Belzutifan

Around the world, events are being held to mark Rare Disease Day (28 February 2025), with the aim of bringing attention to rare diseases and improving access to diagnosis and therapies for patients. There are more than 7,000 known rare diseases that impact an estimated 300 million people globally, yet the lack of scientific knowledge and quality information on rare diseases often results in a delay in diagnosis, and treatment options are only available for a small proportion of rare diseases. Significant progress is, however, continually being made in the rare disease space. Just last week, the US Food and Drug Administration (FDA) approved Mirum Pharmaceuticals’ Ctexli (chenodiol) for adults with cerebrotendinous xanthomatosis (CTX), making it the first treatment to be approved by the regulator for the rare lipid storage disease. Affecting up to 2,000 people in the US, CTX is a progressive genetic disorder caused by a deficiency of an enzyme that allows the body to break down fats. This results in the deposition of atypical cholesterol metabolites in the brain and other areas of the body. Mirum’s chief executive officer, Chris Peetz, described the approval as “tremendous”, noting that it “unlocks an opportunity to better identify and treat adult patients with CTX in the US”. Gilead Sciences’ seladelpar was also granted conditional marketing authorisation by the European Commission (EC) last week to treat patients with the rare liver disease primary biliary cholangitis (PBC). Approximately 163,000 people in Europe are affected by PBC, an autoimmune disease of the bile ducts that disproportionally affects women. Timothy Watkins, vice president, clinical development of inflammation therapeutics at Gilead, said at the time of the announcement: “People living with PBC in Europe have been waiting for treatment advancements for many years. “Up until now, there has been no approved treatment for PBC addressing both the surrogate biomarkers for underlying disease and pruritus, a common and at times debilitating symptom of PBC.” Merck & Co’s – known as MSD outside the US and Canada – Welireg (belzutifan) was conditionally approved by the EC last week to treat certain patients with von Hippel-Lindau disease, a rare tumour-causing genetic disorder affecting up to 15,000 people in Europe. Sobi’s Sanofi-partnered efanesoctocog alfa also recently received approval by the Medicines and Healthcare products Regulatory Agency to treat the rare bleeding disorder haemophilia A, while SpringWorks Therapeutics’ Gomekli (mirdametinib) was approved by the FDA earlier this month to treat neurofibromatosis type 1, a rare genetic disorder that causes a variety of symptoms across multiple organ systems. Since being established in 2008 by the European Organisation for Rare Diseases, Rare Disease Day has played a critical role in building an international rare disease community and has seen a significant increase in events and campaigns across the world, with patient organisations, medical professionals and research institutions uniting to drive progress in rare disease research and advocacy.

编者按：透明细胞肾细胞癌（ccRCC）普遍与VHL通路失调相关，这会导致HIF-2α过度表达并上调多种致癌通路。而针对HIF-2α的治疗策略，如贝组替凡等药物为这类VHL患者，甚至肾癌患者带来了新的希望。在今年ASCO GU年会上，肿瘤瞭望-泌尿时讯特邀北京大学第一医院龚侃教授对话MD安德森癌症中心VHL临床中心主任Eric Jonasch教授，共同解读贝组替凡获益人群及不良反应管理，以及未来应用前景。 01 《肿瘤瞭望-泌尿时讯》 贝组替凡已经在2021年获FDA批准治疗VHL病，能否分享一下您的临床实践经验？您在临床实践中，主要在什么疾病阶段（治疗时机）选择贝组替凡？以及对贫血、疲劳等常见不良事件的管理？ Eric Jonasch 教授 MD安德森癌症中心VHL临床中心主任 对于患有VHL病的患者，我们会观察患者最终是否有可能出现多种威胁性病变，从而决定是否需要干预，这因素包括：肾脏肿瘤≥3 cm、可能出现中枢神经系统血管母细胞瘤、胰腺神经内分泌肿瘤等。一般而言，如果患者仅存在一个病变（例如肾脏的一个部位），通过消融或手术干预即可使患者正常生存，而不需要额外干预，此时我们不会为他们推荐贝组替凡。而对于存在多个病变的患者（可能会影响患者生存，并导致患者多次手术），我们通常会推荐贝组替凡。 使用贝组替凡时，我们也会随访并跟踪分析患者的毒副作用。研究发现，最常见的不良反应（AE）是贫血，贫血原因是HIF-2α通过结合促红细胞生成素（EPO）基因中控制其氧依赖性转录的特异性调节元件来介导红细胞生成素的生成；而使用贝组替凡会抑制EPO的转录，因而会造成贫血。在我的实践中，我们通常会使用促红细胞生成素刺激剂来提高血红蛋白水平。 其次常见的AE是缺氧，在年轻的VHL病患者中，我们很少见到这种症状。但在老年VHL病患者和晚期肾癌患者中，确实会出现这种副作用。我们会跟踪随访，并要求每位患者通过血氧仪分析期血氧水平：如果血氧水平低于90%，会暂停用药；等到血氧水平超过92%后，再降低使用剂量。 第三个副作用是疲劳，我们通常通过减少剂量来进行改善。 That looks like they're beginning to potentially cause neurological problems or pancreatic neuroendocrine tumors that are approaching three centimeters in size. And in general, if we have a patient that has only one lesion, for example, one spot in the kidney, where an intervention with an ablation or a surgery would allow them to then have a long period of time where they would not need additional interventions, we would not offer Belzutifan to them. We typically are offering Belzutifan to patients who have multiple lesions that look like they're going to cause problems and would result in them having multiple surgeries. So we start Belzutifan on those individuals, and we then follow them for the toxicities. The major toxicities include anemia, and the reason they get anemia is because erythropoietin (EPO) is a HIF-2α client gene. So we're basically knocking down transcription of EPO. We, in my practice, typically are using erythropoietin-stimulating agents to bring up the hemoglobin levels. The second major toxicity is hypoxia, which we don’t see very often in patients with VHL disease when they’re younger, but we do see it in older VHL disease patients and also in patients with advanced kidney cancer. There, what we do is we will follow. We ask every patient to get a pulse oximeter, we have them watch their oxygen levels. If it goes below 90%, we have them hold the drug, we wait till it goes above 92%, and then have them lower the dose. The third side effect is fatigue, and that is something that we manage usually with dose reduction. 上下滑动查看 龚侃 教授 北京大学第一医院 为什么嗜铬细胞瘤和副神经节瘤（PPGL）患者使用贝组替凡的疗效不佳？ Eric Jonasch 教授 MD安德森癌症中心VHL临床中心主任 我们也观察到了这种现象，但我们对PPGL的诊治经验较少，暂时还未进行深入研究。 龚侃 教授 北京大学第一医院 在中国的VHL患者数据中，贝组替凡治疗PPGL患者的疗效并不明显；但在VHL综合征肾癌患者中，贝组替凡的疗效显著。 Eric Jonasch 教授 MD安德森癌症中心VHL临床中心主任 那么这些PPGL患者均与VHL相关吗？这个现象很有趣。 龚侃 教授 北京大学第一医院 是的，因此我们团队收集了PPGL相关数据，并试图分析其中的原因。我们想了解为什么贝组替凡在PPGL患者中表现不佳。 Eric Jonasch 教授 MD安德森癌症中心VHL临床中心主任 可能还存在您所提及的VHL以及其他突变，这些突变共同导致了该疾病的生物学特性。这非常有趣，值得进一步探索。 02 《肿瘤瞭望-泌尿时讯》 贝组替凡用于晚期透明细胞肾细胞癌（ccRCC）治疗也取得了突破性进展，例如2024年发表于NEJM的III期临床研究。两位对贝组替凡未来的应用前景有怎样的展望？ 龚侃 教授 北京大学第一医院 这一问题具有重要意义。在晚期肾癌治疗领域，当前已有众多药物可供选择，无论是欧洲泌尿外科协会（EAU）还是美国泌尿外科协会（AUA）发布的指南，针对晚期肾癌的一线、二线乃至后线治疗方案，均已被广泛熟知与应用。对于肾透明细胞癌及非透明细胞癌的治疗，临床实践中也积累了丰富的参考依据。 然而，就目前所获取的数据而言，贝组替凡在肾透明细胞癌，尤其是晚期肾透明细胞癌的治疗中，展现出了令人振奋的疗效。因此，我个人认为其将在晚期肾癌治疗领域开启一个全新的纪元。现阶段指南或将其列为二线治疗方案，但随着临床经验的不断积累以及更多数据的证实，贝组替凡在晚期肾癌治疗中的地位与作用将会日益凸显。 从此次LITESPARK-015研究的中国数据来看，贝组替凡的表现令人惊喜。在安全性方面，其导致的贫血、乏力、缺氧等不良反应总体处于可控范围，安全性良好。在治疗过程中，我们需要组建多学科诊疗团队（MDT），联合内科医生共同为患者提供全程规范的治疗。故而，我坚信贝组替凡有望成为未来晚期肾癌治疗的有力武器。 至于联合免疫治疗是否将成为未来的新方向，贝组替凡与免疫治疗联合能否带来更佳疗效，仍有待进一步探索与验证。因此，我与Eric Jonasch教授就此进行了深入交流，双方机构计划进一步开展合作研究，期望通过共同努力为该领域带来新的突破与惊喜。 Eric Jonasch 教授 MD安德森癌症中心VHL临床中心主任 贝组替凡获得FDA批准用于晚期肾细胞癌（RCC）治疗，这一进展对患者而言意义非凡。LITESPARK-005研究入组了既往接受过免疫联合TKI的患者，中位治疗线数为2。研究结果显示，患者客观缓解率约23%，疾病进展比例为34%，这表明部分患者能够从中获益，但另一部分患者则未能改善。值得注意的是，部分患者的缓解持续时间接近两年，且治疗耐受性良好。因此，我认为贝组替凡有望成为既往治疗失败的晚期肾细胞癌患者的单药治疗方案。 然而，关于贝组替凡是否应早期与其他疗法联合应用，仍存在较大争议。来自LITESPARK 003研究的数据显示，贝组替凡与卡博替尼联合使用，未接受任何系统治疗患者的客观缓解率约70%，无进展生存期接近30个月，这提示联合治疗是一种可行的治疗策略。此外，我们还开展了多项研究，探索贝组替凡与免疫疗法及免疫+TKI联合使用的疗效，但目前这些研究的数据尚不成熟。例如，LITESPARK 011研究旨在分析贝组替凡联合仑伐替尼和帕博利珠单抗的效果，我们也在期待这些数据的早日揭晓。 目前，我们已经取得了贝组替凡联合免疫治疗的初步数据，尽管样本量有限，但这些数据表明，贝组替凡联合免疫疗法的无进展生存期可能并不优于其与TKI联合的效果，且协同作用似乎相对较小。未来，我们需要更深入地探究贝组替凡的作用机制，明确其在何种疾病状态下使用最为适宜，以及哪些药物组合能够最大化其疗效。我相信，在接下来的几年里，我们将逐步揭示这些问题的答案，为晚期肾细胞癌的治疗开辟新的篇章。 Yeah, so the approval of Belzutifan in advanced renal cell carcinoma clearly is a great advance for patients with renal cell carcinoma. This study looked at individuals who had received prior therapy, either with an IO agent plus a TKI. They had to have received both, and the median number of treatments that the patients had received was three. What we saw with that study was the objective response rate was around 23%. But the other thing that we did see was that the progressive disease as best response was 34%. So clearly, some people are benefiting, but others not. If patients responded, their responses lasted close to two years, and the treatment is very well tolerated. So I see the future for Belzutifan in advanced renal cell carcinoma as being a monotherapy in individuals who have received prior treatments. But the big question is whether or not Belzutifan should be combined with other therapies in earlier lines of treatment. We have data from LITESPARK-003 that shows that in combination with cabozantinib, there’s an objective response rate of around 70% and a progression-free survival of 30 months in a predominantly favorable-risk population. So maybe combination with cabozantinib is a good idea. We have a number of other studies combining Belzutifan with IO therapies and IO/TKIs, and we don’t have information on those yet. For example, there’s also a study of Belzutifan plus lenvatinib compared to cabozantinib, that’s LITESPARK-011, and we’re waiting for those data. We do have a few data on Belzutifan with IO therapy. There are the KEYMAKER studies that are being run right now. Very small numbers, but they show that Belzutifan together with immune therapy does not seem to have quite the same progression-free survival as Belzutifan with TKI. So maybe there is less synergy or additivity between Belzutifan plus immune therapy compared to TKI. I think we need to keep on working very hard on understanding how to use this drug. It’s clearly helpful, and which combinations are going to be best and in which disease state to use, we will find out in the next few years. 上下滑动查看 往期推荐 1 ASCO GU丨龚侃教授&Eric Jonasch教授共话肾癌相关治疗新策略与展望（上篇） 注：ASCO GU：美国临床肿瘤学会泌尿生殖系统癌症研讨会ccRCC：透明细胞肾细胞癌VHL：Von Hippel－Lindau，希佩尔－林道综合征HIF-2α：低氧诱导因子2αFDA：美国食品药品监督管理局Belzutifan：贝组替凡EPO：促红细胞生成素PPGL：嗜铬细胞瘤/副神经节瘤EAU：欧洲泌尿外科协会AUA：美国泌尿外科协会MDT：多学科诊疗团队RCC：肾细胞癌 TKI：酪氨酸激酶抑制剂 龚侃 教授 教授、博导、主任医师 北京大学泌尿外科研究所副所长  北京大学第一医院肿瘤转化中心副主任 北京大学第一医院科研处处长 国家高层次人才特殊支持计划（中组部万人） 科技部“中青年科技创新领军人才” 教育部“新世纪优秀人才 中华医学会泌尿外科分会肿瘤学组委员 中华医学会泌尿外科分会转化学组副组长 中华医学会罕见病分会第一届委员会委员 中国医促会泌尿外科分会副主任委员 中华医学会泌尿外科分会遗传及罕见病协作组组长 中国医师协会泌尿外科肿瘤委员会委员 中国抗癌协会家族遗传性肿瘤专业委员会常务委员 中国研究型医院学会罕见病分会常务理事 北京医学会肿瘤专业委员会常务委员 北京医学会罕见病分会专业委员会常务委员 国际VHL联盟咨询委员 长期致力于泌尿生殖系统肿瘤的罕见疑难病的诊、防、治攻关研究，主持科技部重大项目课题、国自然重点专项和面上基金、北京市自然科学基金等20余项。在Cancer Discovery、PNAS、Cancer Research等权威杂志发表SCI论文100余篇，授权发明专利3项，其中1项成功转化成产品上市。 Eric Jonasch 教授 MD安德森癌症中心VHL临床中心主任 Eric Jonasch医学博士是德克萨斯大学MD安德森癌症中心癌症医学部泌尿生殖医学肿瘤学系教授。Jonasch博士还担任MD安德森癌症中心的Von Hippel–Lindau(VHL)临床中心主任和MD安德森癌症中心肾癌研究项目联合主任。 Jonasch博士的临床兴趣集中在肾细胞癌和VHL疾病的组织转化研究。他领导了这些疾病的多项研究者发起的临床试验和正在进行的实验室研究工作，以评估对靶向疗法的反应和耐药性的决定因素。Jonasch博士是美国癌症研究协会、美国临床肿瘤学会等成员。 Jonasch 博士目前担任NCCN肾癌小组副主席。 （来源：《肿瘤瞭望-泌尿时讯》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。