-安斯泰来VYLOY(zolbetuximab-clzb)获美国 FDA 批准用于治疗晚期胃和胃食管交界处(GEJ)腺癌
-VYLOY是美国首个也是目前唯一被批准的靶向CLDN18.2药物，用于治疗成人CLDN18.2阳性的晚期胃和胃食管交界处腺癌
东京，2024年10月18日--安斯泰来制药集团(TSE：4503，总裁兼首席执行官：冈村直树，“安斯泰来”)今天宣布，
美国食品和药品监督管理局(FDA)已批准 VYLOY®(zolbetuximab-clzb)与含氟尿嘧啶和铂类化疗药物联合用于一线治疗患有局部晚期不可切除或转移性胃或胃食管交界处(GEJ)腺癌，且人表皮生长因子受体2HER2)阴性、经FDA批准的检测确定其肿瘤为紧密连接蛋白(CLDN)18.2阳性的成年患者。1VYLOY是美国首个且目前唯一一个得到FDA批准的CLDN18.2靶向疗法。
在SPOTLIGHT和GLOW两项临床试验中，约38%的患者肿瘤筛查为CLDN18.2表达阳性。2,3[场景1：同时批准- CLDN18.2阳性定义为由罗氏VENTANA®CLDN18(43-14A) RxDx检测确定，≥75%的肿瘤细胞膜显示中至强染色强度的CLDN18。2,3安斯泰来与罗氏合作开发新批准的免疫组织化学(IHC)伴随诊断(CDx)测试，用来辨识可能适用 VYLOY治疗的患者。4场景2：VENTANA之前批准- CLDN18.2阳性定义为经由FDA批准的检测确定， ≥75%的肿瘤细胞膜显示中至强染色强度的CLDN18。2,3安斯泰来与罗氏合作开发免疫组织化学(IHC)伴随诊断(CDx)测试，用来辨识可能适用VYLOY治疗的患者。4]
Moitreyee Chatterjee-Kishore
博士、工商管理学硕士，安斯泰来公司高级副总裁兼免疫肿瘤学开发主管
“这项批准，使VYLOY成为美国首个且目前唯一的靶向CLDN18.2阳性的治疗药物，体现出我们对科学进步不懈地追究，特别是像胃和胃食管交界处腺癌这类通常进展到晚期才被发现的严重的致命疾病。这一成就源于多年来专注于靶向新型生物标志物研发，我们对参与其中的患者、研究人员和安斯泰来团队成员表示感谢。”
Samuel J. Klempner
医学博士，哈佛医学院副教授，波士顿马萨诸塞州总医院肿瘤内科医生
“虽然过去几年局部晚期不可切除和转移性胃和胃食管交界处腺癌的一线治疗取得了进展，但我们的患者仍然存在巨大的未满足的需求。VYLOY的批准基于SPOTLIGHT和 GLOW两项关键的III期试验，为 CLDN18.2阳性并处于晚期一线治疗决策的患者带来了新型生物标志物和新疗法。”
批准是基于两个III期研究SPOTLIGHT和GLOW临床试验的结果。2,3SPOTLIGHT试验评估了VYLOY+mFOLFOX6(一种包括奥沙利铂、亚叶酸钙和氟尿嘧啶的联合用药方案)与安慰剂+mFOLFOX6的疗效对比结果。GLOW试验评估了VYLOY+CAPOX(一种包括卡培他滨和奥沙利铂的联合化疗方案)与安慰剂+CAPOX的疗效对比结果。两项试验均达到了主要终点无进展生存期(PFS)以及关键的次要终点总生存期(OS)，与安慰剂加化疗相比，接受VYLOY加化疗的患者的PFS和OS具有统计学意义。SPOTLIGHT和GLOW 2项中，VYLOY治疗组最常见的治疗中出现的不良事件(TEAE) 是恶心、呕吐和食欲下降。2,3
场景1：同时批准–经由FDA批准的检测，辨识可能适用VYLOY的患者。1罗氏的VENTANA CLDN18(43-14A) RxDx检测是一种IHC测试，用于帮助确定CLDN18.2表达。在美国可通过多个参考实验室和主要实验室进行检测，预计后续将扩展到更多实验室。请访问VYLOYhcp.com，查看可以检测CLDN18.2表达的地点。
场景2：VENTANA之前批准-经由FDA批准的检测，明确可能受益VYLOY和化疗的患者。1在美国可通过多个参考实验室和主要实验室进行检测，预计后续将扩展到更多实验室。请访问VYLOYhcp.com，查看可以检测CLDN18.2表达的地点。
随着FDA的批准决定，VYLOY当前已经在全球五个市场获得批准，分别是日本、英国、欧盟、韩国和美国。日本厚生劳动省(MHLW)于2024年3月26日批准了VYLOY的上市许可，标志着该治疗的全球首次批准。8月，VYLOY被英国药品和健康产品管理局批准，9月VYLOY分别被欧盟委员会和韩国食品药品管理局授予上市批准。安斯泰来已经在全球递交了VYLOY的上市申请，目前正处于审核阶段。
安斯泰来已在本财年(截至2025年3月31日)的财务预测中体现了这一批准的影响。
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关于VYLOY®(zolbetuximab-clzb)
VYLOY®(zolbetuximab-clzb)是一种靶向claudin-18.2溶细胞抗体，被美国FDA批准与氟尿嘧啶和铂类化疗联合用于一线治疗HER2阴性、其肿瘤经FDA批准的检测确定为CLDN 18.2阳性的局部晚期不可切除或转移性胃或胃食管交界处(GEJ)腺癌。作为同类首创的单克隆抗体(mAb)，VYLOY靶向并与紧密连接蛋白CLDN18.2结合。VYLOY通过抗体依赖性细胞毒性(ADCC)和补体依赖性细胞毒性(CDC)消除CLDN18.2阳性细胞。1
适应症
VYLOY与含氟尿嘧啶和铂类化疗联合，用于一线治疗人表皮生长因子受体2(HER2)阴性、其肿瘤经FDA批准的检测确定为紧密连接蛋白CLDN 18.2阳性的局部晚期不可切除或转移性胃或胃食管交界处 (GEJ)腺癌。
关于局部晚期不可切除或转移性胃癌和胃食管交界处腺癌
胃和胃食管交界处癌，通常也被称为胃部肿瘤，是全球第五高发肿瘤。5胃食管交界处(GEJ)腺癌始于食道与胃的连接处。6在美国，估计有130,263人患有胃和胃食管交界处癌，将其列为一种罕见疾病。7,8美国2024年胃和胃食管交界处癌诊断病例约为26,890例，死亡病例约为10,800例。6胃癌的症状和体征可包括消化不良或烧心；腹部疼痛或不适；恶心和呕吐；饭后胃胀以及食欲不振。9晚期胃和胃食管交界处癌的症状可能包括不明原因的体重减轻；虚弱和疲劳；以及呕血或便血。10与胃癌相关的风险因素包括年龄增长、男性、家族史、幽门螺杆菌感染、吸烟和胃食管反流病(GERD)。11,12由于早期胃癌的症状常与更常见的胃良性疾病重叠，胃和胃食管交界处癌往往在晚期或转移阶段，或癌细胞从肿瘤原发部位扩散到身体其他组织或器官后，才被诊断出来。8转移性胃癌患者的五年相对生存率仅为7%。6
研究性试验
关于SPOTLIGHT III期临床试验
SPOTLIGHT是一项全球、多中心、双盲、随机的III期试验，评估zolbetuximab+mFOLFOX6(一种包括奥沙利铂、亚叶酸钙和氟尿嘧啶的联合用药方案)与安慰剂+mFOLFOX6一线治疗CLDN18.2阳性、HER2阴性的局部晚期不可切除或转移性胃癌或胃食管交界处腺癌患者的疗效和安全性。该研究在美国、加拿大、英国、澳大利亚、欧洲、南美和亚洲(包括中国在内)的215个研究中心招募了565名患者。主要终点是对比接受zolbetuximab联合mFOLFOX6治疗的参与者与接受安慰剂联合mFOLFOX6治疗的参与者的无进展生存期(PFS)。次要终点包括总生存期(OS)、客观缓解率(ORR)、缓解持续时间(DOR)、安全性和耐受性以及生活质量参数。
SPOTLIGHT的临床试验数据已于1月19日在2023年美国临床肿瘤学会(ASCO)胃肠道肿瘤研讨会上以口头报告方式公布，随后于4月14日在《柳叶刀》杂志上发表。
欲了解更多信息，请访问clinicaltrials.gov网站，识别码为NCT03504397。
关于GLOW III期临床试验
GLOW是一项全球、多中心、双盲、随机的III期试验，评估zolbetuximab+CAPOX(一种包括卡培他滨和奥沙利铂的联合化疗方案)与安慰剂+CAPOX一线治疗CLDN18.2阳性、HER2阴性的局部晚期不可切除或转移性胃癌或胃食管交界处腺癌患者的疗效和安全性。该研究在美国、加拿大、英国、欧洲、南美和亚洲(包括中国在内)的166个研究中心招募了507名患者。主要终点是对比接受zolbetuximab联合CAPOX治疗的参与者与接受安慰剂联合CAPOX治疗的参与者的无进展生存期(PFS)。次要终点包括总生存期(OS)、客观缓解率(ORR)、缓解持续时间(DOR)、安全性和耐受性以及生活质量参数。
GLOW研究数据最初在2023年3月美国临床肿瘤学会(ASCO)全体会议上公布，应邀在6月3日的2023 ASCO年度会议上就该研究数据再次做了口头报告，后续在7月31日发表于《自然医学》期刊。3
欲了解更多信息，请访问clinicaltrials.gov网站，识别码为NCT03653507。
靶向CLDN 18.2研究性产品管线
转移性胰腺癌的II期试验正在进行中。该试验是一项随机、多中心、开放标签研究，旨在评估研究性zolbetuximab联合吉西他滨加白蛋白结合型紫杉醇一线治疗CLDN18.2阳性转移性胰腺癌患者（即根据经验证的免疫组化检测分析判定，≥75%的肿瘤细胞中显示中至强染色强度的CLDN18）的安全性和疗效。
欲了解更多信息，请访问clinicaltrials.gov网站，识别码为NCT03816163。
除zolbetuximab之外，我们的首要焦点免疫肿瘤学开发团队正在开发ASP2138。ASP2138是一种双特异性单克隆抗体，可以与CD3和Claudin 18.2结合，目前正处于胃癌、胃食管交界处腺癌或胰腺癌患者的1/1b期临床试验。在研药剂的安全性和疗效尚未在讨论中的应用领域得到证实。
欲了解更多信息，请访问clinicaltrials.gov网站，识别码为NCT05365581。
不保证这些研究性药物能获得监管部门的批准在商业上用于正在研究的应用领域。
关于安斯泰来
安斯泰来制药集团是一家制药企业，业务遍及全球70多个国家和地区。目前，我们正在推进“焦点领域的研究策略(Focus Area Approach)”，旨在通过聚焦生理机制和治疗手段，确定持续研发新药的机会，解决尚未被满足的医疗需求。与此同时，我们正在将目光投向处方药以外的业务领域，将我们的专业技能和知识与不同领域外部合作伙伴的尖端技术相结合，打造Rx+®医疗解决方案。通过这些努力，安斯泰来立志处于不断变化的医疗行业的最前沿，将科学的进步转变为患者的价值。更多信息，请访问我们的网站https://www.astellas.com/en。
警示说明
本新闻稿中，有关当前计划、估计、战略和信念以及其他非历史事实的陈述，均为关于安斯泰来未来表现的前瞻性陈述。这些陈述是根据管理层结合当前可获得的信息而形成的当前假设和信念得出的，并涉及已知和未知的风险与不确定性。许多因素可能导致实际结果与前瞻性陈述中讨论的结果产生重大差异。这些因素包括但不限于：(i)与制药市场有关的一般经济条件和法律法规的变化，(ii)货币汇率波动，(iii)新产品上市的延迟，(iv)安斯泰来无法有效地销售现有产品和新产品，(v)安斯泰来无法继续有效地研究和开发在竞争激烈的市场中被客户接受的产品，以及(vi)第三方侵犯安斯泰来的知识产权。
本新闻稿中涉及的药物的安全性和有效性正在研究中，尚未确定。不能保证这些研究中的药品将获得监管当局的批准，可用于商业用途。本新闻稿中包含的有关药品(包括当前正在开发的产品)的信息不构成广告或医疗建议。
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IMPORTANT SAFETY INFORMATION
Warnings and Precautions
Hypersensitivity reactions, including serious anaphylaxis reactions, and serious infusion-related reactions(IRR)have been reported in clinical studies when VYLOY has been administered.
Any grade hypersensitivity reactions, including anaphylactic reactions, occurring with VYLOY in combination with mFOLFOX6 or CAPOX was 18%. Severe(Grade 3 or 4)hypersensitivity reactions, including anaphylactic reactions, occurred in 2% of patients. Seven patients(1.3%)permanently discontinued VYLOY for hypersensitivity reactions, including two patients(0.4%)who permanently discontinued VYLOY due to anaphylactic reactions. Seventeen(3.2%)patients required dose interruption, and three patients(0.6%) required infusion rate reduction due to hypersensitivity reactions.All grade IRRs occurred in 3.2% in patients administered VYLOY in combination with mFOLFOX6 or CAPOX. Severe(Grade 3)IRRs occurred in 2(0.4%) patients who received VYLOY. An IRR led to permanent discontinuation of VYLOY in 2(0.4%)patients and dose interruption in 7(1.3%)patients. The infusion rate was reduced for VYLOY for 2(0.4%)patients due to an IRR. Monitor patients during infusion with VYLOY and for 2 hours after completion of infusion or longer if clinically indicated, for hypersensitivity reactions with symptoms and signs that are highly suggestive of anaphylaxis(urticaria, repetitive cough, wheeze and throat tightness/change in voice) Monitor patients for signs and symptoms of IRRs including nausea, vomiting, abdominal pain, salivary hypersecretion, pyrexia, chest discomfort, chills, back pain, cough and hypertension. If a severe or life-threatening hypersensitivity or IRR reaction occurs, discontinue VYLOY permanently, treat symptoms according to standard medical care, and monitor until symptoms resolve. For any Grade 2 hypersensitivity or IRR, interrupt the VYLOY infusion until Grade ≤1, then resume at a reduced infusion rate for the remaining infusion. Follow Grade 2 management for Grade 3 infusion-related nausea and vomiting. Premedicate the patient with antihistamines for the subsequent infusions, and closely monitor the patient for symptoms and signs of a hypersensitivity reaction. The infusion rate may be gradually increased as tolerated.
Severe Nausea and Vomiting. VYLOY is emetogenic. Nausea and vomiting occurred more often during the first cycle of treatment. All grade nausea and vomiting occurred in 82% and 67% respectively of patients treated with VYLOY in combination with mFOLFOX6 and 69% and 66% in combination with CAPOX, respectively.
Severe(Grade 3)nausea occurred in 16% and 9% of patients treated with VYLOY in combination with mFOLFOX6 or CAPOX respectively. Severe(Grade 3)vomiting occurred in 16% and 12% of patients treated with
VYLOY in combination with mFOLFOX6 or CAPOX. Nausea led to permanent discontinuation of VYLOY in combination with mFOLFOX6 or CAPOX in 18(3.4%) patients and dose interruption in 147(28%)patients. Vomiting led to permanent discontinuation of VYLOY in combination with mFOLFOX6 or CAPOX in 20(3.8%) patients and dose interruption in 150 (28%)patients. Pretreat with antiemetics prior to each infusion of VYLOY. Manage patients during and after infusion with antiemetics or fluid replacement. Interrupt the infusion, or permanently discontinue VYLOY based on severity.
ADVERSE REACTIONS
Most common adverse reactions(≥15%): Nausea, vomiting, fatigue, decreased appetite, diarrhea, peripheral sensory neuropathy, abdominal pain, constipation, decreased weight, hypersensitivity reactions, and pyrexia.
Most common laboratory abnormalities(≥15%): Decreased neutrophil count, decreased leucocyte count, decreased albumin, increased creatinine, decreased hemoglobin, increased glucose, decreased lymphocyte count, increased aspartate aminotransferase, decreased platelets, increased alkaline phosphatase, increased alanine aminotransferase, decreased glucose, decreased sodium, increased phosphate, decreased potassium, and decreased magnesium.
SPOTLIGHT Study: 279 patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive who received at least one dose of VYLOY in combination with mFOLFOX6
Serious adverse reactions occurred in 45% of patients treated with VYLOY in combination with mFOLFOX6; the most common serious adverse reactions(≥2%)were vomiting(8%), nausea(7%), neutropenia(2.9%), febrile neutropenia(2.9%), diarrhea(2.9%), intestinal obstruction(3.2%), pyrexia(2.5%), pneumonia(2.5%), respiratory failure(2.2%), pulmonary embolism(2.2%), decreased appetite(2.1%)and sepsis (2.0%). Fatal adverse reactions occurred in 5% of patients who received VYLOY in combination with mFOLFOX6 including sepsis(1.4%), pneumonia(1.1%), respiratory failure(1.1%), intestinal obstruction(0.7%), acute hepatic failure (0.4%), acute myocardial infarction (0.4%), death(0.4%), disseminated intravascular coagulation(0.4%), encephalopathy(0.4%), and upper gastrointestinal hemorrhage(0.4%).Permanent discontinuation of VYLOY due to an adverse reaction occurred in 20% of patients; the most common adverse reactions leading to discontinuation(≥2%)were
nausea and vomiting.Dosage interruptions of VYLOY due to an adverse reaction occurred in 75% of patients; the most common adverse reactions leading to dose interruption(≥5%)were nausea, vomiting, neutropenia, abdominal pain, fatigue, and hypertension.
GLOW Study: 254 patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive who received at least one dose of VYLOY in combination with CAPOX
Serious adverse reactions occurred in 47% of patients treated with VYLOY in combination with CAPOX; the most common serious adverse reactions(≥2%) were vomiting (6%), nausea (4.3%), decreased appetite (3.9%), decreased platelet count (3.1%), upper gastrointestinal hemorrhage (2.8%), diarrhea (2.8%), pneumonia (2.4%), pulmonary embolism (2.3%), and pyrexia (2.0%). Fatal adverse reactions occurred in 8% of patients who received VYLOY in combination with CAPOX including sepsis (1.2%), pneumonia (0.4%), death (0.8%), upper gastrointestinal hemorrhage (0.8%), cerebral hemorrhage (0.8%), abdominal infection (0.4%), acute respiratory distress syndrome (0.4%), cardio-respiratory arrest (0.4%), decreased platelet count (0.4%), disseminated intravascular coagulation (0.4%), dyspnea (0.4%), gastric perforation (0.4%), hemorrhagic ascites (0.4%), procedural complication (0.4%), sudden death (0.4%), and syncope (0.4%). Permanent discontinuation of VYLOY due to an adverse reaction occurred in 19% of patients; the most common adverse reaction leading to discontinuation (≥2%) was vomiting. Dosage interruption of VYLOY due to an adverse reaction occurred in 55% of patients; the most common adverse reactions leading to dose interruption (≥2%) were nausea, vomiting, neutropenia, thrombocytopenia, anemia, fatigue, infusion-related reaction, and abdominal pain.
SPECIFIC POPULATIONS
Lactation Advise lactating women not to breastfeed during treatment with VYLOY and for 8 months after the last dose.
For more information, please see the U.S. full Prescribing Information for VYLOY here.
(https://www.astellas.com/us/system/files/vyloy_pi.pdf?utm_source=press_release&utm_medium=pr%20&utm_campaign=us_vyloy_approval)
References
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2.Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2023;401(10389):1655-1668. Errata in: Lancet 2023;402(10398):290; Lancet 2024;403(10421):30.
3.Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med 2023;29(8):2133-2141.
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11.American Cancer Society. Stomach cancer risk factors (01-22-2021). Available at https://www.cancer.org/cancer/types/stomach-cancer/causes-risks-prevention/risk-factors.html. Accessed 11-13-2023.
12.American Cancer Society. Esophageal cancer risk factors (06-09-2020). Available at https://www.cancer.org/cancer/esophagus-cancer/causes-risks-prevention/risk-factors.html. Accessed 11-13-2023.
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