Tri-Service General Hospital

点击上方蓝字 关注我们 编者按：INAVO120研究数据自2024年10月在《新英格兰医学杂志》（NEJM）发表以来，引发了广泛关注。基于该研究数据，美国食品药品监督管理局（FDA）已经获批Inavolisib（伊那利塞）联合哌柏西利+氟维司群用于治疗在辅助内分泌治疗期间或完成后复发后的内分泌治疗耐药、PIK3CA突变的HR+/HER2-的局部晚期或转移性乳腺癌成人患者。2025年1月16日，NEJM再度刊发INAVO120研究读者来信与作者回信，就该研究患者入组情况进行深入探讨。读者来信指出研究中黑人和西班牙裔患者比例过低的问题，而作者回信则对此作出回应，并承诺将在后续研究中关注并解决多样性问题。本文将对INAVO120研究及其后续讨论进行全面回顾与解读，以期为读者提供更为全面的研究视角与临床启示。 研究简介 研究背景 伊那利塞是磷脂酰肌醇3-激酶复合物（由PIK3CA编码）中p110催化亚基α亚型的强效和选择性抑制剂，该复合物也可促进突变的p110α的降解。Inavolisib联合哌柏西利+氟维司群在临床前模型中显示出协同活性，在早期试验中显示出有前景的抗肿瘤活性。 研究方法 在3期、双盲、随机的INAVO120研究中，纳入了辅助内分泌治疗完成后12个月内或12个月内复发的PIK3CA突变、HR+/HER2-局部晚期或转移性乳腺癌患者，比较了伊那利塞（口服剂量为每日1次，每次9 mg）+哌柏西利+氟维司群一线治疗（伊那利塞组）和安慰剂+哌柏西利+氟维司群一线治疗（安慰剂组）的疗效和安全性。主要终点是研究者判定的无进展生存期（PFS）。 研究结果 共161例患者被分配至伊那利塞组，164例被分配至安慰剂组。中位随访时间分别为21.3个月和21.5个月。两个试验组的基线特征平衡（表1）。患者中位年龄为54.0岁，60.0%的患者已绝经。总体而言，患者疾病负担较重：51.4%的患者至少有3个器官转移，80.0%有内脏转移，51.7%有肝转移。大多数患者既往接受过新辅助或辅助化疗（82.8%），且既往未接受过CDK4/6抑制剂治疗（98.8%），47.7%的患者既往仅接受过新辅助或他莫昔芬辅助治疗。各组的相关危险因素分布均衡。黑人或非裔美国患者的代表性不足。 表1. INAVO120研究中患者的基线人口统计学和临床特征 疗效 伊那利塞组和安慰剂组的中位PFS分别为15.0个月（95% CI：11.3～20.5）和7.3个月（95% CI：5.6～9.3）[疾病进展或死亡的风险比（HR），0.43；95% CI：0.32～0.59；P＜0.001]。（图1.A）。 △图1. INAVO120研究患者的PFS结果 在生存分析中，伊那利塞组6个月的PFS率为82.9%，12个月为55.9%，18个月为46.2%；而安慰剂组分别为55.9%、32.6%和21.1%。PFS分析显示，各关键亚组（包括根据有无内脏转移和有无肝转移定义的亚组）的治疗效果总体一致，尽管某些亚组的患者数量较少（图1B）。在65岁以上的患者以及既往接受过芳香化酶抑制剂和他莫昔芬治疗的患者中，伊那利塞+氟维司群+哌柏西利相比安慰剂+哌柏西利+氟维司群似乎改善效果有限，但这些亚组的患者数量也较少。作为敏感性分析，研究者还通过盲态独立中央审查评估了PFS，结果与研究者评估的PFS结果一致（疾病进展或死亡的分层风险比，0.50；95% CI：0.36～0.68；P＜0.001）。 总生存（OS）分析显示，伊那利塞组6个月、12个月和18个月的OS率分别为97.3%、85.9%和73.7%，而安慰剂组对应的OS分别为89.9%、74.9%和67.5%。死亡分层风险比（伊那利塞 vs 安慰剂）为0.64（95%CI：0.43～0.97；P=0.03，未跨过预设的显著性界值P＜0.0098）（图2）。 △图2. INAVO120研究中患者的OS 伊那利塞组58.4%的患者和安慰剂组25.0%的患者达到了客观缓解（差异为33.4%；95% CI：23.3～43.5）。中位缓解持续时间（DOR）分别为18.4个月和9.6个月（HR 0.57；95% CI：0.33 ～0.99）（图3）。 △INAVO120研究中客观缓解时间和中位缓解持续时间 安全性 在安全性分析人群中，伊那利塞组98.8%的患者和安慰剂组100%的患者发生了至少1起不良事件（AE）。两组中至少有20%患者发生的任何级别选定不良事件包括中性粒细胞减少（inavolisib组88.9%的患者发生，安慰剂组90.7%的患者发生）、口腔炎或黏膜炎（分别为51.2%和26.5%）、高血糖（分别为58.6%和8.6%）、腹泻（分别为48.1%和16.0%）以及皮疹（分别为25.3%和17.3%）（表2）。伊那利塞组和安慰剂组的3/4级中性粒细胞减少发生率分别为80.2%和78.4%。3/4级高血糖分别为5.6%和0%；3/4级口腔或黏膜炎5.6%和0%；3/4级腹泻分别为3.7%和0%。未观察到3/4级皮疹。伊那利塞组6.8%的患者和安慰剂组0.6%的患者因不良事件停用任何试验药物。 表2. INAVO120研究中的不良事件 讨论 研究达到了主要终点，表明在辅助内分泌治疗完成后12个月内或12个月内复发的PIK3CA突变的HR+/HER2-局部晚期或转移性乳腺癌患者中，与安慰剂+哌柏西利+氟维司群相比，伊那利塞+哌柏西利+氟维司群显著延长了PFS。在所有预设的关键临床亚组和敏感性分析中，均观察到了伊那利塞的获益，并且次要终点分析也支持这一获益。OS分析也显示，伊那利塞方案的数值趋势较好，随访正在进行中。伊那利塞治疗组安全性与方案中各药物的安全性一致，并且因不良事件而停用伊那利塞方案中任何药物的患者百分比低。 该研究纳入了对内分泌治疗耐药且有可测量疾病的患者，这些导致患者疾病负担较重，包括至少3个器官转移（51.4%）、内脏疾病（80.0%）和肝转移（51.7%）。此外，本研究的一个独特之处在于，90%以上患者的肿瘤PIK3CA突变状态是通过ctDNA的检测确定。在入组人群中，安慰剂组PFS显著短于伊那利塞组，这反映了一些不良预后因素，并突显了伊那利塞+哌柏西利+氟维司群带来的改善。 该研究中观察到的显著临床获益可归因于同时阻断了驱动PIK3CA突变、HR+/HER2-局部晚期或转移性乳腺癌的三条关键信号通路（PI3K、雌激素受体和CDK4/6通路），从而延迟和防止了主要由这些通路之间的交互作用指导的治疗耐药的出现。此外，如第一次肿瘤评估时和整个随访期间PFS的KM曲线分离所示，伊那利塞方案的临床获益发生在治疗开始后早期，并且持久。生存分析表明，截至6个月时，安慰剂组和inavolisib组的死亡率分别为10.1%和2.7%，这强调了将伊那利塞+哌柏西利+氟维司群作为一线治疗用于这一患者人群的重要性。 研究表明，伊那利塞联合CDK4/6抑制剂+内分泌治疗具有可接受的安全性水平和副作用。伊那利塞组发生高血糖的患者比例高于安慰剂组，BMI≥30.0的患者高血糖发生率略高于BMI＜30.0的患者。这两项发现均可归因于高血糖是与PI3K通路抑制剂相关的靶毒性作用。与PI3K抑制剂相关的其他不良事件（即腹泻、口腔炎和皮疹）的发生率在伊那利塞组中也较高，但通过支持性治疗和剂量调整，高血糖、腹泻、口腔炎和皮疹得到了控制。该研究未报告3/4级皮疹、3/4级肺炎或结肠炎，在伊那利塞组和安慰剂组中，中性粒细胞减少（包括3/4级事件）的发生率相似，每组均有一小部分患者发生发热性中性粒细胞减少。 该研究有以下局限性。首先，研究设计仅评估了目前被批准用于治疗HR+/HER2-晚期或转移性乳腺癌的三种CDK4/6抑制剂（哌柏西利）中的一种应用。然而，在研究过程中，医学界的偏好和国际指南对使用一种或多种特定CDK4/6抑制剂的建议发生了变化。其次，考虑到患者招募主要发生在辅助CDK4/6抑制剂上市之前，因此既往接受过辅助CDK4/6抑制剂治疗的患者很少。既往使用CDK4/6抑制剂作为辅助治疗是否会损害CDK4/6抑制剂作为晚期乳腺癌治疗组成部分的疗效仍有待观察。第三，需要持续治疗的1/2型糖尿病患者被排除。因此，未来评估该人群获益-风险特征的研究将很有必要。第四，患者之间的多样性有限，尤其是黑人或非洲裔美国患者的百分比。大多数患者是在Covid-19大流行期间纳入的，这影响了总体纳入工作，并可能导致多样性有限。 研究结论 在PIK3CA突变、HR+/HER2-局部晚期或转移性乳腺癌患者中，与安慰剂+哌柏西利+氟维司群相比，伊那利塞+哌柏西利+氟维司群显著延长了PFS，因不良事件停止治疗的患者百分比较低（但伊那利塞组的一些毒性作用发生率略高于安慰剂组）。伊那利塞+哌柏西利+氟维司群可能是这些患者的新治疗方案。 读者来信及作者回复 VK Gadi 博士 （通信作者） 致编辑：Turner等人（2024年10月31日）[1]报道称，在HR+/HER2-携带PIK3CA突变的局部晚期或转移性乳腺癌患者中，将伊那利塞添加到哌柏西利+氟维司群的标准治疗组合中作为一线治疗，可延长患者的PFS，这一发现支持了美国食品药品监督管理局（FDA）最近对该药物的批准。我们希望强调该研究的一个重要问题：黑人或非裔美国女性的比例很低（0.6%），并且未报告西班牙裔女性参与该试验。黑人女性的年龄校正乳腺癌死亡率比非西班牙裔白人女性高约40%[2]。晚期乳腺癌PIK3CA-mTOR通路的真实世界数据表明，黑人女性发生血糖并发症的可能性是白种人女性的两倍[3]。此外，在联合治疗的背景下，具有与生殖细胞系Duffy等位基因丢失相关的西非遗传血统的黑人女性也可能因哌柏西利而出现恶化的中性粒细胞减少，这可能导致进一步的伤害[4]。此外，研究的地理重点通常排除了大量黑人人口的地区，例如非洲大陆内的地区，这加剧了这一问题。解决这些差距对于确保公平的卫生保健结果至关重要。 Nicholas C. Turner 博士 作者回复：我们赞同Ibraheem等人的观察结果，即INAVO120研究中黑人或非裔美国人患者比例不足。我们还在文章的讨论部分强调，种族多样性是本研究的一个局限性。我们想澄清的是，在我们的研究中被纳入研究的6.2%的参与者为西班牙裔或拉丁裔。INAVO120试验中有限的多样性是可能影响黑人或非洲裔美国人患者、西班牙裔或拉丁裔患者参与试验的因素。这些因素包括严格的糖化血红蛋白水平纳入标准和Covid-19大流行的影响[5]，研究观察到黑人和西班牙裔人群的糖化血红蛋白水平高于白人人群[6]。 我们一致认为，纳入代表性不足的群体对于全面评估基于伊那利塞的治疗方案（伊那利塞+哌柏西利+氟维司群）的获益-风险特征至关重要。我们计划继续加强肿瘤学界与制药行业之间的紧密合作，以解决这一重要问题，其中包括做出上市后承诺，分析不同种族群体在接受基于伊那利塞治疗方案时可能存在的差异。 ▌参考文献： [1]. Turner NC, Im S-A, Saura C, et al. Inavolisib-based therapy -mutated advanced breast cancer. N Engl J Med 2024;391:1584-96. [2]. DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA Cancer J Clin 2019;69:438-51. [3]. Sathe C, Accordino MK, DeStephano D, Shah M, Wright JD,Hershman DL. Disparities in PI3K/mTOR inhibitor use, toxicities,and outcomes among patients with metastatic breast cancer. Breast Cancer Res Treat 2024;206:519-26.4. [4]. Lynce F, Blackburn MJ, Zhuo R, et al. Hematologic safety of palbociclib in combination with endocrine therapy in patients with benign ethnic neutropenia and advanced breast cancer. Cancer 2021;127:3622-30. [5]. Fasano GA, Bayard S, Bea VJ. Breast cancer disparitiesand the COVlD-19 pandemic. Curr Breast Cancer Rep 2022;14:192-8. [6]. Cavagnolli G, Pimentel AL, Freitas PAC, Gross JL, CamargoJL. Effect of ethnicity on HbA1c levels in individuals withoutdiabetes: systematic review and meta-analysis. PLoS One 2017;12(2):e0171315. （来源：《肿瘤瞭望》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。

TAIPEI and SAN DIEGO, March 20, 2024 /PRNewswire/ -- Senhwa Biosciences, Inc. (TPEx: 6492), a drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, announced today that their first patient has been successfully dosed in the phase II study of Silmitasertib (CX-4945) in patients with community-acquired pneumonia (CAP) associated with viral infection in Taiwan. This trial is to investigate whether early medical intervention of Silmitasertib restrains the progression of CAP by inhibiting the elevated cytokine release associated with SARS-CoV-2 and Influenza viruses. This phase II trial is led by an inter-hospital team specializing in infectious diseases, with extensive experiences in carrying out large-scale international clinical trials for various anti-viral new drugs. The study team consists of five well-known hospitals including National Taiwan University Hospital, National Taiwan University Cancer Center, Far Eastern Memorial Hospital, Tri-Service General Hospital and Taoyuan General Hospital, Ministry of Health and Welfare. According to the latest warning issued by the World Health Organization (WHO) that the globe may face another wave of pandemic of Disease X, possibly caused by the evolution of influenza, novel coronavirus strains, or a new pathogen unknown to humans. In addition, the reported case of the first human infection with avian flu and subsequent death in mainland China earlier this year promoted the WHO to conduct a risk assessment for transmission. Silmitasertib (CX-4945) developed by Senhwa Biosciences possesses a novel mechanism that targets human host cells, making it less susceptible to the effects of viral mutations. The purpose of this trial is to give early medical intervention in the course of the disease with Silmitasertib (CX-4945) as to prevent the progression of CAP, to avoid hospitalization and enhance the subject's clinical condition, while reducing the risks associated with elevated cytokine release related to infections of new coronaviruses or influenza viruses. Furthermore, compared to Silmitasertib (CX-4945), the next-generation drug CX-8184 exhibits higher activity and better neutralizing and inhibiting abilities against viruses. It is currently being developed to be administered directly to the lungs, aiming to become a novel treatment with convenient usage and broad-spectrum antiviral potential, if successful. About Silmitasertib Silmitasertib is a first-in-class small molecule drug that targets the CK2 protein and acts as a CK2 inhibitor. Clinical studies thus far have shown Silmitasertib to be safe and well-tolerated in humans and is easily administered with its oral formulation. Silmitasertib is currently under development through several oncology programs in adults and children with recurrent/advanced or metastatic cancer. To date, three Phase I and one Phase I/II study of Silmitasertib in oncology, as well as two Phase II trials in infectious diseases, have been completed. The US FDA has granted Silmitasertib Orphan Drug Designation for the treatment of Cholangiocarcinoma in December 2016, Rare Pediatric Disease Designation and Orphan Drug Designation for the treatment of Medulloblastoma in July 2020 and December 2021, respectively. Fast Track Designation was granted in August 2021 for the treatment of recurrent Sonic Hedgehog driven Medulloblastoma. About Senhwa Biosciences Senhwa Biosciences, Inc. is a leading clinical-stage company focused on developing first-in-class, next-generation DNA Damage Response therapeutics and seeks to address unmet medical needs in oncology and infectious diseases. Headquartered in Taiwan, with an operational base in San Diego, California, Senhwa is well-positioned to oversee the development of its compounds. Silmitasertib (CX-4945) and Pidnarulex (CX-5461), both with novel mechanisms of action as anti-cancer drugs for the treatment of multiple indications, are the core products in Senhwa Bioscience's pipeline. Clinical trials are currently ongoing in Australia, Canada, United States and Taiwan. Visit Senhwa Biosciences' website for more details: SOURCE Senhwa Biosciences, Inc.

TAIPEI and SAN DIEGO, Dec. 26, 2023 /PRNewswire/ -- Senhwa Biosciences, Inc. (TPEx: 6492), a drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, announced today that Taiwan Food and Drug Administration has approved its Phase II IND application of Silmitasertib (CX-4945) to treat patients with community-acquired pneumonia (CAP) caused by viral infection. The trial is a phase II multi-center, randomized-controlled interventional prospective study, and the purpose of this trial is to investigate whether early intervention of Silmitasertib restrains the progression of CAP by inhibiting the elevated cytokine release associated with SARS-CoV-2 and Influenza viruses. This trial will be led by an inter-hospital team, which is specialized in infectious diseases and possesses extensive experiences in carrying out large-scale international clinical trials for various anti-viral new drugs, across five well-known hospitals including National Taiwan University Hospital, National Taiwan University Cancer Center, Far Eastern Memorial Hospital, Tri-Service General Hospital and Taoyuan General Hospital, Ministry of Health and Welfare. Silmitasertib works by inhibiting CK2 protein kinase, which have implicated in regulation of several signaling pathways that are important for innate immune responses. CK2 modulates inflammatory pathways, including NF-κB, PI3K–Akt–mTOR, and JAK–STAT. Inhibition of CK2 by Silmitasertib diminishes the secretion of IL-6 and MCP-1 (Rosenberger et al.). Silmitasertib treatment also reduces the expression of TNF-α and CCL4 in NiSO4-stimulated MoDCs (Bourayne et al.). "Senhwa regards this phase II as the proof-of-concept study to demonstrate Silmitasertib can be a therapeutic strategy that are not restricted to only a specific viral infection, but applicable to various viruses," said Jin-Ding Huang, CEO of Senhwa Biosciences, Inc. The global market for related therapeutic drugs has exceeded a value of over $120.6 billion USD in 2020 and it's projected to grow at a CAGR of 7.88% and reach more than $339 billion USD by 2030 according to market research. About Silmitasertib Silmitasertib is a first-in-class small molecule drug that targets the CK2 protein and acts as a CK2 inhibitor. Clinical studies thus far have shown Silmitasertib is safe and well-tolerated in humans and is easily administered with its oral formulation. Silmitasertib is currently under development through several oncology programs in adults and children with recurrent/advanced or metastatic cancer. To date, three Phase I trials and one Phase II trial of Silmitasertib in cancer patients have been completed while two other Phase I and II studies of Silmitasertib are still ongoing. The US FDA has granted Silmitasertib Orphan Drug Designation for the treatment of Cholangiocarcinoma in December 2016, Rare Pediatric Disease Designation and Orphan Drug Designation for the treatment of Medulloblastoma in July 2020 and December 2021, respectively. Fast Track Designation was granted in August 2021 for the treatment of recurrent Sonic Hedgehog driven Medulloblastoma. About Senhwa Biosciences Senhwa Biosciences, Inc. is a leading clinical-stage company focused on developing first-in-class, next-generation DNA Damage Response therapeutics and seeks to address unmet medical needs in oncology and infectious diseases. Headquartered in Taiwan, with an operational base in San Diego, California, Senhwa is well-positioned to oversee the development of its compounds. Silmitasertib (CX-4945) and Pidnarulex (CX-5461), both with novel mechanisms of action as anti-cancer drugs for the treatment of multiple indications, are the core products in Senhwa Bioscience's pipeline. Clinical trials are currently ongoing in Australia, Canada, United States and Taiwan. Visit Senhwa Biosciences' website for more details: SOURCE Senhwa Biosciences, Inc.