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点击蓝字 关注我们 陈洛海，梁贇，陈洁（复旦大学附属肿瘤医院  神经内分泌肿瘤科  复旦大学上海医学院肿瘤学系，上海  200032） 基金项目：国家自然科学基金（82141104） 通信作者：陈洁 E-mail：chen0jie@hotmail.com 通讯作者 陈 洁  教授 主任医师，教授，博士研究生导师 复旦大学附属肿瘤医院神经内分泌肿瘤多学科首席专家 复旦大学附属肿瘤医院神经内分泌肿瘤中心主任 复旦大学附属肿瘤医院神经内分泌肿瘤科主任 欧洲神经内分泌肿瘤学会(ENETS)顾问委员会委员 欧洲肿瘤内科学会(ESMO)神经内分泌及内分泌肿瘤学组委员 国际神经内分泌肿瘤联盟(INCA)医疗顾问委员会委员 中国抗癌协会神经内分泌肿瘤专业委员会主任委员 中国抗癌协会胰腺癌专业委员会神经内分泌肿瘤学组(CSNET)组长 中国抗癌协会肿瘤内分泌专业委员会副主任委员 中国医师协会胰腺病分会胰腺神经内分泌肿瘤专委会副主任委员 中国临床肿瘤学会(CSCO)罕见肿瘤专家委员会委员 中国抗癌协会理事 中国胰腺病学会理事 上海市抗癌协会常务理事 ENETS官刊Journal of Neuroendocrinology高级编委 Journal of Pancreatology编委 《中国癌症杂志》编委 【摘要】  神经内分泌肿瘤（neuroendocrine neoplasms，NENs）的发病率仍在不断上升，但晚期高分化神经内分泌瘤（neuroendocrine tumor，NET）和低分化神经内分泌癌（neuroendocrine carcinoma，NEC）的治疗仍存在较多挑战。2024年度NENs领域有一定进展，最令人关注的是177Lu-DOTATATE肽受体放射性核素治疗（peptide receptor radionuclide therapy，PRRT）和卡博替尼2项Ⅲ期临床试验NETTER-2和CABINET结果正式发表。此外，新靶向药物、新化疗方案、靶向δ样经典Notch配体3（delta-like canonical Notch ligand 3，DLL3）的免疫治疗药物及不同药物联合治疗等，均有积极的临床研究结果发表。总体上，2024年公布的研究结果仍以Ⅱ期研究为主，Ⅲ期研究仍相对较少。本文将回顾并总结2024年度NENs药物治疗的进展。 【关键词】  神经内分泌肿瘤；药物治疗；肽受体放射性核素治疗；靶向治疗；免疫治疗 神经内分泌肿瘤（neuroendocrine neoplasms，NENs）的发病率在不断上升，随着NENs病理分类分级标准的完善，临床上对于高分化神经内分泌瘤（neuroendocrine tumor，NET）和低分化神经内分泌癌（neuroendocrine carcinoma，NEC）的生物学行为差异认识也逐渐加深。针对晚期NET的治疗，2024年度有数项大样本或Ⅲ期临床试验结果公布；针对晚期NEC的治疗，2024年也有不少积极的Ⅰ期或Ⅱ期研究结果公布。本文将对2024年度NENs药物治疗领域重要研究结果进行总结。 1 生物治疗 长效生长抑素类似物（somatostatin analogues，SSAs）是晚期NET抗肿瘤治疗的重要生物治疗药物，主要包括长效奥曲肽和兰瑞肽水凝胶。在晚期支气管肺NET中，尽管长效SSAs被国内外多部指南推荐用于抗肿瘤治疗，但其临床应用缺乏前瞻性Ⅲ期临床试验数据支持。来自欧洲多中心研究SPINET Ⅲ期试验于2024年正式发表[1]，该试验分析兰瑞肽水凝胶对照安慰剂在SSTR阳性支气管肺典型类癌及不典型类癌中的疗效和安全性，该临床试验因入组缓慢提前终止，共纳入了77例患者，随机进入兰瑞肽水凝胶组（典型类癌29例，不典型类癌22例）和安慰剂组（典型类癌16例，不典型类癌10例），双盲期兰瑞肽水凝胶组患者中位无进展生存（progression-free survival，PFS）时间为16.6个月（典型类癌21.9个月，不典型类癌13.8个月），安慰剂组为13.6个月（典型类癌13.9个月，不典型类癌11.0个月），兰瑞肽和安慰剂对比PFS时间无显著差异。兰瑞肽治疗的客观缓解率（objective response rate，ORR）为14.0%，较安慰剂组（0）有所提升。该研究因提前终止未能纳入足够数量的患者，且揭盲前总体随访时间不足，其结果提示兰瑞肽水凝胶在支气管肺NET的安全性，对典型类癌治疗可能有临床获益。 2 分子靶向治疗 目前针对NENs的分子靶向治疗主要靶向雷帕霉素哺乳动物靶蛋白（mammalian target of rapamycin，mTOR）和血管形成通路，前者以mTOR抑制剂依维莫司为代表药物，后者以主要靶向血管内皮生长因子受体的酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）舒尼替尼、索凡替尼等为代表药物。2024年度抗血管分子靶向治疗的重要进展之一为TKI类药物卡博替尼（cabozantinib）的Ⅲ期临床试验CABINET结果正式发表[2]。该研究为国际多中心安慰剂对照研究，共纳入了298例前线治疗进展的高分化、G1～G3级NET患者，分为2个独立队列：胰腺来源（95例）和胰腺以外来源（203例），均以2∶1的比例随机分为卡博替尼组（60 mg/d）和安慰剂组，主要研究终点为PFS。该研究证实卡博替尼能显著延长晚期NET患者的PFS时间，在胰腺NET队列中，卡博替尼组中位PFS时间为13.8个月（安慰剂组为4.4个月），ORR为19%（安慰剂组为0）；在胰腺以外NET队列中，卡博替尼组中位PFS时间为8.4个月（安慰剂组为3.9个月），ORR为5%（安慰剂组为0）。卡博替尼治疗主要不良反应包括疲劳、腹泻、转氨酶升高、高血压、血小板减少等，蛋白尿报道相对较少。与既往舒尼替尼和索凡替尼Ⅲ期临床试验不同，CABINET研究纳入了G3级NET患者（共24例：胰腺队列13例，胰腺以外队列11例），在胰腺队列中，亚组分析提示卡博替尼显著降低进展风险[风险比（hazard ratio，HR）＝0.02，95%置信区间（confidential interval，CI）：0～0.11]，但在胰腺以外队列亚组分析中，卡博替尼治疗未能显著降低进展风险。在2024年欧洲肿瘤内科学会（European Society for Medical Oncology，ESMO）年度会议上，一项单臂Ⅱ期临床试验CABONEN公布了中期分析结果[3]，该研究探索卡博替尼在晚期低增殖指数G3级NET或NEC（Ki-67指数20%～60%）中的安全性和疗效，共纳入29例G3级NET和5例NEC患者，中位Ki-67指数为32%，3个月和6个月疾病控制率（disease control rate，DCR）为90.1%和64.1%，PFS时间为6.7个月，治疗3个月后的DCR（20例可供分析）为85%，其中，部分缓解（partial remission，PR）率为10%。CABINET和CABONEN研究均提示卡博替尼在晚期G3级NET中的潜在应用价值，尤其对于胰腺NET，期待后续进一步大样本临床研究证实卡博替尼或其他TKI在G3级NET肿瘤控制中的价值。 肿瘤的生长离不开营养供应，除了血管内皮构成的血管作为经典营养供应通道外，血管形成拟态（vasculogenic mimicry）是另一种由肿瘤细胞直接形成的不含血管内皮的营养供应管道。在多种肿瘤的研究中发现，抑制血管形成拟态具有抑制肿瘤生长的作用[4]。2024年ESMO年度会议报道了一种新型抑制血管形成拟态的靶向药物CVM-1118在晚期NET中的初步疗效数据[5]，该研究为Ⅱa期单臂研究，共纳入43例晚期NET患者，其中35例患者已有疗效评估数据，包括22例胰腺NET、12例胃肠道NET和1例肺NET，中位PFS时间为10.5个月，联合SSAs患者中位PFS时间达22.4个月，ORR为2.9%，DCR为77%。与既往TKI研究中胰腺与胰腺以外NET疗效数据相反，CVM-1118治疗在胰腺以外NET中显示出更佳疗效，胃肠道NET中位PFS时间为22.4个月，胰腺NET中位PFS时间仅8.4个月。这一研究提示血管形成拟态可能是NET治疗的潜在新靶点，尤其对于非胰腺来源NET，但仍需进一步Ⅲ期对照试验证实。 约5% NENs的发生与胚系基因突变引起的遗传综合征相关，其中，Von Hippel-Lindau（VHL）综合征是遗传性NENs常见类型之一，其发生与抑癌基因VHL基因突变相关，该基因突变导致VHL蛋白表达丢失，继而使缺氧诱导因子（hypoxia-inducible factor，HIF）通路持续激活，导致多个与肿瘤形成相关的基因表达上调，从而使患者逐渐面临肾细胞癌、胰腺NET、嗜铬细胞瘤、血管母细胞瘤等多种肿瘤的发生风险。贝组替凡作为一种HIF-2α抑制剂，在一项Ⅱ期单臂临床试验LITESPARK-004试验中展现了对VHL综合征相关肿瘤的良好疗效。近期，该研究发布了针对胰腺NET亚组的疗效数据[6]。在22例胰腺NET患者中，贝组替凡治疗的ORR达91%，其中7例患者肿瘤达CR，中位随访时间37.8个月，中位PFS时间尚未达到。鉴于其显著疗效，贝组替凡已于日前在国内获批上市，用于治疗VHL综合征相关肾细胞癌、中枢神经系统血管母细胞瘤及胰腺NET。 3 化疗 目前化疗主要用于NEC或高级别/高肿瘤负荷/肿瘤生长速度快的NET，2024年度化疗相关研究多集中于NEC。一项来自意大利的Ⅱ期随机非对照研究探索卡培他滨联合替莫唑胺（CAPTEM）方案和5-氟尿嘧啶联合伊立替康（FOLFIRI）方案在晚期NEC二线治疗中的疗效和安全性[7]，该研究因有效性原因在中期分析时提前终止。共纳入53例患者，CAPTEM组和FOLFIRI组的12周DCR分别为28.0%和39.1%，12个月总生存（overall survival，OS）率分别为32.4%和28.4%，主要3级不良反应分别为中性粒细胞减少/贫血和血小板减少/呕吐。总的来说，CAPTEM方案和FOLFIRI方案在NEC二线治疗中安全性尚可，但两种方案的疗效无显著差异。意大利开展的另外一项名为TENEC-TRIAL的Ⅱ期多中心单臂研究[8]，探索替莫唑胺间隔1周给药作为晚期NEC二线治疗的疗效和安全性，共纳入38例患者，66.3%的患者Ki-67指数≥55%，采用替莫唑胺每隔1周给药的方式[替莫唑胺75 mg/（m2·d），连续使用7 d，休息7 d，后重复这一方式]，ORR为18%，1例患者出现CR。中位PFS时间和OS时间分别为5.86个月和12.1个月，1年PFS率为37%。Ki-67指数是否≥55%与中位PFS时间和中位OS时间无关。无3级以上不良反应。该研究证实了替莫唑胺间隔1周给药作为晚期NEC二线治疗的安全性，对于体力状况较差的患者，可能是可行的治疗方案。另外一项来自意大利的Ⅱ期单臂MeTe研究在2024年欧洲神经内分泌肿瘤学会（European Neuroendocrine Tumor Society，ENETS）和ESMO年度会议上公布了中期分析结果[9-10]，该研究旨在探索替莫唑胺单药节拍化疗（60 mg/d，持续使用）在一般状况较差的晚期GEP-NET和肺NET患者中的疗效和安全性，目前已纳入20例患者，7例患者美国东部肿瘤协作组（Eastern Cooperative Oncology Group，ECOG）体力活动状态（performance status，PS）评分2分、14例患者至少合并1种严重共存病、9例患者存在肾功能减退，超过半数的患者使用该方案作为二线或三线治疗。其中18例患者肿瘤可评估，中位随访9个月后，中位PFS时间和中位OS时间尚未达到，5个月PFS率和OS率分别为71%和83%，ORR和DCR分别为6%和88%。使用该方法治疗的患者3个月时生活质量无明显下降。该研究提示替莫唑胺节拍化疗对于一般状况较差的晚期NET患者可能是耐受性较高的有效方案，目前该研究正在继续入组患者，期待最终结果公布。 针对晚期NET的化疗，2024年也有新发表的研究结果。MGMT-NET研究是一项前瞻性Ⅱ期研究[11]，基于肿瘤细胞O6-甲基鸟嘌呤DNA甲基转移酶（O6 -methylguanine-DNA methyltransferase，MGMT）状态，评估以奥沙利铂为基础的化疗方案与以烷化剂为基础的化疗方案在晚期NET中的疗效和安全性，MGMT缺失者以2∶1比例入组烷化剂和奥沙利铂为基础方案，MGMT未缺失者以1∶1比例入组，主要研究目标为烷化剂治疗3个月后MGMT缺失者与未缺失者的ORR达到35%的差异。该研究共纳入105例患者，其中102例患者可评估MGMT状态，58例MGMT缺失。结果提示未能达到主要研究终点，MGMT缺失者和MGMT未缺失者的3个月ORR分别为29.4%和8%，MGMT缺失者有更佳疗效，最佳ORR和中位PFS时间分别为52.9%和14.6个月，MGMT未缺失者最佳ORR和中位PFS时间分别为11.5%和11.3个月。该研究虽未达到主要研究终点，但其结果提示MGMT状态与烷化剂化疗疗效相关，MGMT缺失者烷化剂化疗疗效更佳。 除上述在NENs中应用较多的化疗药物外，在2024年度美国临床肿瘤学会（American Society of Clinical Oncology，ASCO）会议上，NENs领域较少使用的化疗药物，包括白蛋白结合型紫杉醇、脂质体伊立替康，也有2项临床试验结果公布。NABNEC是一项Ⅱ期随机化研究，探索白蛋白结合型紫杉醇联合卡铂作为晚期G3级消化系统NENs的一线治疗方案的疗效和安全性[12]，对照组（依托泊苷联合卡铂）入组12例患者后，终止入组。主要研究终点为ORR。共纳入60例患者，43例（75%）患者肿瘤Ki-67指数＞55%，约20%的患者肿瘤为胰腺原发。58例患者可行肿瘤评估（试验组46例，对照组12例），试验组和对照组的ORR分别为53%和42%，两组PFS无差异，24个月的OS率分别为25%和17%，试验组3级不良反应发生率（52%）更高，对照组为42%。总的来说，白蛋白结合型紫杉醇联合卡铂作为G3级消化系统NENs一线治疗，其疗效并未显著优于依托泊苷联合卡铂。需要注意的是，该研究自2016年开始入组患者，当时世界卫生组织病理分类分级标准中对G3级NENs的定义包含了G3级NET和NEC，因此，该研究可能同时纳入了NET和NEC患者，但目前报道的结果中未对NET和NEC进行区分。另外一项针对GEP-NEC一线化疗的Ⅰ/Ⅱ期临床试验公布了Ⅰ期剂量爬坡结果及初步疗效数据[13]，该研究采用纳米脂质体伊立替康联合卡铂作为一线化疗方案，纳入6例患者，确定了后续Ⅱ期试验纳米脂质体伊立替康和卡铂的剂量分别为80 mg/m2和曲线下面积（area under the curve，AUC）＝4（每3周），疗效分析结果提示4例患者肿瘤达PR，2例患者肿瘤达疾病稳定（stable disease，SD）。该研究初步疗效数据提示该方案具有较高的ORR，但目前纳入患者数量较少，仍需后续进一步Ⅱ期及Ⅲ期研究证实其疗效。 4 核素治疗 肽受体放射性核素治疗（peptide receptor radionuclide therapy，PRRT）是近年NET治疗领域最受关注的治疗方式。2024年度最重要的进展为NETTER-2研究结果正式发表[14]。NETTER-2研究是一项开放标签、国际多中心、随机对照Ⅲ期研究，纳入Ki-67指数10%～55%的G2/G3级未经治疗的晚期GEP-NET患者。试验组采用177Lu-DOTATATE PRRT联合长效奥曲肽30 mg，每4周1次（PRRT组）；对照组采用长效奥曲肽60 mg，每4周1次，主要研究终点为PFS时间。该研究共纳入226例患者，随机进入PRRT组（151例）和对照组（75例），中位PFS时间分别为22.8个月和8.5个月，ORR分别为43%和9.3%。该研究证实了177Lu-DOTATATE PRRT可作为晚期高级别G2/G3级GEP-NET患者的一线治疗，该研究也是G3级NET患者一线治疗的首个Ⅲ期临床研究，对G3级患者治疗有重要意义。同时该研究也提示，大剂量（60 mg）长效奥曲肽一线治疗对这部分患者肿瘤控制也具有一定效果。除了NETTER-2研究，2024年正式发表的PRRT相关研究尚有NEOLUPANET研究，该研究探索PRRT作为胰腺NET新辅助治疗的可行性[15]，共纳入31例患者，其中26例患者完成了4个疗程177Lu-DOTATATE治疗，18例患者肿瘤达到PR。最终有29例患者顺利完成了胰腺NET切除，21例患者出现术后并发症，包括7例患者发生3级并发症，胰漏是最常见的术后并发症（10例），无二次手术、胰腺切除术后出血及术后死亡病例。该研究提示PRRT可能作为胰腺NET新辅助治疗的一种手段，但尚缺乏术后复发及OS数据。 177Lu-DOTATATE通过释放β粒子发挥杀伤肿瘤细胞的作用，与之相比，α粒子具有更短射程和更高的线性能量转化，可引起更多DNA双链破坏，可能具有更强杀伤肿瘤细胞的能力[16]。近期越来越多研究关注释放α粒子的PRRT治疗在NENs中的疗效和安全性，部分研究在2024年ENETS和/或ESMO年度会议上报道了初步结果。ACTION-1是一项国际多中心Ⅰb/Ⅲ期临床试验[17,18]，探索RYZ101（225Ac-DOTATATE）在经177Lu-DOTATATE治疗进展的晚期、高分化GEP-NET中的疗效和安全性，目前公布了剂量研究结果，并确定了10.2 MBq/8周、4个疗程作为后续Ⅲ期临床试验的药物剂量，早期的疗效数据提示ORR为29.4%。另一项公布初步数据的研究是Ⅱ期、开放标签的多中心ALPHAMEDIX 02研究[19]，探索212Pb-DOTAMTATE在未经177Lu-DOTATATE治疗（队列1）和177Lu-DOTATATE治疗耐药（队列2）的晚期GEP-NETs患者中的疗效和安全性，其中，队列1公布了初步数据结果，在纳入的36例患者中，ORR为47.2%，高于先前NETTER-1研究的结果。但该研究目前报道了4次严重不良事件，包括2例死亡/疾病进展、1例类癌综合征和1例脓毒症。总体上，基于α粒子的PRRT研究尚处于早期阶段，初步数据提示其在晚期NET中具有较好的应用前景，尤其对于先前177Lu-DOTATATE治疗失败/进展的患者。 5 免疫治疗 常规免疫检查点抑制剂剂（immune checkpoint inhibitors，ICIs）单药在晚期NENs中效果有限，目前NENs领域免疫治疗的研究重点主要针对NEC的多靶点免疫治疗药物研发。其中，以靶向δ样经典Notch配体3（delta-like canonical Notch ligand 3，DLL3）的免疫治疗药物研发最受瞩目，目前已开展多项临床试验。2024年ENETS和ESMO年度会议公布了DLL3/CD3 IgG样T细胞衔接器药物BI 764532的Ⅰ期临床试验初步研究数据[20]，该研究旨在探索BI 764532在局部晚期/转移性DLL3阳性小细胞肺癌（80例）、大细胞肺癌（13例）和肺外NEC（70例）中的安全性和初步疗效。总体而言，该药物耐受性尚可，初步疗效数据提示总体ORR和DCR分别为23%和42%，其中，小细胞肺癌的ORR和DCR分别为18%和36%，肺外NEC中的ORR和DCR分别为23%和41%，而大细胞肺癌的ORR和DCR可高达54%和77%。该研究提示BI 764532对NEC具有一定疗效，值得进一步研究。另一种靶向DLL3的T细胞衔接器药物HPN328在2024年ASCO年度会议上更新了其Ⅰ/Ⅱ期研究数据[21]，该研究纳入了复发/耐药/转移性小细胞肺癌、前列腺NEC和其他NEC患者，初步疗效数据也较为可观，小细胞肺癌中确认的ORR达到50%（12/24），且出现1例CR；在其他NEC中，确认的ORR达到44%（4/9），也有1例CR；在前列腺NEC中，4/11例患者肿瘤达到PR（未确认）。从这两项靶向DLL3的临床试验初步疗效数据来看，该类药物在NEC中具有较好的前景，有望为NEC治疗带来突破。 LBL-024是一种由国内药企研发的双靶点免疫治疗药物，同时靶向程序性死亡配体-1（programmed death ligand-1，PD-L1）和41-BB（T细胞共刺激受体）。在2024年ASCO年度会议上，北京大学肿瘤医院团队公布了LBL-024的Ⅰ/Ⅱ期多中心临床研究数据，旨在探索其在晚期实体瘤中的安全性以及在至少一线化疗治疗失败的肺外NEC中的初步疗效[22]。研究结果显示，LBL-024总体安全性较高，尤其令人关注的是其在肺外NEC中展现出了良好的疗效。在41例接受LBL-024治疗的患者中，ORR和DCR分别达到42.3%和57.7%。对治疗选择较少且总体疗效欠佳的肺外NEC患者而言，LBL-024单药治疗能达到如此高的ORR和DCR，提示该药在NEC治疗领域也展现出非常广阔的前景，期待后续进一步研究数据发表。 6 药物联合治疗 尽管既往关于不同类型药物或不同靶点药物联合使用治疗NENs收效甚微，但目前仍有不少临床试验探索药物联合治疗的价值，其中主要的联合方案包括免疫治疗与化疗联合、免疫治疗与靶向药物联合，以及不同靶向药物联合等。 6.1 化疗联合免疫治疗 目前免疫治疗与化疗联合的研究主要聚焦于高级别NET或NEC中，以后者为多。NICE-NEC是一项来自西班牙的单臂、多中心、Ⅱ期临床试验[23]，纳入未经化疗且不可手术切除的晚期胃肠道来源或原发不明的G3级NET或NEC，采用依托泊苷＋卡铂化疗（每3周1次，不超过6个周期）联合纳武利尤单抗（化疗期间每3周1次360 mg；后每4周480 mg直至12个月或疾病进展）方案，主要研究终点为12个月OS率。共纳入37例患者，其中25例患者为NEC或Ki-67指数＞55%。总体ORR为56.8%（NET 50.0%，NEC 60.0%），12个月OS率为54.1%，中位PFS时间和OS时间分别为5.7个月（NET和NEC均为5.7个月）和13.9个月（NET 23.3个月，NEC 11.7个月）。尽管该研究报道24个月OS率可达到37.6%，但可能与该研究同时纳入了G3级NET有关。该方案作为一线治疗能否延长G3级NET和NEC患者的OS时间，尚存疑问。另一项来自美国的小样本Ⅰb期临床试验探索在一线化疗方案基础上联合帕博利珠单抗的疗效和安全性[24]，共纳入7例膀胱Ⅲ/Ⅳ期NEC患者（队列1）和8例Ⅲ/Ⅳ期前列腺NEC患者（队列2），采用依托泊苷联合顺铂/卡铂（队列1和2）或多西他赛联合卡铂（队列2）化疗方案，并在此基础上联合帕博利珠单抗。总体ORR为43%，队列1和队列2的2年OS率分别为86%和57%。队列1中有4例患者进行后续膀胱切除术，其中1例患者肿瘤达到病理学CR。另外，该研究对PFS相关的预测标志物进行研究，发现为外周血多样T细胞库克隆性扩增与PFS相关。该研究探索了免疫治疗联合一线化疗在膀胱和前列腺NEC中的潜在价值，但受限于有限的样本量，在化疗基础上联合免疫治疗的有效性尚不确切。四川大学华西医院开展的CAMEC研究也探索了一线EP/EC化疗联合免疫治疗（卡瑞利珠单抗）在肺外NEC中的疗效，其初步结果在2024年ENETS年度会议上公布，在已纳入的7例患者中，ORR为71.4%（5/7），6个月PFS率为71.4%[25]。总的来说，当前临床试验以Ⅰ/Ⅱ期单臂研究为主，尚不能明确在化疗基础上联合免疫治疗作为NEC一线治疗的价值。目前，已有Ⅱ/Ⅲ期临床试验（如SWOG S2012）正在开展，旨在进一步探索该联合治疗方案在晚期肺外NEC中的价值[26]，有待其研究结果发布以证实该联合治疗方式的有效性。 6.2 靶向治疗联合免疫治疗 免疫治疗与分子靶向治疗联合也是目前NENs领域联合药物治疗的研究重点，旨在通过靶向治疗发挥潜在免疫调节作用，以增强免疫治疗效果。一项由北京大学肿瘤医院牵头的多中心Ⅱ期研究[27]，探索了索凡替尼联合特瑞普利单抗在晚期NET、混合性神经内分泌-非神经内分泌肿瘤（mix neuroendocrine non-neuroendocrine neoplasms，MiNENs）、NEC中的疗效，纳入既往治疗进展、不耐受的患者，采用索凡替尼（250 mg/d）联合特瑞普利单抗（240 mg/3周）治疗。共纳入40例患者，包括19例NET和21例MiNENs或NEC，ORR分别为21.1%和23.8%，中位PFS时间分别为9.6个月和4.1个月，中位OS时间分别为27.3个月和10.9个月，18例（45.0%）患者出现3级以上不良反应。这项研究提示索凡替尼联合特瑞普利单抗可能对NENs患者具有一定的抗肿瘤效果。然而，该联合方案治疗NET是否优于单药治疗，仍需进一步明确。同时，对于NEC，该联合方案尚未展现出相较于其他化疗方案的明显优势，仍需进一步研究。另一项靶向治疗联合免疫治疗的Ⅱ期研究在2024年ENETS年度会议上公布了初步结果[28]，该研究纳入了G3 NET和NEC患者，探索索凡替尼联合信迪利单抗及IBI310[细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte antigen-4，CTLA-4）抗体]的疗效和安全性。目前有11例患者可行疗效评估，90.9%的患者曾接受前线治疗。确认的ORR和DCR分别为36.4%和72.8%，中位PFS时间为4.5个月。8例患者既往接受不超过一线治疗，其ORR和DCR可达50%和87.5%。目前该研究3级不良反应发生率为7.1%。从初步结果来看，索凡替尼联合“双抗”免疫治疗对高级别NENs安全性尚可，且似乎具有一定的疗效，有待入组更多患者进一步明确其疗效和安全性。 一项来自美国的Ⅱ期研究探索了帕博利珠单抗联合仑伐替尼在晚期高分化非胰腺NET中的疗效[29]。该研究仅纳入了20例患者，其中2例患者肿瘤达到PR，中位PFS时间为8个月，且14例患者在治疗期间需药物减量或停药。总体来说，在胰腺以外NET中，帕博利珠单抗与仑伐替尼的联合疗效欠佳，不支持进一步开展临床试验。另一项关于免疫治疗与分子靶向治疗联合的临床试验为CABATEN，该研究设计为一项单臂篮式试验，试验组采用卡博替尼与阿替利珠单抗的联合治疗方案。该试验包含了4个NENs队列（共55例）：肺NET、嗜铬细胞瘤/副神经节瘤（pheochromocytoma/paragangliomas，PPGL）、GEP-NET和肺外NEC。在2024年ENETS和ASCO年度会议上公布了这4个队列的研究结果[30-31]。遗憾的是，仅在PPGL队列（ORR为15.4%，中位PFS时间为12.2个月）和GEP-NET队列（ORR为16.7%，中位PFS时间为15.8个月）中观察到有限的肿瘤反应和可能的PFS延长，总体疗效一般。此外，分别有80%和40%的患者因不良反应需中断卡博替尼和阿替利珠单抗治疗。因此，卡博替尼与阿替利珠单抗单抗的联合治疗方案可能仅在GEP-NET和PPGL中展现出一定的疗效，但在GEP-NET中，与CABINET试验中卡博替尼单药治疗相比，其疗效提升似乎并不显著。 6.3 其他联合治疗 不同靶点靶向治疗联合是另一种值得探索的联合治疗策略。在2024年ENETS年度会议上，一项来自美国的仑伐替尼（14 mg/d）和依维莫司（5 mg/d）联合的Ⅱ期临床试验公布了其结果[32]，该研究针对晚期高分化胰腺以外NET，从目前纳入的31例可评估患者的疗效来看，该联合方案的PR率高达39%，中位PFS时间达到15.8个月，56%的患者出现3级不良反应。该研究通过联合应用抗血管生成靶向药物与mTOR抑制剂，两种药物剂量均较单药有所下调，但3级不良反应发生率仍较高，目前的结果提示该联合似乎具有较可观的ORR，但PFS时间较仑伐替尼单药治疗无显著改善[33]，仍需开展进一步的临床对照试验明确该联合方案的价值。 关于靶向治疗与化疗的联合应用，2024年有数项研究的初步结果在ENETS或ESMO年度会议上公布。来自中山大学附属肿瘤医院的一项研究，在2024年ENETS年度会议上公布了索凡替尼与CAPTEM（卡培他滨联合替莫唑胺）化疗方案联合治疗晚期G2、G3级NET的初步结果[34]。该研究共纳入27例G2级NET患者，包括8例胰腺NET和19例胰腺以外NET，目前中位PFS时间尚未达到，12个月PFS率为87.7%。胰腺NET的ORR和DCR分别为16.7%和87.5%。胰腺以外NET的ORR和DCR分别为6.3%和100%。同样在2024年ENETS年度会议上，四川大学华西医院也公布了一项关于索凡替尼联合CAPTEM化疗方案的研究初步结果[35]。该研究主要探索了该联合方案在不可切除胰腺NET转化治疗中的价值，已纳入9例患者，7例患者可评估，ORR和DCR分别为28.6%和100%。已有5例患者完成4个疗程治疗并行R0切除，另外2例患者治疗6个疗程后未能进一步行手术治疗。上述2项研究均提示索凡替尼与CAPTEM化疗方案联合在胰腺NET中具有一定疗效，但与单独CAPTEM化疗方案相比[36]，未见疗效显著提升，这或许与不同研究中纳入患者的肿瘤MGMT缺失情况不同有关。因此，该联合方案的价值仍需进一步探索。另一项来自德国的多中心、单臂Ⅱ期研究在2024年ESMO年度会议上公布了其研究结果，该研究探索了雷莫芦单抗（抗血管生长因子受体2）与达卡巴嗪联合在晚期胰腺NET中的疗效与安全性[37]。共纳入45例晚期进展性G1～G3级胰腺NET患者，ORR为17.8%，3级以上不良反应发生率为12.6%。与上述研究类似，该研究也提示抗血管生成靶向药物与化疗的联合对胰腺NET具有一定疗效。然而，该联合方案是否优于单药治疗，仍需进一步研究明确。 7 总结 2024年度NENs领域最重要的进展为PRRT和卡博替尼治疗晚期NET患者的Ⅲ期临床试验结果正式发表，尤其对于G3级NET的治疗，这两项研究填补了该领域的空白。此外，一些新的靶向药物，如抗血管形成拟态药物，在NET治疗中初露锋芒，期待这些新靶向药物后续研究结果的公布。在NEC治疗方面，靶向DLL3的治疗药物以及LBL-024新型免疫治疗药物的初步研究结果均显示出较高的有效率，有望为肺外NEC的治疗带来突破性进展。对于不同种类药物的联合治疗，部分方案已展现出一定的疗效，但与现有单药治疗相比，疗效提升仍有限，因此后续仍需开展大样本对照研究以进一步验证。总体上，2024年公布的研究结果以Ⅱ期研究为主，虽然多数研究结果尚不足以改变临床治疗决策，但也为后续Ⅲ期研究的开展提供了思路。期待2025年NENs治疗领域能够取得更多突破性进展。 参考文献 BAUDIN E, CAPDEVILA J, HÖRSCH D, et al. Treatment of advanced BP-NETS with lanreotide autogel/depot vs placebo: the phase Ⅲ SPINET study[J]. Endocr Relat Cancer, 2024, 31(9):e230337. CHAN J A, GEYER S, ZEMLA T, et al. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors[J]. N Engl J Med, 2024. Epub ahead of print. KOENIG A O, REINECKE J, HALFEN J, et al. 1146MO Interim analysis of CABONEN: A multicenter phase Ⅱ trial investigating cabozantinib in patients with advanced, low proliferative NEN G3[J]. Ann Oncol, 2024, 35(suppl_2):S752. WEI X, CHEN Y, JIANG X, et al. Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments[J]. Mol Cancer, 2021, 20(1):7. YEN C J, CHEN M H, CHEN Y Y, et al. 1145MO CVM-005: Phase Ⅱa study of CVM-1118, a novel oral anti-vasculogenic mimicry (VM) agent, in advanced neuroendocrine tumors (NET) after progression on prior therapy[J]. Ann Oncol, 2024, 35(suppl_2):S751. ELSE T, JONASCH E, ILIOPOULOS O, et al. Belzutifan for von Hippel-Lindau Disease: Pancreatic Lesion Population of the Phase 2 LITESPARK-004 Study[J]. Clin Cancer Res, 2024, 30(9):1750-1757. BONGIOVANNI A, LIVERANI C, FOCA F, et al. A randomized phase Ⅱ trial of Captem or Folfiri as second-line therapy in neuroendocrine carcinomas[J]. Eur J Cancer, 2024, 208:114129. VON ARX C, DELLA VITTORIA SCARPATI G, CANNELLA L, et al. A new schedule of one week on/one week off temozolomide as second-line treatment of advanced neuroendocrine carcinomas (TENEC-TRIAL): a multicenter, open-label, single-arm, phase Ⅱ trial[J]. ESMO Open, 2024, 9(5):103003. SPADA F, JEMOS C, PISA E, et al. An Italian multi-center phase Ⅱ trial of Metronomic Temozolomide in unfit patients with advanced neuroendocrine neoplasms: MeTe study[J]. J Neuroendocrinology, 2024, 36:249. SPADA F, JEMOS C, BARBERIS M, et al. 1160P An Italian multicenter phase Ⅱ trial of metronomic temozolomide in unfit patients with advanced neuroendocrine neoplasms: Interim analysis of the MeTe study[J]. Ann Oncol, 2024, 35(suppl_2):S757. WALTER T, LECOMTE T, HADOUX J, et al. Oxaliplatin-Based Versus Alkylating Agent in Neuroendocrine Tumors According to the O6-Methylguanine-DNA Methyltransferase Status: A Randomized Phase Ⅱ Study (MGMT-NET)[J]. J Clin Oncol, 2024:JCO2302724. CHANTRILL L A, RANSOM D, CHAN D, et al. NABNEC: A randomised phase Ⅱ study of nab-paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas (GI-NECs)[J]. J Clin Oncol, 2024, 42(3_suppl):589. CHIANG N J, LI C F, BAI L Y, et al. A phase Ⅰ/Ⅱ study of nanoliposomal irinotecan and carboplatin in patients with advanced or metastatic, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma characterized by tissue and liquid next-generation sequencing[J]. J Clin Oncol, 2024, 42(23_suppl):52. SINGH S, HALPERIN D, MYREHAUG S, et al. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study[J]. Lancet, 2024, 403(10446):2807-2817. PARTELLI S, LANDONI L, BARTOLOMEI M, et al. Neoadjuvant 177Lu-DOTATATE for non-functioning pancreatic neuroendocrine tumours (NEOLUPANET): multicentre phase Ⅱ study[J]. Br J Surg, 2024, 111(9):znae178. NAVALKISSOOR S, GROSSMAN A. Targeted Alpha Particle Therapy for Neuroendocrine Tumours: The Next Generation of Peptide Receptor Radionuclide Therapy[J]. Neuroendocrinology, 2019, 108(3):256-264. STROSBERG J, ULANER G, HALPERIN D, et al. Phase Ⅰb portion of the ACTION-1 Phase Ⅰb/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings[J]. J Neuroendocrinol, 2024, 36:220. HALPERIN D M, MORRIS M, ULANER G A, et al. Phase Ⅰb portion of the ACTION-1 phase Ⅰb/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings[J]. J Clin Oncol, 2024, 42(16_suppl):3091. STROSBERG J R, NAQVI S, COHN A L, et al. Safety, tolerability and efficacy of 212Pb-DOTAMTATE as a targeted alpha therapy for subjects with unresectable or metastatic somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors (SSTR+GEP-NETs): A phase 2 study[J]. J Clin Oncol, 2024, 42(16_suppl):4020. WERMKE M, GAMBARDELLA V, KUBOKI Y, et al. 670P Phase Ⅰ trial of the delta-like ligand-3 (DLL3)/CD3 IgG-Like T cell engager BI 764532 in patients (pts) with DLL3-positive tumors: Updated data[J]. Ann Oncol, 2024, 35(suppl_2):S525-S526. BELTRAN H, JOHNSON M L, JAIN P, et al. Updated results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine cancers (NEC)[J]. J Clin Oncol, 2024, 42(16_suppl):8090. LU M, ZHANG P, LUO S, et al. A novel and uniquely designed bispecific antibody (LBL-024) against PD-L1 and 4-1BB in patients with advanced malignant tumors and neuroendocrine carcinoma: A report of safety and robust efficacy of LBL-024 monotherapy in phase Ⅰ/Ⅱ, first-in-human, open-label, multicenter, dose escalation/expansion study[J]. J Clin Oncol, 2024, 42(16_suppl):4010. RIESCO-MARTINEZ M C, CAPDEVILA J, ALONSO V, et al. Nivolumab plus platinum-doublet chemotherapy in treatment-naive patients with advanced grade 3 Neuroendocrine Neoplasms of gastroenteropancreatic or unknown origin: The multicenter phase 2 NICE-NEC trial (GETNE-T1913)[J]. Nat Commun, 2024, 15(1):6753. GU Y, LY A, RODRIGUEZ S, et al. PD-1 blockade plus cisplatin-based chemotherapy in patients with small cell/neuroendocrine bladder and prostate cancers[J]. Cell Rep Med, 2024, 5(11):101824. LI X, LI R, CHENG K, et al. Camrelizumab plus chemotherapy as first-line treatment for advanced extrapulmonary neuroendocrine carcinoma: An investigator-initiated phase 2 study (CAMEC trial)[J]. J Neuroendocrinol, 2024, 36:241. ZHEN D B, MOSELEY A, CHIOREAN E G, et al. SWOG S2012: Randomized phase Ⅱ/Ⅲ trial of first line platinum (P)/etoposide (E) with or without atezolizumab (NSC #783608) in patients with advanced or metastatic poorly differentiated extrapulmonary neuroendocrine carcinomas (NEC)[J]. J Clin Oncol, 2024, 42(16_suppl):TPS4201. ZHANG P, SHI S, XU J, et al. Surufatinib plus toripalimab in patients with advanced neuroendocrine tumours and neuroendocrine carcinomas: An open-label, single-arm, multi-cohort phase Ⅱ trial[J]. Eur J Cancer, 2024, 199:113539. ZHANG P, WANG Y, LI J, et al. Surufatinib plus Sintilimab and IBI310 in patients with high-grade advanced-neuroendocrine neoplasm (HG-NEN): A multi-center, single arm phase 2 study[J]. J Neuroendocrinol, 2024, 36:259. AL-TOUBAH T, SCHELL M J, MORSE B, et al. Phase Ⅱ study of pembrolizumab and lenvatinib in advanced well-differentiated neuroendocrine tumors[J]. ESMO Open, 2024, 9(4):102386. MOLINA-CERRILLO J, GRANDE E, BENAVENT M, et al. Responses to Cabozantinib plus Atezolizumab in a wide population of advanced and progressive neuroendocrine neoplasms (NENs): A prospective multi-cohort basket phase Ⅱ Trial (CABATEN/GETNE-T1914)[J]. J Neuroendocrinol, 2024, 36:245. HERNANDO J, MOLINA-CERRILLO J, GRANDE E, et al. Cabozantinib plus atezolizumab in patients with advanced and progressive neuroendocrine neoplasms (NENs): A prospective multi-cohort basket phase Ⅱ trial (CABATEN/GETNE-T1914)[J]. J Clin Oncol, 2024, 42(16_suppl):4128. DASARI A, QIAO W, HALPERIN D, et al. A phase Ⅱ study of Lenvatinib and Everolimus in advanced well-differentiated extra pancreatic neuroendocrine tumors[J]. J Neuroendocrinol, 2024, 36:232. CAPDEVILA J, FAZIO N, LOPEZ C, et al. Lenvatinib in Patients With Advanced Grade 1/2 Pancreatic and Gastrointestinal Neuroendocrine Tumors: Results of the Phase Ⅱ TALENT Trial (GETNE1509)[J]. J Clin Oncol, 2021, 39(20):2304-2312. WANG W, LIU Z, YANG X, et al. Efficacy and safety of Surufatinib in combination with CAPTEM for patients with advanced G2/G3 NETs: Preliminary results from a single-arm, phase Ⅱ study[J]. J Neuroendocrinol, 2024, 36:255. WANG Z, CAO D, KE N. A prospective, open-label study evaluating the efficacy and safety of Surufatinib (S) in combination with CAPTEM as conversion therapy in patients with unresectable pancreatic neuroendocrine tumors (pNET)[J]. J Neuroendocrinol, 2024, 36:254. KUNZ P L, GRAHAM N T, CATALANO P J, et al. A Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients with Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211)[J]. J Clin Oncol, 2022:101200JCO2201013. APOSTOLIDIS L, KOENIG A O, KRUG S, et al. 1147MO Ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors (RamuNET): An AIO phase Ⅱ multicenter single-arm study[J]. Ann Oncol, 2024, 35(suppl_2):S752. 推荐阅读 ●   盘点2023 | 陈洁教授：2023年度神经内分泌肿瘤治疗研究进展 ●   盘点2022丨陈洁教授：2022年度神经内分泌肿瘤药物治疗进展盘点 ●   2023年度肿瘤学科盘点集锦(共17个) 声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。 排版：lagertha 校对：松月

RAHWAY, N.J.--( BUSINESS WIRE )--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending the conditional approval of WELIREG ® (belzutifan), Merck’s oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, as monotherapy for: The treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated, localized renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), and for whom localized procedures are unsuitable; The treatment of adult patients with advanced clear cell renal cell carcinoma (RCC) that progressed following two or more lines of therapy that included a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and at least two vascular endothelial growth factor (VEGF) targeted therapies. The CHMP’s recommendation will now be reviewed by the European Commission for marketing authorization in the European Union (EU), and a final decision is expected in the first quarter of 2025. “ Today’s positive CHMP opinion brings us closer to offering WELIREG, a first-in-class HIF-2α inhibitor, to certain patients in the European Union, in order to help address critical gaps in care for these patients,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “ We are committed to providing innovative treatment options that address serious unmet needs for patients globally and look forward to the European Commission’s decision.” The CHMP recommendation in VHL disease-associated tumors is based on objective response rate (ORR) and duration of response (DOR) results from the LITESPARK-004 trial. If approved, WELIREG would be the first and only systemic treatment for patients with VHL disease-associated tumors in the EU. In August 2021 , WELIREG was approved in the U.S. for the treatment of adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas or pNET not requiring immediate surgery based on the results from LITESPARK-004, an open-label clinical trial in 61 patients with VHL-associated RCC. In the LITESPARK-004 trial, WELIREG showed an ORR of 49% (95% CI, 36-62) in patients with VHL-associated RCC (n=30/61); all responses were partial responses (PR). Median DOR for these patients was not reached, with ongoing responses ranging from 2.8+ to 22+ months; among responders, 56% (n=17/30) maintained a response for at least 12 months. Patients enrolled in LITESPARK-004 had other VHL-associated tumors, including CNS hemangioblastomas and pNET. In patients with VHL-associated CNS hemangioblastomas (n=24) in this trial, WELIREG showed an ORR of 63% (95% CI, 41-81) (n=15/24), with a complete response (CR) rate of 4% (n=1/24) and a PR rate of 58% (n=14/24). Median DOR for these patients was not reached, with ongoing responses ranging from 3.7+ to 22+ months; among responders, 73% (n=11/15) maintained a response for at least 12 months. In patients with VHL-associated pNET (n=12) in this trial, WELIREG showed an ORR of 83% (95% CI, 52-98) (n=10/12), with a CR rate of 17% (n=2/12) and a PR rate of 67% (n=8/12). Median DOR for these patients was not reached, with ongoing responses ranging from 11+ to 19+ months; among responders, 50% (n=5/10) maintained a response for at least 12 months. The CHMP recommendation in advanced clear cell RCC that progressed following two or more lines of therapy that included a PD-(L)1 inhibitor and at least two VEGF targeted therapies, is based on PFS and ORR results from the LITESPARK-005 trial, the first positive Phase 3 trial in these patients. In December 2023 , WELIREG was approved in the U.S. for the treatment of adult patients with advanced RCC following a PD-1 or PD-L1 inhibitor and a VEGF-TKI based on the results from LITESPARK-005, an open-label clinical trial in 746 patients with unresectable, locally advanced or metastatic clear cell RCC that progressed following PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies either in sequence or in combination. In the trial, WELIREG reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus everolimus in these patients. Median PFS was 5.6 months (95% CI, 3.9-7.0) for WELIREG versus 5.6 months (95% CI, 4.8-5.8) for everolimus. The ORR for WELIREG was 22% (n=82) (95% CI, 18-27), with a CR rate of 3% (n=10) and a PR rate of 19% (n=72), and the ORR for everolimus was 4% (n=13) (95% CI, 2-6), with no patients achieving a CR and a PR rate of 4% (n=13). About von Hippel-Lindau disease Von Hippel-Lindau disease is a rare genetic disease, which impacts an estimated 200,000 people worldwide and an estimated 10,000 to 15,000 people in Europe. Patients with VHL are at risk for recurrent, benign blood vessel tumors as well as some cancerous ones. The most commonly occurring tumor is RCC, a form of kidney cancer, which occurs in about 70% of patients with VHL disease. About renal cell carcinoma Renal cell carcinoma is by far the most common type of kidney cancer. In 2020, more than 130,000 new cases of RCC were diagnosed in Europe. Renal cell carcinoma is about twice as common in men than in women. Approximately 30% of patients with kidney cancer are diagnosed at an advanced stage. About WELIREG ® (belzutifan) 40 mg tablets, for oral use Indications in the U.S. Certain von Hippel-Lindau (VHL) disease-associated tumors WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. Advanced Renal Cell Carcinoma (RCC) WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Selected Safety Information for WELIREG Warning: Embryo-Fetal Toxicity Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective. Anemia WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG. In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established. In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs. Hypoxia WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider. In LITESPARK-004, hypoxia occurred in 1.6% of patients. In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months). Embryo-Fetal Toxicity Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Adverse Reactions In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each). WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%). The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%). In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%). WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage (0.5%). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%). Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%). Drug Interactions Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended. Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding. Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose. Females and Males of Reproductive Potential WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG. Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown. Pediatric Use Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established. Merck’s focus on cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/ . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovation products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). Please see Prescribing Information, including information for the Boxed Warning about embryo-fetal toxicity, for WELIREG (belzutifan) at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf and Medication Guide for WELIREG at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_mg.pdf .