A First-in-Human Study of PI3Kα Inhibitor, RLY-5836, in Combination With Targeted and Endocrine Therapies in Participants With Advanced Breast Cancer and as a Single Agent in Advanced Solid Tumors

This is a Phase 1, first-in-human, open-label study designed to evaluate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of RLY-5836 in advanced solid tumors in participants harboring a PIK3CA mutation in blood and/or tumor per local assessment. The study consists of 2 parts, a dose escalation (Part 1) and a dose expansion (Part 2).

开始日期2023-03-29

申办/合作机构

Relay Therapeutics, Inc.

100 项与 PIK3CA E545K x PIK3CA E542K 相关的临床结果

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100 项与 PIK3CA E545K x PIK3CA E542K 相关的转化医学

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0 项与 PIK3CA E545K x PIK3CA E542K 相关的专利（医药）

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项与 PIK3CA E545K x PIK3CA E542K 相关的文献（医药）

2024-01-12·Medicine

Whether specific genetic feature predicted immunotherapy efficacy: A case report

Article

作者: Chen, Jun ; Cheng, Xiaochun ; Pang, Linrong ; Li, Ting ; He, Lianxiang

Rationale:Blockade of programmed death protein 1 (PD-1), have been observed to have quite good efficacy in recurrent and metastatic cervical cancer. Generally, we believe that the biomarkers of PD-1 inhibitors are programmed cell death-ligand 1, tumor mutational burden, high microsatellite instability, or deficient mismatch repair. However, in the case reported below, we observed that the patient with negative existing predictive biomarkers have significant benefits after zimberelimab monotherapy, indicating that there were other biomarkers that may predict immunotherapy efficacy. However, currently, no one has explored and studied the other potential biomarkers of PD-1 inhibitors.Patient concerns:A 51-year-old patient, diagnosed with cervical adenocarcinoma nearly 11 years ago, requested treatment.Diagnoses:The next-generation sequencing has shown PIK3CA E545K, SMAD4 1309-1G, and ALK E717K gene mutations, receptor tyrosine kinase 2 (ErbB-2) amplification, microsatellite stability, and low tumor mutational burden of 6.3 mutations per megabase. And immunohistochemistry revealed that the tumor was programmed cell death-ligand 1 negative.Intervention:Zimberelimab monotherapy was accepted as third-line treatment.Outcomes:The patient had received zimberelimab for nearly 10 months, the best tumor response was PR (Response Evaluation Criteria in Solid Tumours) and no noticeable adverse reactions were observed.Lessons:PIK3CA-E542K, ErbB2 amplification, and SMAD4 mutations could be potential biomarkers for PD-1 inhibitors, but a single instance is insufficient to validate the hypotheses. A larger number of patients or more clinical data will be necessary to determine whether these gene mutations are appropriate biomarkers for patients when treatment with PD-1 inhibitors.

2023-10-02·Cancer prevention research (Philadelphia, Pa.)

Analysis of Several Common APOBEC-type Mutations in Bladder Tumors Suggests Links to Viral Infection.

Article

作者: Real, Francisco X ; Rao, Nina ; Dean, Michael ; Kogevinas, Manolis ; Rothman, Nathaniel ; Schwenn, Molly ; Malats, Nuria ; Johnson, Alison ; Garcia-Closas, Montserrat ; Lawrence, Scott M ; Baris, Dalsu ; Golubeva, Yelena ; Butler, Kelly E ; Prokunina-Olsson, Ludmila ; Starrett, Gabriel J ; Dyrskjøt, Lars ; Yan, Wusheng ; Silverman, Debra T ; Koutros, Stella ; Piaskowski, Mary L ; Buck, Christopher B

FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10-5), 25 of 554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms.PREVENTION RELEVANCETobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination.

项与 PIK3CA E545K x PIK3CA E542K 相关的新闻（医药）

2023-05-11

·SYNAPSE

浅谈新一代PI3Kα抑制剂RLY-2608

CDK4/6抑制剂联合雌激素受体(ER)降解剂氟维司特可显著提高晚期激素受体阳性(HR+)乳腺癌患者的无进展生存期和总生存期，这是该疾病的标准治疗方法。然而，这种组合用药并不能治愈HR+乳腺癌患者，耐药性限制了临床受益的持续时间。在高达40%的HR+乳腺癌中，PIK3CA突变导致磷酸肌醇3-激酶α (PI3Kα)的激活，是耐药的关键驱动因素。因此，PI3Kα抑制剂联合CDK4/6抑制剂和/或氟维司特在预防和克服HR+、PIK3CA突变型乳腺癌的治疗耐药方面具有很高的市场价值。如图1左，与KRAS一起，PI3Kα是癌症中最常发生突变的激酶。在不同的适应症中，PIK3CA是癌症中最常见的突变基因之一。图1中间图表明PI3Kα信号通路对生长和代谢至关重要，其抑制会破坏葡萄糖稳态，导致高血糖症。如图1右，针对PI3K靶点的药物研发工作已经进展了许多年。PI3K的脂质激酶结构域和mTOR的蛋白激酶结构域之间的高度同源性，这使得2010年以前开发的同时针对PI3K和mTOR的pan抑制剂毒性显著增加。2010年后开发的Pan-PI3K抑制剂因对PI3K其他亚型的抑制，均有显著毒性。 PI3Kα的正构位点抑制剂的治疗指标受到双重问题的限制，即对突变型与野生型(WT) PI3Kα没有临床意义的选择性和非异构体抑制活性。Alpelisib是唯一批准的正构型PI3Kα抑制剂，因其具有与抑制野生型PI3Kα和其他PI3K亚型相关的毒性，导致对突变型PI3Kα不能有效抑制，因而频繁停药，与CDK4/6抑制剂联合使用也面临挑战。目前仍未有针对突变的PI3Kα抑制剂成功上市。 Relay Therapeutics解决了PI3Kα的全长冷冻电镜结构，进行了长时间尺度的分子动力学模拟，以阐明WT和突变形式之间的构象差异，并利用这些设计了RLY-2608。这是第一个已知的变构、泛突变、选择性PI3Kα抑制剂，能够抑制H1047X、E542X、E545X三种主要致癌突变，同时对野生型PI3Kα没有活性。（如图2所示为热点突变） RLY-2608的部分临床前数据图3A和B可以看出，通过表面等离子体共振进行评估(SPR)计算得到的KD，与Alpelisib相比，RLY-2608优先结合突变蛋白。且buparlisib(一种矫形部位抑制剂)不能消除结合，证明RLY-2608产生了一个新的结合位点。图3C表明，RLY-2608与突变蛋白结合更快。图3D表明，RLY-2608对突变体PI3Kα的生化选择性优于WT和其他家族成员亚型。图3E的激酶谱表明，RLY-2608具有超高的激酶选择性，减少了脱靶产生副作用的可能性。如图4A、B所示，RLY-2608在PIK3CA突变癌细胞株中抑制磷酸化AKT (pAKT)，与热点突变无关；在较长时间的孵育(5天)后，RLY-2608可抑制其增殖。图4D表明，RLY-2608以剂量依赖的方式显示出有效的肿瘤生长抑制作用，与正构抑制剂相比，在对胰岛素水平影响较小的剂量下便可完全消退。但是图4C的药效数据表明，同等剂量下，RLY-2608并不能显示出抑制肿瘤生长更好的效果（与GDC-077和Alpelisib相比）。这可能是因为PI3K的其他亚型如δ也可以通过免疫调控来发挥抗肿瘤作用，RLY-2608作为单一的PI3Kα抑制剂，理论上是牺牲了药效来提高安全性。其他披露的数据中，RLY-2608在激酶和螺旋结构域PIK3CA突变体体内异种移植模型中均达到最大疗效，与正构抑制剂相比，胰岛素水平的升高显著降低。且各种属中，RLY-2608剂量的暴露量超过突变的PI3Kα细胞PD IC90，而不会导致葡萄糖水平升高或与糖代谢失调相关的组织病理学变化。这些临床前的结果支持RLY-2608作为突变PI3Kα抑制剂的临床研究。搜索关键词Relay Therapeutics，公开数据显示，可以看到16条公开的专利信息。其中，与PI3Kα相关的专利有三篇，分别是WO2023039532、WO2023288242、WO2021222556。WO2021222556最早优先权日为2020.04.29，PCT尚未进入中国。WO2023288242最早优先权日为2021.07.13。WO2023288242最早优先权日为2021.09.10。综合时间线和具体申请情况看RLY-2608很有可能出自专利WO2023288242。目前，RLY-2608正在临床一期进行研究。这是一项开放标签的FIH研究，旨在评估RLY-2608在血液和/或肿瘤中有PIK3CA突变的晚期实体肿瘤患者的最大耐受剂量、安全性、耐受性、PK、药动力学和初步抗肿瘤活性。如图5，该研究将评估RLY-2608作为单药治疗不可切除或转移性实体瘤患者，以及RLY-2608 +氟维司特联合治疗HR+ HER2-局部晚期或转移性乳腺癌患者。本研究包括两个部分，剂量递增(第一部分)和剂量扩大(第二部分)。 2023年4月18日，AACR会议上将公布选择性PI3Kα抑制剂RLY-2608在PIK3CA突变型实体瘤患者的首次人体研究ReDiscover试验结果。总结 PI3K-Akt-mTOR是肿瘤发生的经典通路，但是Pan-PI3K抑制剂具有某些靶向相关毒性，包括腹泻、皮疹、疲劳和高血糖等。PI3K抑制剂的毒性与其异构体选择性有关。PI3Kα的抑制与高血糖和皮疹有关，而PI3Kδ或PI3Kγ的抑制与腹泻、骨髓抑制和转氨炎有关。越来越多的PI3Kα抑制剂在临床试验上取得突破性进展，但是PI3Kα抑制剂所带来的高毒性等副作用也成为应用于临床所面临的巨大挑战。 PI3Kα是所有癌症中最常突变的激酶，在约13%的实体瘤患者中检测到致癌突变。传统上，PI3Kα抑制剂的开发主要集中在活性位点或矫形位点。矫形体抑制剂的治疗指标受到缺乏临床意义的突变型与野生型(WT) PI3Kα选择性和非异构体活性的限制。 RLY-2608是已知的第一个变构泛突变体(H1047X, E542X和E545X)，以及旨在克服这些限制的异构体选择性PI3Kα抑制剂。RLY-2608目前正在进行临床试验，旨在治疗带有PIK3CA (PI3Kα)突变的晚期实体肿瘤患者。期待更多的临床数据披露，为患者带来福音。参考资料： 1.https://relaytx.com/publications. 2.Dexin Kong et.al. Development of PI3Kα inhibitors for tumor therapy.https://doi.org/10.1080/07391102.2022.2132293. 3.Bart Vanhaesebroeck et.al. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021 October ; 20(10): 741-769. 4.Robert T. Abraham et.al. The PI3K pathway in human disease. Cell. 2017 August 10; 170(4): 605–635.