Her2-targeted ADC(Phigenix)

Since its original FDA approval for previously treated metastatic breast cancer in late 2019, Enhertu has continuously transformed the standard of care in HER2-positive breast cancer. Enhertu’s market conquest is continuing apace. Already tracking at $5 billion in annual sales, the star antibody-drug conjugate from Daiichi Sankyo and AstraZeneca has secured FDA approval to treat early breast cancer, further encroaching on Roche’s Kadcyla territory.The FDA has simultaneously greenlighted Enhertu for both the neoadjuvant and adjuvant treatment of patients with HER2-positive early breast cancer, the two companies said Friday. The adjuvant nod came nearly two months ahead of schedule, as the FDA had originally targeted a decision by July 7.While early, the adjuvant label comes with a catch: It precludes patients who’ve received Enhertu before surgery from continuing on the HER2-directed ADC in the post-operative setting. Specifically, in the adjuvant setting, Enhertu is now approved for patients with HER2-positive breast cancer who have residual invasive disease following treatment with trastuzumab (Herceptin)—with or without Roche’s Perjeta—and taxane-based treatment. When announcing an FDA priority review in March, Daiichi and AZ described the indication as for “after neoadjuvant HER2 targeted treatment,” which, if approved verbatim, would cover prior use of Enhertu. But apparently a broad label did not pan out.As for the neoadjuvant setting, Enhertu is cleared on top of the THP regimen (a taxane, Herceptin and Perjeta) for treating adults with HER2-positive stage 2 or stage 3 breast cancer. Despite the label restriction, some doctors may still use Enhertu in the adjuvant setting following neoadjuvant Enhertu.Enhertu’s adjuvant early breast cancer indication is backed by data from the Destiny-Breast05 trial showing the drug reduced the risk of invasive disease recurrence or death by 53% compared with Kadcyla.In the neoadjuvant setting, the Destiny-Breast11 study linked Enhertu, followed by THP, to a pathologic complete response (pCR) rate of 67.3%, significantly higher than the 56.3% for dose-dense doxorubicin and cyclophosphamide followed by THP. A pCR means no residual disease is found in resected tissues.  In interviews with Fierce at the European Society for Medical Oncology annual meeting in October, executives from Daiichi and AZ suggested that because neoadjuvant treatment only involves four cycles of Enhertu, doctors would not hesitate to retreat patients who have residual disease.“If you’ve only had four cycles of Enhertu and you’ve had a really good response, I don’t think that that says that you’re going to necessarily be resistant to Enhertu for a re-challenge in that setting,” AZ’s oncology R&D chief Susan Galbraith, Ph.D., said at the time.In a separate interview in January on the sidelines of the J.P. Morgan Healthcare Conference, Daiichi’s head of global oncology business, Ken Keller, acknowledged that doctors are split on whether reusing Enhertu is appropriate, but he suggested that “the majority” agree with the proposed practice because Enhertu is so far the most potent HER2 agent.But with the adjuvant label excluding prior Enhertu use and the fact that the Destiny-Breast05 study did not enroll patients who had received the ADC as a neoadjuvant treatment, reimbursement for continued use may be a challenge. Either way, Enhertu’s latest expansion is expected to do a number on Kadcyla, which has been counting heavily on its adjuvant use for any residual growth in the U.S. after losing out to Enhertu in the metastatic setting. Since its original FDA approval for previously treated metastatic breast cancer in late 2019, Enhertu has transformed the standard of care in HER2-positive breast cancer. It was only in December that the FDA signed off on Enhertu combined with Perjeta as a first-line treatment.  Sales of Enhertu have been on the rise as it has moved up in the treatment sequence and established HER2-low as a new therapeutic area. Combined sales recorded by AZ and Daiichi jumped 31% in the first quarter of 2026, reaching $1.4 billion. For its 2026 fiscal year, which ends in March 2027, Daiichi has projected Enhertu global sales of 861.3 billion Japanese yen ($5.4 billion). Enhertu is a key pillar in Daiichi’s freshly unveiled five-year plan to have sales above 3 trillion yen by fiscal 2030. The company also aims to be a global top-5 oncology player by 2035, by which time Enhertu will have lost its patient protection.

-01- 引言 卵巢癌是美国女性癌症相关死亡的第六大原因。它在早期基本上是无症状的，导致大多数患者在晚期才被诊断出来。大多数（90%）卵巢恶性肿瘤起源于上皮，并按组织学分类，包括浆液性、粘液性、子宫内膜样和透明细胞癌。高级浆液性卵巢癌根据它们是否携带BRCA1和BCRA2突变进行细分，这些突变发生在10-15%的卵巢癌中。 -02- 一、目前的治疗方法 在早期（I-II期），辅助化疗是具有高风险病理特征患者的标准护理，卡铂和紫杉醇治疗可降低复发风险。低风险I期肿瘤通常仅通过手术进行治疗，有高治愈率。 晚期（III-IV期）的治疗模式包括细胞减灭术、卡铂和紫杉醇化疗（作为新辅助剂和/或佐剂）以及对一些患者的维持治疗。具有高肿瘤负荷或IV期的患者也可接受贝伐单抗治疗。在BRCA1/2突变状态和同源重组缺陷（HRD）的指导下，PARP抑制剂已经改变了一线维持治疗。奥拉帕尼是BRCA1/2突变肿瘤的标准治疗方法，建议与贝伐单抗联合治疗HRD阳性肿瘤。在2025年对III期PRIMA试验的最终总体生存数据进行审查后，Niraparib现在仅限于治疗HRD阳性肿瘤。Rucaparib被指定为一线维护选择，无论BRCA或HRD状态如何，但仅在欧洲获得批准。贝伐单抗维持治疗是已经开始抗血管生成治疗的患者或HRD阴性疾病患者的替代方案。 在疾病复发时，铂敏感和铂耐药之间的区别是临床决策的核心。铂敏感复发——通常定义为至少六个月的无铂间隔期——通常用基于铂的联合方案治疗，如卡铂加紫杉醇、卡铂加吉西他滨或卡铂加阿霉素脂质体，并在选定的患者中加入贝伐单抗。由于PARP抑制剂在一线的广泛使用，这种情况下的维护选项变得越来越有限，这减少了PARP抑制剂再次干预的机会；因此，贝伐单抗仍然是继铂类治疗反应后的主要维持治疗。 抗铂卵巢癌的定义是在最后一次服用铂后六个月内复发，由于预后不良和对现有疗法的反应持久性有限，这是一个有大量临床需求的领域。治疗主要依赖于连续的非铂类单一药物，如聚乙二醇化脂质体阿霉素、紫杉醇、拓扑替康或吉西他滨，加上贝伐单抗，可以适度改善贝伐单抗初治患者的无进展生存率。美国食品药品监督管理局于2026年3月批准了relacorilant，这是一种第一类选择性糖皮质激素受体拮抗剂，与nab-paclitaxel联合使用，为复发性抗铂卵巢癌症提供了一种机制上独特的生物标志物识别治疗选择。它适用于接受过最多三种先前治疗的患者，包括贝伐单抗。 靶向治疗也扩大了对生物标志物定义的复发性抗铂癌症患者的治疗。抗体偶联药物（ADC）mirvetuximab soravtansine是高叶酸受体-α（FRα）表达患者的标准治疗方法，正在进行的III期试验（GLORIOSA）中与贝伐单抗联合评估。PD-1抑制剂pembrolizumab与紫杉醇联合使用，联合或不联合贝伐单抗，适用于PDL1阳性肿瘤（联合阳性评分，CPS≥1；美国食品药品监督管理局于2026年批准）。Avutometinib加defactinib，一种RAF/MEK和FAK抑制剂组合，被批准用于KRAS-突变的复发性低级别浆液性癌症，一种罕见的亚型（上皮肿瘤<5%）。该组合在2025年获得了美国食品药品监督管理局的加速批准，继续批准取决于在验证性试验中确认临床效益。 -03- 二、新兴疗法 癌症III期管线在过去三年中大幅扩张，目前主要由具有不同分子靶点的ADC主导，如下表所示。 三种FRα导向的ADC—— rinatabart sesutecan (Genmab), sofetabart mipitecan (Eli Lilly) 和torvutatug samrotecan (AstraZeneca) ——正在治疗复发性铂耐药性疾病的III期试验中进行评估。尽管这些药物与mirvetuximab soravtansine具有相似的作用机制，但它们正在未经选择的人群中进行研究，而不管FRα的表达如何，这可能会扩大它们的用途。Rinatabart sesutecan和sofetabart mipitecan也正在接受复发性铂敏感性疾病的评估。Rinatabart sesutecan正在RAINFOL-04试验中作为二线维持治疗进行评估，无论是否使用贝伐单抗，而sofetabart mipitecan正在FRAmework-01试验中进行研究，其中一部分纳入了接受贝伐单抗治疗的铂类敏感患者。 Sacituzumab-tirumotecan，一种TROP2靶向ADC，目前正在两项III期试验中评估，无论是否使用贝伐单抗，用于复发性对铂敏感的卵巢癌。它正在被研究作为二线维持疗法（TroFuse-022试验）和HRD阴性疾病的一线维持疗法（TroFuse-021试验）。Trastuzumab deruxtecan是一种HER2靶向ADC，也被评估为表达HER2的BRCA野生型患者的一线维持治疗，有或没有贝伐单抗。 Raludotatug deruxtecan靶向钙粘蛋白-6（CDH6），后者在65%以上的上皮性卵巢癌中表达。在复发性铂耐药性疾病的II/III期试验（REJOICE-Ovarian01）中，正在对其进行评估，并根据CDH6表达对患者进行分层。GSK-5733584（GSK）靶向B7-H4，B7-H4在90%以上的卵巢癌中过表达，ADC也在这种情况下进行评估。 除了ADC，INCB-123667（Incyte）是一种小分子细胞周期蛋白依赖性激酶2抑制剂，正在研究复发性铂耐药性卵巢癌。NP-G2-044（Novita Pharmaceuticals）是一种领先的fascin抑制剂，正在与聚乙二醇化脂质体阿霉素联合使用进行评估；其II/III期试验（ULTIMUS-1）也在该人群中进行。Olvimulogene nanivacirepvec（Genelux）是一种溶瘤病毒免疫疗法，也正在该人群中进行评估。 相比之下，在疾病过程的早期，有几种药物也正在开发中。IMNN-001（Imunon）是一种基于质粒的DNA载体，编码通过纳米颗粒递送系统递送的白细胞介素-12，正在与新诊断的晚期卵巢癌症的（新）辅助化疗联合研究（OVATION-3试验）。Oregovomab（CanariaBio）是一种靶向CA125的单克隆抗体，在这种情况下也正在与化疗联合进行评估。然而，其试验（FLORA-5）排除了BRCA1/2突变或HRD阳性肿瘤的参与者。 -04- 三、卵巢癌的药物市场 根据Clarivate Disease Landscape&Forecast，2025年卵巢癌药物在主要市场的销售总额为39.2亿美元，预计2034年将达到73.7亿美元，主要受高价ADC的批准和标签扩展的推动。 2025年，PARP抑制剂是卵巢癌症最畅销的药物类别（19.7亿美元），其中奥拉帕尼在类别销售额中所占份额最大。然而，由于成本较低的仿制药的预期进入，预计到2034年，这类药物在主要市场的销售额将稳步下降。相比之下，预计到2034年，ADC将成为最畅销的药物类别（47.4亿美元），占市场总销售额的近65%。在这一类别中，Trastuzumab deruxtecan预计将成为主要产品，2034年的预计销售额为11亿美元，反映出其有望扩展到一线维护用途，尽管其使用可能会受到其他疗法的竞争和生物标志物限制的影响。 最近的市场进入者提供了急需的治疗选择，并满足了临床需求；然而，他们的销售效果预计不会太大。Avutometinib和defactinib仅限于一种罕见的卵巢癌症亚型，而relacorilant和pembrolizumab预计主要用于符合条件的患者较少的晚期环境。 参考资料： The ovarian cancer drug market. Nat Rev Drug Discov. 2026 May 8 公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。