A Proof of Concept Study to Evaluate Treatments' Efficacy by Monitoring Minimal Residual Disease Using ctDNA in HR-positive/HER2-negative Early Breast Cancer Population

This trial is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2-negative early-stage BC at higher risk of relapse, who have undergone surgery within the previous five years, with no evidence of locoregional, contralateral, or distant disease.
The study design is composed by an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase).
After informed consent is obtained, a total of1,260 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature).
At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy:
Arm A: Control Arm (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10)
If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study.

开始日期2024-04-01

申办/合作机构

Medica Scientia Innovation Research SL

NCT06496568 / Recruiting临床1期

A Phase I/Ib Study Evaluating Single-Agent Inavolisib and Inavolisib Plus Atezolizumab in PIK3CA-Mutated Cancers

The purpose of the study is to assess the safety and efficacy of inavolisib as a single-agent and in combination with atezolizumab in participants with phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)-mutated cancers, including previously treated head and neck squamous cell carcinoma (HNSCC).

开始日期2023-12-11

申办/合作机构

Hoffmann-La Roche, Inc.

ISRCTN11899726 / Recruiting临床1期

A Phase 1, open-label, single-dose study to evaluate the effect of moderate or severe renal impairment on the pharmacokinetics of inavolisib

开始日期2023-10-26

申办/合作机构-

100 项与伊那利塞相关的临床结果

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100 项与伊那利塞相关的转化医学

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100 项与伊那利塞相关的专利（医药）

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项与伊那利塞相关的文献（医药）

2024-11-20·JOURNAL OF CLINICAL ONCOLOGY

Phase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for PIK3CA -Mutated, Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced or Metastatic Breast Cancer

Article

作者: Jhaveri, Komal L. ; Schmid, Peter ; Saura, Cristina ; Italiano, Antoine ; Cheeti, Sravanthi ; Hutchinson, Katherine E. ; Accordino, Melissa K. ; Hamilton, Erika ; Cervantes, Andrés ; Royer-Joo, Stephanie ; Hilz, Stephanie ; Schutzman, Jennifer L. ; Turner, Nicholas C. ; Varga, Andrea ; Krop, Ian E. ; Kalinsky, Kevin ; Oliveira, Mafalda ; Juric, Dejan ; Gambardella, Valentina ; Shankar, Noopur ; Bedard, Philippe L. ; Jin, Yanling ; Peters, Ubong

PURPOSE:

To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA -mutated, hormone receptor–positive/human epidermal growth factor receptor 2–negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172 ).

METHODS:

Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability.

RESULTS:

Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug–drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response.

CONCLUSION:

Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.

2024-10-31·NEW ENGLAND JOURNAL OF MEDICINE

Inavolisib-Based Therapy in PIK3CA -Mutated Advanced Breast Cancer

Article

作者: Sunpaweravong, Patrapim ; Musolino, Antonino ; Leung, Roland ; Shankar, Noopur ; Jhaveri, Komal L ; Song, Chunyan ; Kalinsky, Kevin ; Lei, Guiyuan ; Im, Seock-Ah ; Schutzman, Jennifer L ; Li, Huiping ; Juric, Dejan ; Thanopoulou, Eirini ; Schmid, Peter ; Zhang, Qingyuan ; Hutchinson, Katherine E ; Stout, Thomas J ; Saura, Cristina ; Loi, Sherene ; Loibl, Sibylle ; Nowecki, Zbigniew ; Turner, Nicholas C

BACKGROUND:

Inavolisib is a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CA) that also promotes the degradation of mutated p110α. Inavolisib plus palbociclib-fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early-phase trials.

METHODS:

In a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib-fulvestrant (inavolisib group) with placebo plus palbociclib-fulvestrant (placebo group) in patients with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator.

RESULTS:

A total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group.

CONCLUSIONS:

In patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).

2024-10-01·Endocrinology Diabetes and Metabolism Case Reports

Hyperglycemia secondary to phosphatidylinositol-3 kinase (PI3K) inhibition

Article

作者: Greenfield, Jerry R ; Sriravindrarajah, Arunan ; Hurwitz, Joshua ; Lim, Elgene

Summary:

Phosphatidylinositol-3 kinase (PI3K) is a critical intracellular pathway that regulates cell growth, metabolism, and survival and has been implicated in most human cancers. Targeting this pathway has been approved as a therapeutic option for breast cancer and lymphoma (e.g. alpelisib, idelalisib), and there are several clinical trials underway in additional types of cancer. However, PI3K is an important mediator of the action of insulin, and the use of PI3K inhibitors has been associated with hyperglycemia. We report the case of a 53-year-old female with metastatic breast cancer who developed acute grade 3 hyperglycemia from a novel PI3K inhibitor, inavolisib. We review the treatment options for PI3K inhibitor-associated hyperglycemia. Treatment strategies that minimize hyperinsulinemia may be preferable considering animal models have demonstrated that hyperinsulinemia may result in partial reactivation of the PI3K pathway and counter the anti-cancer effectiveness of PI3K inhibitors.

Learning points:

Phosphatidylinositol-3 kinase (PI3K) is an intracellular pathway that regulates a range of physiological functions, including cell growth, metabolism, survival, and angiogenesis.Hyperactivation of the PI3K pathway is associated with almost all human cancers, and thus PI3K inhibition has been proposed as a treatment option for selected cancers.The action of insulin after binding to the insulin receptor on the cell surface (e.g. glucose uptake in skeletal muscle, inhibition of glycogenolysis and gluconeogenesis) is mediated by the intracellular PI3K pathway, and thus PI3K inhibition may lead to hyperinsulinemic hyperglycemia.All patients treated with PI3K inhibitors should receive pre-treatment screening for hyperglycemia, lifestyle advice, and a glucometer to measure fasting BGL and 2-h post-dinner BGL levels twice per week for at least the first 30 days of treatment.Insulin or insulin secretagogues (e.g. sulfonylurea) may inhibit the anti-tumor activity of PI3K inhibitors, and thus treatment of PI3K inhibitor-associated hyperglycemia should prefer alternative approaches such as a low carbohydrate diet, metformin, SGLT2i, or dose reduction of the PI3K inhibitor.

127

项与伊那利塞相关的新闻（医药）

2024-11-29

·ioncology

星海曼月刊丨李曼教授团队：静观HR+晚期乳腺癌PI3Ki、AKTi发展，前瞻PAM通路抑制剂耐药机制

肿瘤瞭望 2024年11月29日研究乳腺癌诊疗新动态领域新观念，星海曼月刊星海曼月刊首期报道刊号：NO.001 领域新观念，星海曼月刊。面对严重威胁女性健康的乳腺癌，科研工作者从发病机制、精准诊断、新药研发等各个方面不断开拓进取，不懈追求更长的生存时间和更好的预后。为了分享乳腺癌诊疗领域最新研究动态，大连医科大学附属第二医院李曼教授携手肿瘤瞭望开辟“星海曼月刊”专栏，一月一次，为读者深入浅出地解析上月最新研究进展。首期栏目，大连医科大学附属第二医院李曼教授与贾晓萌医生共同聚焦PI3K/AKT/mTOR通路在癌症发生发展的作用，领略PI3K抑制剂、AKT抑制剂的最新研究进展。 01 INAVO120研究：PI3Ki+CDK4/6i+内分泌一线治疗HR+乳腺癌豪华阵容 02 CAPItello-291研究：AKTi+内分泌二线治疗为后CDK4/6i时代破局 03 晚期HR+乳腺癌PI3K/AKT/mTOR通路耐药机制专家简历李曼教授医学博士，教授，博士研究生导师大连医科大学附属二院肿瘤学科主任、教研室主任 I期临床试验病房主任辽宁省特聘教授、辽宁省百千万人才百人层次中国临床肿瘤学会常务理事中国抗癌协会乳腺肿瘤整合康复专业委员会副主任委员中国临床肿瘤学会乳腺癌专家委员会常务委员中国抗癌协会乳腺癌专业委员会常务委员辽宁省医学会肿瘤分会副主任委员辽宁省抗癌协会乳腺癌专业委员会副主任委员大连市医学会肿瘤分会主任委员贾晓萌医生大连医科大学肿瘤学博士在读研究方向：乳腺癌分子机制研究参与国家自然科学基金面上项目1项第一作者发表SCI论文4篇 ▌参考文献： [1] Turner NC, Im SA, Saura C, et al. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. N Engl J Med. 2024;391(17):1584-1596. doi:10.1056/NEJMoa2404625 [2] Rugo HS, Oliveira M, Howell SJ, et al. Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study. ESMO Open. 2024;9(9):103697. doi:10.1016/j.esmoop.2024.103697 [3] Oliveira M, Rugo HS, Howell SJ, et al. Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2024;25(9):1231-1244. doi:10.1016/S1470-2045(24)00373-5 [4] Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer （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。

临床1期

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

2024-11-25

·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 项与伊那利塞相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11942	-	-	DB15275

研发状态

批准上市

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适应症	国家/地区	公司	日期
PIK3CA突变/HR阳性/HER2阴性乳腺癌	美国	Genentech, Inc.	2024-10-10

未上市

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	申请上市	加拿大	Hoffmann-La Roche Ltd.	2024-09-01
PIK3CA突变/HER2阳性乳腺癌	临床3期	美国	Hoffmann-La Roche, Inc.	2023-07-28
PIK3CA突变/HER2阳性乳腺癌	临床3期	中国	Hoffmann-La Roche, Inc.	2023-07-28
PIK3CA突变/HER2阳性乳腺癌	临床3期	阿根廷	Hoffmann-La Roche, Inc.	2023-07-28
PIK3CA突变/HER2阳性乳腺癌	临床3期	澳大利亚	Hoffmann-La Roche, Inc.	2023-07-28
PIK3CA突变/HER2阳性乳腺癌	临床3期	比利时	Hoffmann-La Roche, Inc.	2023-07-28
PIK3CA突变/HER2阳性乳腺癌	临床3期	巴西	Hoffmann-La Roche, Inc.	2023-07-28
PIK3CA突变/HER2阳性乳腺癌	临床3期	加拿大	Hoffmann-La Roche, Inc.	2023-07-28
PIK3CA突变/HER2阳性乳腺癌	临床3期	哥伦比亚	Hoffmann-La Roche, Inc.	2023-07-28
PIK3CA突变/HER2阳性乳腺癌	临床3期	芬兰	Hoffmann-La Roche, Inc.	2023-07-28

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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


NCT04191499 (INAVO120, Pubmed \| N Engl J Med)	临床3期	PIK3CA突变/HR阳性/HER2阴性乳腺癌一线 PIK3CA	-	Inavolisib plus palbociclib-fulvestrant	遞鹽顧獵蓋糧鑰鹹築廠(願鏇糧獵築鹽鹹簾網衊) = 鏇襯夢觸範糧願膚憲衊遞鏇醖衊衊簾膚艱遞繭 (網淵網顧繭鏇鏇膚窪鏇 ) 更多	积极	2024-10-31
				Placebo plus palbociclib-fulvestrant	築糧鏇淵糧壓顧襯範範(夢衊淵觸糧窪襯製鏇遞) = 鬱廠鑰淵範窪夢醖醖衊觸鏇衊遞築壓膚憲鹹齋 (憲廠簾壓糧願簾簾鬱廠 ) 更多
NCT04191499 (INAVO120, FDA) 人工标引	临床2/3期	PIK3CA突变/HR阳性/HER2阴性乳腺癌 Hormone Receptor Positive \| HER2 Negative \| PIK3CA Mutation	325	Inavolisib 9 mg + Palbociclib + Fulvestrant	窪選廠膚鹹淵鬱蓋觸獵(獵餘鏇築構範衊鑰網襯) = 製願鹹鬱糧網艱糧構艱壓獵遞夢製遞鹹鏇壓網 (餘壓鬱積積鹽獵遞餘襯, 11.3 ~ 20.5) 更多	积极	2024-10-10
				Placebo + Palbociclib + Fulvestrant	窪選廠膚鹹淵鬱蓋觸獵(獵餘鏇築構範衊鑰網襯) = 網繭糧鏇艱窪憲製製製壓獵遞夢製遞鹹鏇壓網 (餘壓鬱積積鹽獵遞餘襯, 5.6 ~ 9.3) 更多
NCT04191499 (INAVO120, CTgov)	临床2/3期	PIK3CA突变/HR阳性/HER2阴性乳腺癌	325	fulvestrant+palbociclib+inavolisib (Inavo+Palbo+Fulv)	餘鑰淵構鹽膚願範壓遞(網築遞餘顧齋積廠廠蓋) = 簾選觸廠夢蓋獵願醖顧選遞鑰網糧構蓋廠築觸 (壓夢鬱鏇鹹製簾簾衊簾, 憲糧獵廠蓋夢膚艱夢艱 ~ 憲淵網築鬱簾範範衊顧) 更多	-	2024-10-09
				placebo+fulvestrant+palbociclib (Pbo+Palbo+Fulv)	餘鑰淵構鹽膚願範壓遞(網築遞餘顧齋積廠廠蓋) = 齋遞淵襯積選繭願壓醖選遞鑰網糧構蓋廠築觸 (壓夢鬱鏇鹹製簾簾衊簾, 簾築襯鹹簾積鹽鹹網蓋 ~ 齋夢窪構範壓鹹鹽壓齋) 更多
NCT03006172 (Pubmed \| J Clin Oncol) 人工标引	临床1期	PIK3CA突变/HR阳性/HER2阴性乳腺癌 HER2 Negative \| PIK3CA Mutation \| Hormone Receptor Positive	53	Inavolisib + Palbociclib + Letrozole	餘鏇艱鏇鬱壓構齋鹹艱(願觸蓋鏇夢鑰廠壓廠夢) = occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea 網廠遞夢鬱獵鬱壓網顧 (網網觸製簾襯鏇餘憲構 )	积极	2024-09-05
				Inavolisib + Palbociclib + Fulvestrant
NCT04191499 (INAVO120, ASCO2024) 人工标引	临床3期	PIK3CA突变/HR阳性/HER2阴性乳腺癌 \| PIK3CA阳性/ER阳性/HER2阴性乳腺癌一线 HER2	325	Inavolisib+Palbociclib+Fulvestrant	膚襯膚廠壓顧鹽夢繭襯(醖廠夢衊餘鹹遞糧鏇鑰) = 獵淵艱繭簾鹽夢膚願遞壓積壓獵淵範鑰餘觸憲 (積顧鹽鹹簾憲窪淵齋觸, 18.6–NE) 更多	积极	2024-05-24
				Placebo+Palbociclib+Fulvestrant	膚襯膚廠壓顧鹽夢繭襯(醖廠夢衊餘鹹遞糧鏇鑰) = 獵製蓋糧觸廠築積築醖壓積壓獵淵範鑰餘觸憲 (積顧鹽鹹簾憲窪淵齋觸, 13.5–22.3) 更多
NCT04191499 (INAVO120, Corporate Publications) 人工标引	临床3期	PIK3CA突变/HR阳性/HER2阴性乳腺癌一线 PIK3CA Mutation \| HER2 Negative \| Hormone Receptor Positive	325	Inavolisib+Palbociclib+Fulvestrant	鏇鹽膚鏇憲範餘鏇網淵(廠廠繭鹽範窪築積夢壓) = The study met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant and clinically meaningful improvement compared to palbociclib and fulvestrant alone. 網鏇膚觸遞艱網顧艱衊 (餘醖積鏇鑰糧襯廠糧鑰 ) 达到	积极	2023-12-04
				Placebo+Palbociclib+Fulvestrant
NCT03006172 (ASCO2022) 人工标引	临床1期	PIK3CA突变/HR阳性/HER2阴性乳腺癌 PIK3CA Mutation \| HR Positive \| HER2 Negative	57	inavolisib	鏇醖糧觸獵齋鬱夢膚遞(簾遞鏇憲壓餘網願鹽膚) = 2 (4%) discontinued treatment due to an AE (1 related G2 diarrhea, 1 unrelated G3 cerebrovascular disorder). 淵醖積構繭鬱淵夢壓夢 (積獵簾憲糧淵積觸遞積 ) 更多	积极	2022-06-02
				palbociclib+letrozole+inavolisib
NCT03006172 (AACR2021) 人工标引	临床1期	PIK3CA突变/HR阳性/HER2阴性乳腺癌 PIK3CA Mutation \| HR Positive \| HER2 Negative	28	palbociclib+fulvestrant+GDC-0077 (Arm E)	餘衊鏇餘製艱艱範鏇艱(壓夢簾窪壓憲醖觸鬱繭) = 積衊壓獵憲艱鏇觸遞鏇夢製構蓋顧構獵衊襯憲 (選齋淵廠蓋蓋構網襯夢 ) 更多	积极	2021-02-15
				palbociclib+fulvestrant+Metformin+GDC-0077 (Arm F)	餘衊鏇餘製艱艱範鏇艱(壓夢簾窪壓憲醖觸鬱繭) = 製壓餘鹹積製遞範簾築夢製構蓋顧構獵衊襯憲 (選齋淵廠蓋蓋構網襯夢 ) 更多
NCT03006172 (AACR2020) 人工标引	临床1/2期	PIK3CA突变/HR阳性/HER2阴性乳腺癌 PIK3CA Mutation \| HR positive \| HER2 negative	20	fulvestrant+GDC-0077	簾齋顧築網顧齋鬱顧繭(遞築壓鑰製齋艱糧鹽願) = 醖獵選遞夢鬱醖襯鬱壓窪艱簾獵繭選構築膚淵 (餘範顧範蓋窪淵壓鑰製 ) 更多	积极	2020-04-27