sided p value 0·0037).

然而，观察到从基线到第26周的数值改善（最小二乘均值-0·74，标准误0·12 vs -0·36，0·12；最小二乘均值差异-0·38，标准误0·13；95%置信区间-0·64至-0·12；名义双侧p值0·0037）。

Overall least squares mean change in EORTC QLQ-C30 Global Health Status (GHS)/QOL from baseline up to week 26 favoured enfortumab vedotin plus pembrolizumab (least squares mean difference 2·54, 95% CI 0·41-4·67).

从基线到第26周，EORTC QLQ-C30全球健康状况（GHS）/生活质量（QOL）的整体最小二乘均值变化，倾向于恩福他木单抗联合派姆单抗（最小二乘均值差异2.54，95%置信区间0.41-4.67）。

In patients with moderate to severe baseline pain (worst pain score ≥5) receiving enfortumab vedotin plus pembrolizumab, there were clinically meaningful improvements from baseline up to week 26 in worst pain (least squares mean change: enfortumab vedotin plus pembrolizumab -2·96 [SE 0·22], platinum-based chemotherapy -2·43 [0·21]; least squares mean difference -0·53, 95% CI -1·03 to -0·02; nominal p=0·041) and in EORTC QLQ-C30 GHS/QOL (least squares mean change: enfortumab vedotin plus pembrolizumab 8·88 [1·53], platinum-based chemotherapy 4·11 [1·45]; least squares mean difference 4·77, 95% CI 1·24-8·29; nominal p=0·0083).

在接受恩福他木单抗联合派姆单抗治疗的中度至重度基线疼痛（最痛评分≥5）患者中，从基线到第26周，在最痛（最小二乘均值变化：恩福他木单抗联合派姆单抗-2.96 [SE 0.22]，铂类化疗-2.43 [0.21]；最小二乘均值差异-0.53，95%置信区间-1.03至-0.02；名义p=0.041）和EORTC QLQ-C30 GHS/QOL（最小二乘均值变化：恩福他木单抗联合派姆单抗8.88 [1.53]，铂类化疗4.11 [1.45]；最小二乘均值差异4.77，95%置信区间1.24-8.29；名义p=0.0083）方面，有临床上有意义的改善。

interpretation

Enfortumab vedotin plus pembrolizumab significantly improved survival outcomes versus platinum-based chemotherapy without detriment to GHS/QOL, pain, or functioning.

恩沃利单抗联合帕博利珠单抗显著改善了生存结果，与含铂化疗相比，未对全球健康状况/生活质量、疼痛或功能造成损害。

Patients with moderate to severe baseline pain had clinically meaningful improvements in worst pain and GHS/QOL with enfortumab vedotin plus pembrolizumab.

基线疼痛为中度至重度的患者在接受恩沃利单抗联合帕博利珠单抗治疗后，在最差疼痛和整体健康状况/生活质量方面有临床上显著的改善。

These data provide further evidence to support the use of enfortumab vedotin plus pembrolizumab as a preferred treatment option for patients with previously untreated locally advanced or metastatic urothelial cancer.

这些数据进一步证明了将恩福妥单抗维多替尼联合派姆单抗作为先前未接受治疗的局部晚期或转移性尿路上皮癌患者的首选治疗方案的合理性。

funding

Seagen (acquired by Pfizer in December, 2023), Astellas Pharma, and Merck Sharp & Dohme.

Seagen（2023年12月被辉瑞收购）、安斯泰来制药和默克夏普与多姆公司。