Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the European Commission (EC) has approved KEYTRUDA ® (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with Padcev (enfortumab vedotin-ejfv), an antibody-drug conjugate, for the first-line treatment of unresectable or metastatic urothelial carcinoma in adults. The decision follows the adoption of the European Society for Medical Oncology and European Association of Urology clinical guidelines recommending the combination as the preferred first-line treatment for these patients, regardless of platinum eligibility.

默克公司 (NYSE: MRK)（在美国和加拿大以外称为 MSD）今天宣布，欧盟委员会 (EC) 已批准默克公司的抗 PD-1 疗法 KEYTRUDA® ( pembrolizumab) 与抗体-药物偶联物 Padcev (enfortumab vedotin-ejfv) 联合用于成人不可切除或转移性尿路上皮癌的一线治疗。该决定遵循了欧洲肿瘤内科学会和欧洲泌尿外科协会的临床指南，该指南推荐将联合疗法作为这些患者的首选一线治疗，无论是否符合铂类治疗条件。

This approval by the EC also follows the positive recommendation from the Committee for Medicinal Products for Human Use received in July 2024 , which was based on results from the first interim analysis of the Phase 3 KEYNOTE-A39 trial (also known as EV-302), which was conducted in a research collaboration with Pfizer (previously Seagen) and Astellas. In KEYNOTE-A39, KEYTRUDA plus enfortumab vedotin demonstrated statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) versus platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin).

欧盟委员会的此次批准也遵循了2024 年 7 月 收到的人用药品委员会的积极建议 ， 该建议基于 3 期 KEYNOTE-A39 试验（也称为 EV-302）的第一次中期分析结果 ，该试验由辉瑞公司（前身为 Seagen）和安斯泰来公司合作进行研究。在 KEYNOTE-A39 中，与铂类化疗（吉西他滨加顺铂或卡铂）相比，KEYTRUDA 加 enfortumab vedotin 在总生存期 (OS) 和无进展生存期 (PFS) 方面表现出统计学上显着且具有临床意义的改善。

At a median follow-up of 17.3 months (range, 0.3 to 37.2 months), the KEYTRUDA plus enfortumab vedotin combination reduced the risk of death by 53% (HR=0.47 [95% CI, 0.38-0.58]; p<0.00001) versus platinum-based chemotherapy (with 133/442 [30%] vs. 226/444 [51%] events observed, respectively), with the combination also reducing the risk of disease progression or death by 55% (HR=0.45 [95% CI, 0.38-0.54]; p<0.00001) versus platinum-based chemotherapy (with 223/442 [50%] vs. 307/444 [69%] events observed, respectively).

经中位随访期 17.3 个月（范围：0.3 至 37.2 个月）后，KEYTRUDA 加 enfortumab vedotin 联合治疗使死亡风险降低了 53%（HR=0.47 [95% CI, 0.38-0.58]；p<0.00001），而铂类化疗组则分别观察到 133/442 [30%] 和 226/444 [51%] 起事件，且该联合治疗还使疾病进展或死亡的风险降低了 55%（HR=0.45 [95% CI, 0.38-0.54]；p<0.00001），而铂类化疗组则分别观察到 223/442 [50%] 和 307/444 [69%] 起事件。

“For the first time in decades, adult patients with unresectable or metastatic urothelial carcinoma have the option of a potential new first-line standard of care that may help extend their lives,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “We are pleased with the European Commission’s decision, and we look forward to being able to provide KEYTRUDA as part of this novel treatment regimen for this devastating disease to patients in the European Union.”

默克研究实验室高级副总裁兼肿瘤学、全球临床开发负责人 Marjorie Green 博士表示：“几十年来，患有不可切除或转移性尿路上皮癌的成年患者首次有机会选择一种可能有助于延长其寿命的新型一线标准治疗方案。我们对欧盟委员会的决定感到高兴，我们期待能够为欧盟患者提供 KEYTRUDA，作为这种毁灭性疾病的新型治疗方案的一部分。”

This approval allows marketing of KEYTRUDA in combination with enfortumab vedotin for this indication in all 27 European Union (EU) member states, as well as Iceland, Liechtenstein, Norway and Northern Ireland. KEYTRUDA is now approved for three indications in bladder cancer, and for 28 indications overall in the EU. KEYTRUDA was previously approved in the EU as monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy, as well as adults who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 with a combined positive score (CPS) ≥10, based on results from KEYNOTE-045 and KEYNOTE-052, respectively. In December 2023 , KEYTRUDA in combination with enfortumab vedotin was approved in the U.S. for the treatment of adult patients with locally advanced or metastatic urothelial cancer.

此项批准允许 KEYTRUDA 与 enfortumab vedotin 联合用于治疗该适应症，并在所有 27 个欧盟成员国以及冰岛、列支敦士登、挪威和北爱尔兰上市。KEYTRUDA 目前已获批用于治疗三种膀胱癌适应症，在欧盟总共获批用于治疗 28 种适应症。KEYTRUDA 此前已 在 欧盟获批作为单一疗法，用于治疗局部晚期或转移性尿路上皮癌成人患者，这些患者既往接受过含铂化疗，以及不适合接受含顺铂化疗且肿瘤表达 PD-L1 且综合阳性评分 (CPS) ≥10 的成人患者（基于 KEYNOTE-045 和 KEYNOTE-052 的结果）。2023 年 12 月 ，KEYTRUDA 与 enfortumab vedotin 联合用于治疗局部晚期或转移性尿路上皮癌成人患者。

Merck, in collaboration with Pfizer and Astellas, is evaluating this combination as part of an extensive clinical development program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in muscle-invasive bladder cancer in KEYNOTE-B15 ( NCT04700124 , also known as EV-304) and KEYNOTE-905 ( NCT03924895 , also known as EV-303).

默克公司正与辉瑞公司和安斯泰来公司合作，对这一组合进行评估，将其作为尿路上皮癌多阶段广泛临床开发计划的一部分，其中包括两项针对肌层浸润性膀胱癌的 3 期临床试验，即 KEYNOTE-B15（ NCT04700124 ，也称为 EV-304）和 KEYNOTE-905（ NCT03924895 ，也称为 EV-303）。

About KEYNOTE-A39

关于 KEYNOTE-A39

The KEYNOTE-A39 trial is an open-label, multicenter, randomized, active-controlled Phase 3 trial (ClinicalTrials.gov, NCT04223856 ) evaluating KEYTRUDA plus enfortumab vedotin compared to platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) for the treatment of patients with unresectable or metastatic urothelial carcinoma. The primary efficacy outcome measures were PFS as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and OS. Secondary outcome measures included objective response rate (ORR) and duration of response (DOR) as assessed by BICR according to RECIST v1.1. The study enrolled 886 patients who were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

KEYNOTE-A39 试验是一项开放标签、多中心、随机、阳性对照的 3 期试验（ClinicalTrials.gov， NCT04223856 ），评估 KEYTRUDA 加 enfortumab vedotin 与铂类化疗（吉西他滨加顺铂或卡铂）对比治疗不可切除或转移性尿路上皮癌患者的疗效。主要疗效结果指标是 PFS（由盲法独立中央评审 (BICR) 根据实体肿瘤疗效评价标准 (RECIST) v1.1 评估）和 OS。次要结果指标包括客观缓解率 (ORR) 和缓解持续时间 (DOR)（由 BICR 根据 RECIST v1.1 评估）。该研究招募了 886 名患者，他们被随机分配（1:1）到以下治疗组之一；所有研究药物均通过静脉输注给药：

KEYTRUDA 200 mg over 30 minutes on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle. Gemcitabine 1000 mg/m 2 on Days 1 and 8 and investigator’s choice of cisplatin 70 mg/m 2 or carboplatin (AUC 4.5 or 5 mg/mL/min according to local guidelines) on Day 1 of each 21-day cycle.

KEYTRUDA 200 mg，第 1 天，30 分钟内给药，enfortumab vedotin 1.25 mg/kg，在每个 21 天周期的第 1 天和第 8 天给药。 在每个 21 天周期的第 1 天，给予吉西他滨 1000 mg/m 2 ，并由研究者选择给予顺铂 70 mg/m 2 或卡铂（根据当地指南，AUC 为 4.5 或 5 mg/mL/min）。

Treatment with KEYTRUDA and enfortumab vedotin continued until RECIST v1.1-defined progression of disease, unacceptable toxicity or, for KEYTRUDA, a maximum of 35 cycles (up to approximately two years). Assessment of tumor status was performed every nine weeks for 18 months and then every 12 weeks thereafter.

KEYTRUDA 和 enfortumab vedotin 治疗持续至 RECIST v1.1 定义的疾病进展、不可接受的毒性，或对于 KEYTRUDA，最多 35 个周期（最长约两年）。18 个月内每 9 周评估一次肿瘤状态，之后每 12 周评估一次。