Phase 2 Study of Paclitaxel (NSC #673089) + Ipatasertib (NSC #781451) in Taxane-Refractory Participants With PTEN/AKT-Altered Advanced Non-Breast Solid Tumors: A ComboMATCH Treatment Trial

This phase II ComboMATCH treatment trial tests the usual treatment of chemotherapy (paclitaxel) plus ipatasertib in patients with solid tumor cancers that that cannot be removed by surgery (unresectable), has spread to nearby tissue or lymph nodes (locally advanced) or from where it first started (primary site) to other places in the body (metastatic), and has PTEN and AKT genetic changes. Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Targeted therapy, such as Ipatasertib, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The addition of ipatasertib to paclitaxel in solid tumors with PTEN and AKT genetic changes could increase the percentage of tumors that shrink as well as lengthen the time that the tumors remain stable (without progression). Researchers hope to learn if paclitaxel plus ipatasertib will shrink this type of cancer or stop its growth.

开始日期2023-09-22

申办/合作机构

National Cancer Institute

NCT05332561 / Recruiting临床2期IIT

Genomics Guided Targeted Post-neoadjuvant Therapy in Patients With Early Breast Cancer - a Multicenter, Open-label, Umbrella Phase-II Study - COGNITION-GUIDE

In early breast cancer (eBC), pathological complete response (pCR) after neoadjuvant therapy acts as surrogate marker for metastasis and overall survival. Therapy intensification by adding an adjuvant therapy line (post-neoadjuvant treatment) substantially lowers the risk of relapse in high-risk breast cancer patients with residual disease after neoadjuvant treatment (non-pCR). While this approach was exemplified in two phase III trials without biomarker-stratification (CREATE-X, KATHERINE), even higher efficiency might be achieved by individualized genomic-guided post-neoadjuvant therapies.
Within the seven-arm umbrella phase-II clinical trial COGNITION-GUIDE, we aim to deliver molecularly-tailored cancer care by implementing an additional response- and genomics-guided post-neoadjuvant therapy after finishing the guideline-compliant post-neoadjuvant treatment in high-risk breast cancer patients with residual cancer burden after neoadjuvant therapy to reduce the substantial risk of local and distant relapse.
The trial evaluates not a single drug but rather a general strategy of precision oncology in the curative setting and provides the basis for future confirmatory biomarker-driven trials.
Allocation to the therapy-arms is conducted by in depth molecular characterization of tumors within the COGNITION registry program.
The study aims to show an overall benefit of the precision medicine approach in high-risk eBC patients and to allow for secondary exploratory evaluation of each study-arm.
The primary endpoint of the study is invasive Disease-Free Survival (IDFS) after 4 years measured from surgery to local or distant relapse or death. The sample size of the entire trial is 240 eligible patients.

开始日期2023-06-29

申办/合作机构

German Cancer Research Center

NCT05862285 / Recruiting临床3期

An Open-Label, Multicenter Extension Study in Patients Previously Enrolled in a Genentech and/or F. Hoffmann-La Roche Ltd Sponsored Study

The purpose of this extension study is to provide continued treatment with Roche investigational medicinal product (IMP[s]) monotherapy or Roche IMP(s) combined with other agent(s) or comparator agent(s) for eligible participants with cancer who are still on study treatment at the time of roll-over from the parent study and who do not have access to the study treatment locally.

开始日期2023-06-01

申办/合作机构

F. Hoffmann-La Roche Ltd.

100 项与 Ipatasertib Dihydrochloride 相关的临床结果

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100 项与 Ipatasertib Dihydrochloride 相关的转化医学

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100 项与 Ipatasertib Dihydrochloride 相关的专利（医药）

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119

项与 Ipatasertib Dihydrochloride 相关的文献（医药）

2024-11-01·Clinical and Translational Medicine

Chaperonin‐containing TCP1 subunit 6A inhibition via TRIM21‐mediated K48‐linked ubiquitination suppresses triple‐negative breast cancer progression through the AKT signalling pathway

Article

作者: Li, Bin ; Tao, Zhonghua ; Wang, Jinyan ; Guo, Duancheng ; Hu, Xichun ; Yang, Mengdi ; Pan, Shuangyue ; Liu, Tiantian ; Cao, Jianing

Abstract:

Background:

Triple‐negative breast cancer (TNBC) is distinguished by a significant likelihood of distant recurrence and an unfavourable prognosis. However, the underlying molecules and mechanisms have not been fully elucidated.

Methods:

We investigated the expression profile and clinical relevance of chaperonin‐containing TCP1 subunit 6A (CCT6A) in TNBC. We performed cell function assays on TNBC cells with CCT6A knockdown or overexpression. To further explore the mechanism of action of CCT6A, RNA sequencing and co‐immunoprecipitation–mass spectrometry analyses were utilized. Rescue and ubiquitination assays evaluated the impact of TRIM21‐mediated CCT6A ubiquitination and degradation on TNBC progression in vitro and in vivo. Finally, we studied the potential of Ipatasertib, a pharmacological AKT inhibitor, and/or anti‐PD1 therapy in inhibiting TNBC progression.

Results:

Elevated CCT6A expression in TNBC patients was associated with an adverse prognosis and lymph node metastasis. Mechanistically, CCT6A facilitated cell migration, invasion, epithelial‐mesenchymal transition and proliferation by activating the phosphatidylinositol 3‐kinase (PI3K)/AKT pathway. The TRIM21 RING domain is an E3 ligase, facilitating the K48‐linked ubiquitination‐mediated degradation of CCT6A, thereby impeding TNBC progression. Moreover, in the tumour tissues of the CCT6A‐overexpressing mice, the quantity of CD8+ T cells and the concentration of secreted interferon‐gamma were decreased, whereas in the group double‐overexpression of CCT6A and TRIM21, they were elevated; the opposite was observed in the knockdown and double‐knockdown groups. Ipatasertib demonstrated enhanced efficacy in inhibiting cell proliferation, invasion and migration in TNBC cells ectopically expressing CCT6A. When Ipatasertib and anti‐PD1 therapies were combined, both the tumour volume and mass exhibited a notable reduction, while the expression of CD45+CD8+ T cells increased, and that of CD45+CD4+CTLA4+ and CD45+CD4+PD1+ T cells decreased.

Conclusions:

Our findings indicate that TRIM21 inhibits TNBC progression by facilitating the K48‐linked ubiquitination‐mediated degradation of CCT6A via the PI3K/AKT signalling pathway. This highlights the potential of Ipatasertib and/or anti‐PD1 as therapeutic strategies, particularly for TNBC patients overexpressing CCT6A.

Key points:

Chaperonin TCP1 subunit 6A (CCT6A) plays an oncogenic role in triple‐negative breast cancer (TNBC) through the AKT signaling pathway.TRIM21 facilitated K48‐linked ubiquitination‐mediated degradation of CCT6A, thereby impeding TNBC progression.Our study collectively underscores the potential of Ipatasertib in conjunction with anti‐PD1 therapy as a promising strategy to counteract CCT6A/AKT hyperactivity‐driven TNBC progression.

2024-11-01·EUROPEAN JOURNAL OF PHARMACOLOGY

The efficacy and safety of PI3K and AKT inhibitors for patients with cancer: A systematic review and network meta-analysis

Review

作者: Xun, Fanghua ; Song, Aigang ; Hui, Fuhai ; Wang, Chengkang ; Xu, Ziang ; Ren, Tianshu ; Wang, Shuai ; Xu, Chang ; Hou, Shanbo ; Zhang, Yingshi ; Zhao, Qingchun ; Zheng, Fangyuan ; Xu, Xiangbo ; Geng, Hefeng ; Zhang, Tianqi ; Yang, Kaisi

BACKGROUND:

Inhibiting PI3K/AKT pathway activation may hinder the occurrence and progression of cancer. The aim of this study was to evaluate the efficacy and safety of the PI3K/AKT inhibitors and determine the most appropriate inhibitor for different cancer types.

METHODS:

Electronic databases up to June 2024 were used to examine the efficacy and safety of PI3K inhibitors (alpelisib, copanlisib, duvelisib, and idelalisib) and AKT inhibitors (capivasertib, ipatasertib and MK-2206) for the treatment of cancer. Data was assessed with a random-effect pairwise and network meta-analysis. Randomized controlled trials and retrospective studies were eligible if they compared PI3K or AKT inhibitors with non-PI3K/AKT controls with no restriction.

RESULTS:

The results were based on 34 studies from 34 published articles and 6 online registration trials (6710 patients). According to pairwise meta-analysis, PI3K/AKT inhibitors showed to be highly effective, especially for treating mutant cancers, but had poor safety profiles. According to our network meta-analysis, PI3K/AKT inhibitors, especially the AKT inhibitor capivasertib, are effective for treating solid cancers such as breast cancer (BC). Moreover, PI3K inhibitors, especially idelalisib, were effective for treating hematologic cancers such as chronic lymphocytic leukemia (CLL).

CONCLUSIONS:

The PI3K/AKT inhibitors are effective in patients with genetic mutations. For solid cancers such as BC, capivasertib was efficacy and safety. For hematological cancers represented by CLL, idelalisib was efficacy and safety. The above studies can be used when recommending appropriate targeted therapies for patients with different cancer types.

2024-10-01·CLINICAL CANCER RESEARCH

Ipatasertib plus Paclitaxel for Patients with PIK3CA/AKT1/PTEN-Altered Locally Advanced Unresectable or Metastatic Triple-Negative Breast Cancer in the IPATunity130 Phase III Trial

Article

作者: Kim, Sung-Bae ; O’Shaughnessy, Joyce ; Saji, Shigehira ; Oliveira, Mafalda ; Philco, Manuel ; Bradley, Denise ; Freitas-Junior, Ruffo ; Lian, Qinshu ; Dent, Rebecca A. ; Isakoff, Steven J. ; Bondarenko, Igor ; Wongchenko, Matthew J. ; Reilly, Sarah-Jayne ; Hinton, Heather ; Barrios, Carlos ; Turner, Nicholas

Abstract:

Purpose::

In the randomized phase II LOTUS trial, combining ipatasertib with first-line paclitaxel for triple-negative breast cancer (TNBC) improved progression-free survival (PFS), particularly in patients with PIK3CA/AKT1/PTEN-altered tumors. We aimed to validate these findings in a biomarker-selected TNBC population.

Patients and Methods::

In Cohort A of the randomized double-blind placebo-controlled phase III IPATunity130 trial, taxane-eligible patients with PIK3CA/AKT1/PTEN-altered measurable advanced TNBC and no prior chemotherapy for advanced disease were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, both plus paclitaxel (80 mg/m2, days 1, 8, and 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS.

Results::

Between February 2018 and April 2020, 255 patients were randomized (168 to ipatasertib, 87 to placebo). At the primary analysis, there was no significant difference between treatment arms in PFS [hazard ratio 1.02, 95% confidence interval (CI), 0.71–1.45; median 7.4 months with ipatasertib vs. 6.1 months with placebo]. The final analysis showed no difference in overall survival between treatment arms (hazard ratio 1.08, 95% CI, 0.73–1.58; median 24.4 vs. 24.9 months, respectively). Ipatasertib was associated with more grade ≥3 diarrhea (9% vs. 2%) and adverse events leading to dose reduction (39% vs. 14%) but similar incidences of grade ≥3 adverse events (51% vs. 46%). Exploratory subgroup analyses by PAM50 and Burstein gene expression showed inconsistent results.

Conclusions::

Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood.

项与 Ipatasertib Dihydrochloride 相关的新闻（医药）

2024-11-27

·药渡

研究失利，研发遇冷！泛癌种潜力靶点AKT，药物研发现状如何？

上市首年的AKT抑制剂Capivasertib（Truqap），2024年前三季度实现营收2.7亿美元，全年销量有望超4亿美元。表1 阿斯利康2024年前三季度肿瘤药物销量资料来源：阿斯利康 2023年11月，阿斯利康AKT抑制剂Capivasertib获FDA批准上市，与Fulvestrant（氟维司群）联合使用，用于治疗激素受体（HR）阳性、人表皮生长因子受体2（HER2）阴性、伴有一种或多种生物标志物改变（PIK3CA、AKT1或PTEN）的局部晚期或转移性乳腺癌成年患者。这是全球首款乳腺癌AKT抑制剂。相关内容拓展：全球首款！阿斯利康Capivasertib申报上市，浅谈AKT抑制剂研发进展 AKT是一种丝氨酸/苏氨酸激酶，是PI3K（磷脂酰肌醇3-激酶）信号通路中主要的下游效应分子之一。目前，多款AKT抑制剂正处于临床研发阶段，横跨乳腺癌、前列腺癌、卵巢癌等多个癌种，市场潜力非常可观。 01 Capivasertib的治疗版图：多种亚型乳腺癌、前列腺癌 Capivasertib联合疗法能够显著降低HR+乳腺癌患者的疾病进展和死亡风险。 Capivasertib的获批上市是基于CAPItello-291临床试验数据：在总体试验人群中，Capivasertib联合疗法可以降低HR+乳腺癌进展或死亡风险约40%（基于风险比0.6）；在AKT信号通路亚组中，Capivasertib联合疗法可将疾病进展或死亡风险降低50%（基于风险比0.5，中位无进展生存期为7.3个月vs3.1个月）。表2 CAPItello-291试验主要结果资料来源：阿斯利康目前，Capivasertib正在开展多项3期临床试验，以评估其与既定治疗方案联合应用在多种亚型乳腺癌和其他癌种中的治疗效果。图1 Capivasertib相关的临床试验信息资料来源：阿斯利康 Capivasertib联合氟维司群用于一线治疗早期复发/局部晚期内分泌耐药（不可手术）或转移性HR+/HER2-乳腺癌，相关数据预计将于2025年后读出。此前，阿斯利康还评估过Capivasertib联合紫杉醇用于治疗局部晚期或转移性三阴性乳腺癌，但临床试验未到达主要终点。乳腺癌外，Capivasertib还在开展两项关于前列腺癌的3期临床，分别为： Capivasertib联合阿比特龙用于治疗PTEN基因突变的转移性激素敏感性前列腺癌； Capivasertib联合多西他赛治疗转移性去势抵抗性前列腺癌。 02 研发赛道“冷清”，来凯医药遥遥领先 AKT抑制剂的研发格局并不拥挤。基于券商研究报告资料显示，目前全球仅有9款AKT抑制剂进入临床阶段。原因何在？原因在于较早布局AKT抑制剂的公司和产品，例如，默沙东的MK-2206、礼来的LY2780301等均以失败告终，罗氏的Ipatasertib虽在3期IPATential150研究中观察到了中位无进展生存期的改善，但影像学无进展生存期获益一般，且未证明总生存期改善。 MNC的接连受挫，导致AKT的研发遇冷。然而，近年来，本土药企开始将目光投向这个横跨多个大癌种的潜力靶点，多家本土药企，包括恒瑞医药、正大天晴等均有布局AKT抑制剂，其中，来凯医药具备明显的领先优势。表3 AKT抑制剂在研产品情况资料来源：西南证券，公司官网，作者整理来凯医药聚焦肿瘤和代谢减重两大领域，Afuresertib（LAE002）是来凯医药在肿瘤领域最重要的管线资产。目前，针对局部晚期或转移性HR+/HER2-乳腺癌的3期临床试验已在美国和中国同时开展；针对转移性去势抵抗性前列腺癌和铂耐药性卵巢癌也在准备开展3期临床试验。来凯医药的Afuresertib以及阿斯利康的Capivasertib是全球仅有的两款处于晚期临床研发阶段的针对乳腺癌以及前列腺癌的AKT抑制剂。今年9月，来凯医药在ESMO会议上公布了Afuresertib联合氟维司群用于标准治疗失败的局部晚期或转移性HR+/HER2-乳腺癌1b期研究数据：在PIK3CA/AKT1/PTEN生物标志物改变的亚组中，客观缓解率33.3%，临床获益率66.7%，中位无进展生存期7.3个月。 03 AKT抑制剂“追捕”PI3K抑制剂 PI3K信号通路的异常激活与多种肿瘤的发生和发展密切相关，因此，位于该信号通路上下游的靶点也广受青睐。PI3K上游链接受体酪氨酸激酶（包括EGFR、IGF-1、FGFR等），当PI3K被生长因子等信号激活，可磷酸化PIP2，将其转化为PIP3，进而促进丙酮酸脱氢酶激酶1和AKT的结合，从而激活AKT，AKT通过下游信号进一步促进蛋白合成和细胞增殖。目前，全球仅有6款PI3K抑制剂获批上市，其中，诺华的Alpelisib以及今年10月刚刚获批上市的罗氏Inavolisib均用于治疗乳腺癌。其余4款PI3K抑制剂均用于治疗血液瘤，且其中多款药物曾由于安全性问题导致适应症被撤回。图2 诺华Alpelisib销量走势（单位：亿美元）资料来源：诺华年报，2024年Q3业绩报告 AKT靶点的成药性已被验证，未来，势必将蚕食部分的PI3K抑制剂市场份额，乳腺癌或将成为第一战场，是PI3K和AKT抑制剂的必争之地。从产品销量情况来看，诺华的Alpelisib自2019年上市以来，销量逐步攀升，上市后首年销量达3.2亿美元，上市至今最高年销量5.1亿美元，今年前三季度销量增速略有放缓（同比下滑约1%）。AKT抑制剂Capivasertib上市首年销售预计可达4亿美元，有望超过Alpelisib的上市后表现。肿瘤领域创新药市场竞争激烈。但成药性得到验证、研发格局不拥挤、面向大癌种的潜力靶点尚属浩瀚的蓝海市场，目前看来，AKT绝对是破局抗肿瘤新药内卷的潜力靶点。参考资料阿斯利康官网（2024年Q3业绩报告，WCLC/ESMO会议资料）《AKT靶点研发概况》，西南证券，2023年《全球首款！阿斯利康Capivasertib申报上市，浅谈AKT抑制剂研发进展》，药渡公众号，2023年来凯医药官网诺华年度报告，2024年季度业绩报告首款！默沙东抗肿瘤新药HIF-2α抑制剂国内获批上市《中国药典》或添新星——利妥昔单抗：B细胞终结者，精准抗癌战士诺华新药「阿曲生坦」国内申报上市，为IgA肾病患者带来新希望

临床3期临床结果申请上市临床成功

2024-11-27

·九洲药业

【速递】铁树再开花：AKT 抑制剂 capivasertib 治疗前列腺癌的 3 期临床试验达到主要终点

●首个且唯一被证实对这种特定亚型前列腺癌有益的 AKT 抑制剂组合。 Jiuzhou News CAPItello-281第三阶段试验的积极高水平结果表明，对于PTEN缺陷型de novo转移性激素敏感性前列腺癌（mHSPC）患者，阿斯利康的Truqap(capivasertib）联合阿比特龙和雄激素剥夺疗法（ADT）与阿比特龙和ADT联合安慰剂相比，在放射学无进展生存期（rPFS）的主要终点方面表现出统计学上显著差异和临床意义上的显著改善。在进行本分析时，总生存期（OS）数据尚不成熟；然而，Truqap组合与安慰剂相比，显示出OS改善的早期趋势。试验将按计划继续进行，以进一步评估OS作为关键的次要终点。前列腺癌是男性中第二大癌症，也是全球男性癌症死亡的第五大原因。仅有三分之一的转移性前列腺癌患者在确诊后5年内生存。新诊断的转移性前列腺癌是一种恶性程度较高的疾病，预后不良且存活率低。每年约有200，000名患者被诊断出患有转移性前列腺癌，其中四分之一的患者患有PTEN缺陷型肿瘤。肿瘤生物标志物显示为 PTEN 缺陷型的患者预后特别差。阿斯利康肿瘤研发执行副总裁Susan Galbraith表示：“这些结果首次表明，在标准治疗中添加AKT抑制剂可以为生物标志物PTEN缺陷的转移性激素敏感性前列腺癌患者带来益处。通过针对该病的关键驱动因素，我们能够改进目前的治疗方法，并展示这种组合在关键未满足需求领域的潜在作用。重要的是看到包括总体生存期在内的关键次要终点更加成熟。” Truqap与阿比特龙和ADT在CAPItello-281中的联合使用安全性，与每种药物的已知安全性大致一致。转移性激素敏感性前列腺癌在患有mHSPC（也称为转移性去势敏感性前列腺癌mCSPC）的患者中，前列腺癌细胞需要更高水平的雄激素来驱动癌症生长。激素疗法（例如ADT）被广泛用于阻断男性性激素的作用并降低体内雄激素水平。然而，对这些疗法的耐药性很常见，需要扩大其使用范围以延缓疾病进展和去势抵抗性，尽管使用了这些疗法，前列腺癌仍会生长并扩散到身体的其他部位。对于患有de novo mHSPC的患者，首次诊断时癌症已扩散至身体的远处部位。 PTEN缺失或缺乏会促进癌细胞生长，导致PI3K/AKT通路失调，并与前列腺癌患者的不良预后有关。 CAPItello-281 CAPItello-281是一项III期双盲随机试验，评估Truqap联合阿比特龙和ADT与阿比特龙和ADT联合安慰剂治疗PTEN缺陷型de nove mHSPC患者的疗效和安全性。这项全球试验招募了1012名经组织学证实患有de novo激素敏感性前列腺癌且经集中检测证实存在PTEN缺陷的成年患者。CAPItello-281试验的主要终点是研究者评估的rPFS，次要终点是OS。 Truqap Truqap是同类首创的强效三磷酸腺苷（ATP）竞争型抑制剂，可抑制所有三种AKT亚型（AKT1/2/3）。Truqap 400mg每日两次给药，按照四天服药、三天停药的间歇性给药方案给药。这是在早期试验中根据耐受性和靶标抑制程度选择的。小结随着生物标志物的发展，mHSPC的治疗方案正向着个性化的三联方案发展。如PTEN缺失/PIK3A/AKT突变的人群，三联方案为ADT+阿比特龙+AKT抑制剂，如MSI/TMB高负荷的人群，三联方案为ADT+阿比特龙+PD-1抑制剂，如HRR突变的人群，三联方案为ADT+阿比特龙+PARP抑制剂，如Rb完整或不存在肝转移的人群，三联方案为ADT+阿比特龙+CDK4/6抑制剂。上述这些三联方案都在近几年进入了3期临床阶段，直至11月25日，AKT抑制剂capivasertib率先撞线，成为这堆三联方案里首个在mHSPC人群里达到3期临床试验主要终点的药物。和capivasertib同台竞争的另一款竞品ipatasertib，早在2020年就宣布治疗mCRPC（转移性去势抵抗性前列腺癌）3期临床未能达到主要终点，在所有人群中的mPFS没有显著差异，但在PTEN缺失人群中有差异，提示了AKT抑制剂是有潜力给前列腺癌患者带有益处的。但是HR仅为0.77，p=0.034，获益程度并不是十分明显，而且受试者人群在500人左右，对于异质性这么强的前列腺癌，受试者规模越大，试验结果会越稳健。另一方面，在疗效结果的分层分析里，AKT抑制剂ipatasertib对既往接受过紫杉烷类药物（多西他赛）的人群的HR为1.00，和安慰剂效果一样。阿斯利康可能汲取了ipatasertib在mCRPC试验里的经验教训，将PTEN缺失的患者规模扩大了1012名，并且将治疗群体从mCRPC前移到mHSPC，减少了潜在的紫杉烷类药物（多西他赛）暴露，才取得了今天这样的成绩，让开发了十几年的“铁树”capivasertib，接连在乳腺癌和前列腺癌人群里开出花朵。 ▲活跃在临床阶段的AKT抑制剂 ▲AKT抑制剂结构图参考文献 1.https://www.astrazeneca.com/media-centre/press-releases/2024/truqap-improved-rpfs-in-advanced-prostate-cancer.html 2. https://ascopubs.org/doi/10.1200/EDBK_390166 3.https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00580-8/fulltext 免责申明本公众号注明原创的内容权利均属九洲药业所有，未经授权，不得擅自使用或许可他人使用。如需获得授权，请和九洲药业提前联系。已获得授权的，应在授权范围内使用，并注明来源且不得再全部或部分转授权他人。本公众号对转载、分享的内容、陈述、观点判断保持中立，不对所包含内容的合法性、准确性、可靠性或完善性提供任何明示或暗示的保证，该等内容版权归原作者所有，仅供学习参考之用，若对转载、分享的内容有任何权利疑问，烦请联系九洲药业。

临床3期放射疗法临床失败临床结果

2024-11-25

·药渡Daily

AKT：泛癌种潜力靶点

上市首年的AKT抑制剂Capivasertib（Truqap），2024年前三季度实现营收2.7亿美元，全年销量有望超4亿美元。表1 阿斯利康2024年前三季度肿瘤药物销量资料来源：阿斯利康 2023年11月，阿斯利康AKT抑制剂Capivasertib获FDA批准上市，与Fulvestrant（氟维司群）联合使用，用于治疗激素受体（HR）阳性、人表皮生长因子受体2（HER2）阴性、伴有一种或多种生物标志物改变（PIK3CA、AKT1或PTEN）的局部晚期或转移性乳腺癌成年患者。这是全球首款乳腺癌AKT抑制剂。 AKT是一种丝氨酸/苏氨酸激酶，是PI3K（磷脂酰肌醇3-激酶）信号通路中主要的下游效应分子之一。目前，多款AKT抑制剂正处于临床研发阶段，横跨乳腺癌、前列腺癌、卵巢癌等多个癌种，市场潜力非常可观。 01 Capivasertib的治疗版图：多种亚型乳腺癌、前列腺癌 Capivasertib联合疗法能够显著降低HR+乳腺癌患者的疾病进展和死亡风险。 Capivasertib的获批上市是基于CAPItello-291临床试验数据：在总体试验人群中，Capivasertib联合疗法可以降低HR+乳腺癌进展或死亡风险约40%（基于风险比0.6）；在AKT信号通路亚组中，Capivasertib联合疗法可将疾病进展或死亡风险降低50%（基于风险比0.5，中位无进展生存期为7.3个月vs3.1个月）。表2 CAPItello-291试验主要结果资料来源：阿斯利康目前，Capivasertib正在开展多项3期临床试验，以评估其与既定治疗方案联合应用在多种亚型乳腺癌和其他癌种中的治疗效果。图1 Capivasertib相关的临床试验信息资料来源：阿斯利康 Capivasertib联合氟维司群用于一线治疗早期复发/局部晚期内分泌耐药（不可手术）或转移性HR+/HER2-乳腺癌，相关数据预计将于2025年后读出。此前，阿斯利康还评估过Capivasertib联合紫杉醇用于治疗局部晚期或转移性三阴性乳腺癌，但临床试验未到达主要终点。乳腺癌外，Capivasertib还在开展两项关于前列腺癌的3期临床，分别为： Capivasertib联合阿比特龙用于治疗PTEN基因突变的转移性激素敏感性前列腺癌； Capivasertib联合多西他赛治疗转移性去势抵抗性前列腺癌。 02 研发赛道“冷清”，来凯医药遥遥领先 AKT抑制剂的研发格局并不拥挤。基于券商研究报告资料显示，目前全球仅有9款AKT抑制剂进入临床阶段。原因何在？原因在于较早布局AKT抑制剂的公司和产品，例如，默沙东的MK-2206、礼来的LY2780301等均以失败告终，罗氏的Ipatasertib虽在3期IPATential150研究中观察到了中位无进展生存期的改善，但影像学无进展生存期获益一般，且未证明总生存期改善。 MNC的接连受挫，导致AKT的研发遇冷。然而，近年来，本土药企开始将目光投向这个横跨多个大癌种的潜力靶点，多家本土药企，包括恒瑞医药、正大天晴等均有布局AKT抑制剂，其中，来凯医药具备明显的领先优势。表3 AKT抑制剂在研产品情况资料来源：西南证券，公司官网，作者整理来凯医药聚焦肿瘤和代谢减重两大领域，Afuresertib（LAE002）是来凯医药在肿瘤领域最重要的管线资产。目前，针对局部晚期或转移性HR+/HER2-乳腺癌的3期临床试验已在美国和中国同时开展；针对转移性去势抵抗性前列腺癌和铂耐药性卵巢癌也在准备开展3期临床试验。来凯医药的Afuresertib以及阿斯利康的Capivasertib是全球仅有的两款处于晚期临床研发阶段的针对乳腺癌以及前列腺癌的AKT抑制剂。今年9月，来凯医药在ESMO会议上公布了Afuresertib联合氟维司群用于标准治疗失败的局部晚期或转移性HR+/HER2-乳腺癌1b期研究数据：在PIK3CA/AKT1/PTEN生物标志物改变的亚组中，客观缓解率33.3%，临床获益率66.7%，中位无进展生存期7.3个月。 03 AKT抑制剂“追捕”PI3K抑制剂 PI3K信号通路的异常激活与多种肿瘤的发生和发展密切相关，因此，位于该信号通路上下游的靶点也广受青睐。PI3K上游链接受体酪氨酸激酶（包括EGFR、IGF-1、FGFR等），当PI3K被生长因子等信号激活，可磷酸化PIP2，将其转化为PIP3，进而促进丙酮酸脱氢酶激酶1和AKT的结合，从而激活AKT，AKT通过下游信号进一步促进蛋白合成和细胞增殖。目前，全球仅有6款PI3K抑制剂获批上市，其中，诺华的Alpelisib以及今年10月刚刚获批上市的罗氏Inavolisib均用于治疗乳腺癌。其余4款PI3K抑制剂均用于治疗血液瘤，且其中多款药物曾由于安全性问题导致适应症被撤回。图2 诺华Alpelisib销量走势（单位：亿美元）资料来源：诺华年报，2024年Q3业绩报告 AKT靶点的成药性已被验证，未来，势必将蚕食部分的PI3K抑制剂市场份额，乳腺癌或将成为第一战场，是PI3K和AKT抑制剂的必争之地。从产品销量情况来看，诺华的Alpelisib自2019年上市以来，销量逐步攀升，上市后首年销量达3.2亿美元，上市至今最高年销量5.1亿美元，今年前三季度销量增速略有放缓（同比下滑约1%）。AKT抑制剂Capivasertib上市首年销售预计可达4亿美元，有望超过Alpelisib的上市后表现。肿瘤领域创新药市场竞争激烈。但成药性得到验证、研发格局不拥挤、面向大癌种的潜力靶点尚属浩瀚的蓝海市场，目前看来，AKT绝对是破局抗肿瘤新药内卷的潜力靶点。参考资料阿斯利康官网（2024年Q3业绩报告，WCLC/ESMO会议资料）《AKT靶点研发概况》，西南证券，2023年《全球首款！阿斯利康Capivasertib申报上市，浅谈AKT抑制剂研发进展》，药渡公众号，2023年来凯医药官网诺华年度报告，2024年季度业绩报告

临床3期上市批准临床结果财报临床成功

100 项与 Ipatasertib Dihydrochloride 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	Ipatasertib Dihydrochloride	-	DB11743

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适应症	最高研发状态	国家/地区	公司	日期
ER阳性/HER2阴性乳腺癌	临床3期	澳大利亚	Hoffmann-La Roche, Inc.	2021-01-27
ER阳性/HER2阴性乳腺癌	临床3期	加拿大	Hoffmann-La Roche, Inc.	2021-01-27
ER阳性/HER2阴性乳腺癌	临床3期	新西兰	Hoffmann-La Roche, Inc.	2021-01-27
转移性三阴性乳腺癌	临床3期	中国	F. Hoffmann-La Roche Ltd.	2020-09-17
转移性三阴性乳腺癌	临床3期	中国	罗氏（中国）投资有限公司	2020-09-17
HR阳性/HER2阴性乳腺癌	临床3期	美国	Hoffmann-La Roche, Inc.	2018-01-06
HR阳性/HER2阴性乳腺癌	临床3期	日本	Hoffmann-La Roche, Inc.	2018-01-06
HR阳性/HER2阴性乳腺癌	临床3期	阿根廷	Hoffmann-La Roche, Inc.	2018-01-06
HR阳性/HER2阴性乳腺癌	临床3期	澳大利亚	Hoffmann-La Roche, Inc.	2018-01-06
HR阳性/HER2阴性乳腺癌	临床3期	奥地利	F. Hoffmann-La Roche Ltd.	2018-01-06

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04464174 (PATHFINDER, ASCO2024)	临床2期	晚期三阴性乳腺癌 PI3K/AKT/mTOR pathway	54	Ipatasertib (IPA) + Capecitabine (CA)	範鑰網鬱膚壓蓋襯鏇襯(憲膚築夢鬱餘餘觸願衊) = 廠顧夢衊夢鹹鬱膚齋網網獵鏇簾憲構網網糧遞 (夢鏇襯顧鏇餘鏇齋遞蓋 ) 更多	积极	2024-05-24
				Ipatasertib (IPA) + Eribulin (E)	範鑰網鬱膚壓蓋襯鏇襯(憲膚築夢鬱餘餘觸願衊) = 憲願淵顧窪鬱構範鬱壓網獵鏇簾憲構網網糧遞 (夢鏇襯顧鏇餘鏇齋遞蓋 ) 更多
NCT04177108 (IPATunity170, CTgov)	临床3期	三阴性乳腺癌	242	Paclitaxel+Atezolizumab+Ipatasertib (Cohort 1 Arm A: Ipatasertib + Atezolizumab + Paclitaxel)	顧壓餘糧鬱簾醖蓋衊鏇(憲壓蓋夢鹽衊鑰鹽蓋鏇) = 觸襯夢選構構鏇艱夢衊積憲鹹鹽繭網壓糧網餘 (衊窪夢鹹繭齋壓艱網繭, 構網醖窪齋簾築壓蓋醖 ~ 蓋製繭蓋網顧衊鑰願願) 更多	-	2024-03-27
				Paclitaxel+Atezolizumab+Ipatasertib (Cohort 2 Arm A: Ipatasertib + Atezolizumab + Paclitaxel)	顧壓餘糧鬱簾醖蓋衊鏇(憲壓蓋夢鹽衊鑰鹽蓋鏇) = 鑰鏇襯鏇積憲糧齋衊製積憲鹹鹽繭網壓糧網餘 (衊窪夢鹹繭齋壓艱網繭, 積製鏇範簾衊憲鹽憲鏇 ~ 繭觸糧積繭範網廠襯製) 更多
NCT03337724 (IPATunity130, CTgov)	临床3期	HR阳性/HER2阴性乳腺癌	579	Placebo+Paclitaxel (Cohort A: Placebo + Paclitaxel)	繭鏇鹹艱遞網襯艱鑰鹹(遞範餘網築遞襯遞糧齋) = 鏇鬱憲醖襯築衊蓋齋憲餘鏇範艱衊鑰繭憲齋窪 (糧鬱簾鹹網糧鬱淵醖壓, 遞積蓋築膚鏇鬱觸醖齋 ~ 鹹衊膚廠壓夢齋顧鹽糧) 更多	-	2024-03-12
				Paclitaxel+Ipatasertib (Cohort A: Ipatasertib + Paclitaxel)	繭鏇鹹艱遞網襯艱鑰鹹(遞範餘網築遞襯遞糧齋) = 齋願選網餘鬱顧築壓網餘鏇範艱衊鑰繭憲齋窪 (糧鬱簾鹹網糧鬱淵醖壓, 製選餘願壓膚鏇選鏇膚 ~ 糧淵鏇夢選積顧廠憲鏇) 更多
NCT01485861 (A.MARTIN \| A. MARTIN \| GO27983, CTgov)	临床1/2期	去势抵抗性前列腺癌	298	Prednisone+Abiraterone+Prednisolone+Ipatasertib (Phase II: Ipatasertib 400 mg + Abiraterone)	齋積網網網築鹹餘願衊(積獵構衊選範糧餘壓齋) = 積願窪獵鬱窪簾夢簾鹽餘簾鬱遞襯顧繭鬱醖顧 (窪淵觸壓蓋蓋構願積醖, 積淵襯衊廠鬱構餘顧蓋 ~ 淵醖糧觸憲衊壓積鏇積) 更多	-	2023-09-14
				Prednisone+Abiraterone+Prednisolone+Ipatasertib (Phase II: Ipatasertib 200 mg + Abiraterone)	齋積網網網築鹹餘願衊(積獵構衊選範糧餘壓齋) = 鏇鏇憲窪範憲範積襯餘餘簾鬱遞襯顧繭鬱醖顧 (窪淵觸壓蓋蓋構願積醖, 範襯餘製鹽衊鹹繭壓範 ~ 夢鹽獵醖願糧餘網築範) 更多
NCT03673787 (AACR2023) 人工标引	临床1/2期	胶质母细胞瘤二线 PTEN No Expression	19	Ipatasertib+Atezolizumab	簾壓膚鹹範鹹夢鑰構獵(醖顧鑰餘遞淵蓋壓觸廠) = 簾築鏇糧襯選夢艱獵簾壓網壓蓋繭網膚齋獵網 (鬱鏇鏇鏇醖襯鏇製選鹽 ) 更多	积极	2023-04-14
				Ipatasertib+Atezolizumab (pts with PTEN loss)	簾壓膚鹹範鹹夢鑰構獵(醖顧鑰餘遞淵蓋壓觸廠) = 夢膚鏇築簾選鑰獵醖鹽壓網壓蓋繭網膚齋獵網 (鬱鏇鏇鏇醖襯鏇製選鹽 )
NCT04737109 (ADDITION \| BTCRC-GU19-404, ASCO_GU2023) 人工标引	临床1期	去势抵抗性前列腺癌	6	ipatasertib+darolutamide	繭鹹積鏇襯遞鏇遞壓遞(醖鬱選憲選餘製醖鹹壓) = 構鏇廠齋糧築繭壓齋簾鹹顧衊夢夢願鬱夢醖鹹 (衊獵襯觸膚窪襯選觸簾 ) 更多	积极	2023-02-21
SGO	N/A	子宫内膜癌	-	Ipatasertib	範鹹鹽網範積觸蓋積鹽(鬱遞鹹築鹽襯窪窪構製) = 選積範簾淵鹽鹽顧願鬱選餘鬱積糧網夢鏇鑰網 (艱醖築廠蓋膚鹽繭鏇顧 )	-	2022-08-01
				Carboplatin	範鹹鹽網範積觸蓋積鹽(鬱遞鹹築鹽襯窪窪構製) = 餘觸齋鹹遞鑰鑰壓繭顧選餘鬱積糧網夢鏇鑰網 (艱醖築廠蓋膚鹽繭鏇顧 )
NCT01896531 (CTgov)	临床2期	局部晚期胃食管交界处腺癌 \| 转移性胃食管结合部腺癌	153	Leucovorin+Ipatasertib+Oxaliplatin+5-fluorouracil (Ipatasertib + mFOLFOX6)	衊憲遞簾窪築糧憲壓鹽(鏇廠壓鬱製夢廠繭糧醖) = 築構鏇構艱憲遞繭窪襯網鏇糧廠蓋顧獵鬱遞醖 (範鑰壓襯構積壓觸蓋蓋, 淵繭蓋醖選窪獵觸鑰願 ~ 鑰願觸網構築淵鹽製醖) 更多	-	2022-02-17
				Placebo+Leucovorin+Oxaliplatin+5-fluorouracil (Placebo + mFOLFOX6)	衊憲遞簾窪築糧憲壓鹽(鏇廠壓鬱製夢廠繭糧醖) = 鬱餘衊鑰艱齋餘築遞醖網鏇糧廠蓋顧獵鬱遞醖 (範鑰壓襯構積壓觸蓋蓋, 夢積選鬱艱窪繭築齋顧 ~ 觸選餘憲艱鏇鏇糧艱糧) 更多
NCT03337724 (IPATunity130, Pubmed \| Breast Cancer Res)	临床3期	HR阳性/HER2阴性乳腺癌	580	Ipatasertib	(膚淵鑰遞簾憲鑰窪餘蓋) = 襯夢衊構餘餘窪選糧艱齋衊選鏇憲蓋製鹹選壓 (網齋鏇鹽鹽衊觸夢範獵 ) 更多	不佳	2021-12-03
				Placebo	(膚淵鑰遞簾憲鑰窪餘蓋) = 醖繭夢範築網壓餘繭鬱齋衊選鏇憲蓋製鹹選壓 (網齋鏇鹽鹽衊觸夢範獵 ) 更多
NCT03673787 (Ice-CAP, AACR2021) 人工标引	临床1期	多形性胶质母细胞瘤 PTEN Deletion	10	Ipatasertib+Atezolizumab	膚製顧願簾壓壓鑰齋網(鑰範廠齋憲觸鬱遞襯衊) = 400mg Ipa OD + 1200mg A Q3W 齋蓋鏇選廠蓋構繭艱獵 (廠網醖餘齋艱積鹹顧餘 ) 更多	积极	2021-04-10