Entrectinib

4月16日,国家药品监督管理局正式授予罗氏PI3K抑制剂GDC-0077（通用名：Inavolisib）联合哌柏西利与内分泌疗法用于治疗PIK3CA突变、激素受体（HR）阳性、人表皮生长因子受体2（HER2）阴性、局部晚期或转移性乳腺癌成人患者的优先审评资格。Inavolisib有望成为国内乳腺癌领域首个获批的PI3K抑制剂，填补PIK3CA突变HR+/HER2-晚期乳腺癌治疗空白，开启HR+精准治疗新时代。Inavolisib有望为中国乳腺癌患者提供临床获益，且安全可控国家药监局本次授予Inavolisib治疗PIK3CA突变HR+/HER2-局部晚期或转移性乳腺癌优先审评资格，主要依据其关键性III期INAVO120研究[1]的积极结果。INAVO120研究[1]（NCT04191499）是一项全球、多中心、双盲、随机对照的III期临床研究，旨在评估Inavolisib+哌柏西利+氟维司群对比哌柏西利+氟维司群在PIK3CA突变的HR+/HER2-局部晚期或转移性乳腺癌患者中的疗效和安全性。结果显示，与哌柏西利+氟维司群的对照组相比，Inavolisib+哌柏西利+氟维司群的三药联合方案实现PFS临床获益（15.0个月 vs 7.3个月），降低57%的疾病进展或死亡风险（HR=0.43，95%CI 0.32-0.59；P<0.0001）。并且无论是不同地域、绝经前/后、肝转移是/否、原发内分泌耐药/继发内分泌耐药等关键性亚组患者，接受Inavolisib+哌柏西利+氟维司群治疗均观察到与总人群一致的获益。其他次要终点的数据亦显示，联合治疗组的客观缓解率（ORR）、缓解持续时间（DOR）和疾病控制率（DCR）均有明显提高。虽然OS数据尚未成熟，但已观察到获益趋势。此外，Inavolisib联合治疗安全性可控，停药率低，未观察到新的安全性信号。INAVO120研究[1]结果为Inavolisib 联合哌柏西利和氟维司群，作为 PIK3CA 突变 HR+/HER2-局部晚期或转移性乳腺癌患者的一线治疗选择提供了坚实的循证医学证据。Inavolisib获优先审评，引领中国HR+乳腺癌精准诊疗新纪元临床中约40%的HR+/HER2-晚期乳腺癌患者存在PIK3CA突变[2]，相比PIK3CA野生型患者，PIK3CA突变型患者的预后较差，传统治疗效果不佳，且对内分泌治疗和化疗耐药[2,3]。Inavolisib是新一代PI3Kα抑制剂，作为同类中极具潜力的PI3Kα抑制剂，Inavolisib兼具高选择性抑制PI3Κα并且能特异性降解PI3Κα突变蛋白的双重作用机制，可以实现持续的通路抑制[4-6]。此次在中国获优先审评资格，有望加速Inavolisib的审评审批，推动研究成果转化到临床，革新PIK3CA突变HR+/HER2-晚期乳腺癌治疗格局，给这部分乳腺癌患者带来精准、高效、安全的治疗选择。HR+/HER2-晚期乳腺癌约占总体乳腺癌的70%[7]，内分泌治疗是其重要治疗手段，但仍存在预后较差人群。PI3K/AKT/mTOR（PAM）信号通路在乳腺癌中存在广泛激活，与乳腺癌发生、进展以及预后较差密切相关[8,9]。PI3K位于PAM信号通路的上游，通过将PIP2转化为PIP3激活下游效应因子，在该通路中扮演着重要角色。PI3K通路中有很多关键分子，其中PIK3CA是最常见的突变基因。临床中约40%的HR+/HER2-晚期乳腺癌患者存在PIK3CA突变[2]，此类患者预后较差且对内分泌治疗和化疗都存在一定程度的耐药，存在巨大未被满足的临床需求[2,3]。Inavolisib是一款具有高选择性的PI3Kα抑制剂，其对PI3Kα的选择性抑制力是其它I类PI3K亚型的300倍，而且可以特异性地降解p110α突变体，防止PIP3累积，使下游AKT信号传导减弱，从而抑制细胞增殖，且减少因抑制野生型信号传导所致的全身性副作用[4-6]。既往GO39374 I/Ib期研究[10-14]已经证实，Inavolisib单药或联合治疗显示出抗肿瘤活性和可管理的安全性特征，长期治疗安全性佳。目前，Inavolisib仍有两项Ⅲ期临床研究正在进行：●INAVO121研究：旨在评估PIK3CA突变HR+/HER2-局部晚期/转移性乳腺癌患者接受Inavolisib/Alpesilib+氟维司群联合治疗的疗效及安全性。● INAVO122研究：旨在评估Inavolisib+帕妥珠曲妥珠单抗皮下制剂(Phesgo)联合方案与安慰剂+ Phesgo作为PIK3CA突变HER2+晚期乳腺癌患者一线维持治疗的疗效及安全性。参考文献：[1] Jhaveri kl et al. SABCS 2023. Abstract GS03-13.[2] N Vasan, et al. Ann Oncol. 2019 Dec 1;30(Suppl_10):x3-x11.[3] F Mosele, et al. Ann Oncol. 2020 Mar;31(3):377-386.[4] Edgar K et al. SABCS 2019. Poster P3-11-23.[5] Cancer Discov. 2021 Sep 20;candisc.0072.2021.[6] Song KW, et al. Cancer Discov. 2022 Jan;12(1):204-219.[7] DeSantis CE, et al. CA Cancer J Clin, 2016, 66(1):31-42.[8] Liu P, et al. Nat. Med. 17, 1116–1120 (2011).[9]Fruman DA, Rommel C, et al. Nat. Rev. Drug Discov. 13, 140–156 (2014).[10] Juric D, et al. SABCS 2019. Abstract OT1-08-04.[11] Jhaveri K, et al. SABCS 2019. Poster P1-19-46.[12]Jhaveri K, et al. SABCS 2020. Poster PS5–12.[13] Dejan Juric, et al. SABCS 2021. Abstract P5-17-05.[14] Philippe L Bedard, et al. ASCO 2022. Poster 1052.1.本新闻稿旨在分享研发前沿资讯， 仅供中国境内医疗卫生专业人士参阅，非广告用途。2. 罗氏不推荐任何未被批准的药品、适应症的使用。3. Inavolisib为在研药物，目前尚未在中国大陆地区获批。更多新闻罗氏皮下注射生态再添新成员，美罗华®皮下制剂在华获批罗氏罗圣全®又一适应症在华获批，儿童实体瘤治疗迎来新希望

Preclinical data continue to support NVL-330's broad activity against HER2 oncogenic alterations, selectivity over wild-type EGFR, and differentiated brain-penetrant profile Zidesamtinib shown to be effective at suppressing on-target ROS1 resistance mutations in preclinical mutagenesis screens CAMBRIDGE, Mass., April 8, 2024 /PRNewswire/ -- Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, today announced the presentation of new preclinical data for its novel HER2-selective inhibitor, NVL-330, and novel ROS1-selective inhibitor, zidesamtinib (NVL-520). The two posters will be presented at the American Association for Cancer Research (AACR) Annual Meeting taking place from April 5 – 10 in San Diego. The posters will also be available on the Nuvalent website at following the presentations. "Today's presentations continue to reinforce the differentiated profiles of our drug candidates," said Henry Pelish, Ph.D., Senior Vice President of Drug Discovery at Nuvalent. "In comparative in vitro and in vivo analyses of NVL-330 with currently approved and investigational HER2-targeting agents, NVL-330 demonstrated a differentiated preclinical profile by achieving higher CNS penetration and deeper intracranial response. Importantly, in these preclinical studies, NVL-330 also demonstrated potency against a broad range of HER2 oncogenic alterations and selectivity over wild-type EGFR, in line with our goal of designing molecules that can thread the needle between multiple competing challenges." Dr. Pelish continued, "In our ongoing ARROS-1 clinical trial of zidesamtinib, preliminary Phase 1 data has demonstrated a differentiated profile combining activity against ROS1 resistance mutations, CNS penetrance, and TRK avoidance which we believe has the potential to translate to deep, durable responses for patients with ROS1-driven cancers. A new preclinical mutagenesis screen reinforces this potential, showing that on-target resistance is unlikely following treatment with zidesamtinib at its average observed clinical concentration." In 2024, the company expects to initiate a Phase 1 trial for its HER2 program and to share updated data from the ARROS-1 trial at a medical meeting. AACR Presentation Overviews: Title: Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations Authors: Yuting Sun*1, Kristin L. Andrews1, Anupong Tangpeerachaikul1, Tuan M. Nguyen1, Baudouin Gerard1, Nancy E. Kohl2, Joshua C. Horan1, Henry E. Pelish1 Abstract Number: 1979 Session Category: Experimental and Molecular Therapeutics Session Title: Kinase and Phosphatase Inhibitors 2 Session Date and Time: Monday April 8, 2024, from 9:00 – 12:30 p.m. PT Location: Poster Section 25 Presentation summary: NVL-330 had broad preclinical activity on HER2 oncogenic alterations, including HER2 exon20ins, HER2 activating point mutations, and amplified wild-type HER2. In a preclinical comparison with the selective tyrosine kinase inhibitor, zongertinib, NVL-330 demonstrated: Similar potency and selectivity over wild-type EGFR; and, Higher CNS penetrance. In a preclinical comparison with antibody drug conjugate, T-DXd (Enhertu), NVL-330 demonstrated: Deeper response and higher CNS penetrance in an intracranial tumor model; and, Activity in cells with acquired resistance to T-DXd. Title: Mutagenesis screens support potential best-in-class profile for selective, brain-penetrant, and TRK-sparing ROS1 inhibitor zidesamtinib (NVL-520) Authors: Anupong Tangpeerachaikul*1, Franklin Gu1, Henry E. Pelish1 Abstract Number: LB182 Session Title: Late-Breaking Research: Experimental and Molecular Therapies 2 Session Date and Time: Monday April 8, 2024, from 1:30 – 5:00 p.m. PT Location: Poster Section 52 Presentation summary: Comparison of the clinical concentration of zidesamtinib to its efficacious in vitro concentration suggests a potential for a deep and sustained inhibition of ROS1 and ROS1 G2032R fusions in humans, including in the CNS. Zidesamtinib effectively suppressed on-target resistance in ENU mutagenesis screens with both ROS1 and ROS1 G2032R fusions, predicting that on-target resistance is unlikely when used as either a first-line or a later-line therapy. On-target resistance is predicted to be more likely for earlier-generation ROS1 inhibitors crizotinib, entrectinib, and potentially repotrectinib as a first-line therapy. These mutagenesis screens provide additional preclinical support for zidesamtinib's potential to drive deep and durable responses for patients with ROS1-driven cancers. *Presenter, corresponding author; 1Nuvalent, Inc., Cambridge, MA, USA; 2Kohl Consulting, Wellesley, MA, USA About NVL-330 NVL-330 is a novel brain-penetrant HER2-selective tyrosine kinase inhibitor designed to address the combined medical need of treating HER2-mutant tumors, including those with HER2 exon 20 insertion mutations, avoiding treatment related adverse events due to off-target inhibition of wild-type EGFR, and treating brain metastases. About zidesamtinib (NVL-520) Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC. Zidesamtinib is currently being investigated in the ARROS-1 trial (NCT05118789), a first-in-human Phase 1/2 clinical trial for patients with advanced ROS1-positive NSCLC and other solid tumors. About Nuvalent Nuvalent, Inc. (Nasdaq: NUVL) is a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer, designed to overcome the limitations of existing therapies for clinically proven kinase targets. Leveraging deep expertise in chemistry and structure-based drug design, we develop innovative small molecules that have the potential to overcome resistance, minimize adverse events, address brain metastases, and drive more durable responses. Nuvalent is advancing a robust pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-positive non-small cell lung cancer, and multiple discovery-stage research programs. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding Nuvalent's strategy, business plans, and focus; the expected timing of data announcements; the development programs for zidesamtinib (NVL-520) and NVL-330; the potential benefits of zidesamtinib and NVL-330; the potential of Nuvalent's pipeline programs, including zidesamtinib and NVL-330; Nuvalent's research and development programs for the treatment of cancer; and risks and uncertainties associated with drug development. The words "may," "might," "will," "could," "would," "should," "expect," "plan," "anticipate," "aim," "goal," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" or the negative of these terms and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. You should not place undue reliance on these statements or the scientific data presented. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties, and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation: unexpected concerns that may arise from additional data, analysis, or results obtained during preclinical studies or clinical trials; the risk that results of earlier clinical trials may not be predictive of the results of later-stage clinical trials; the risk that data from our clinical trials may not be sufficient to support registration and that Nuvalent may be required to conduct one or more additional studies or trials prior to seeking registration of our product candidates; the occurrence of adverse safety events; risks that the FDA may not approve our potential products on the timelines we expect, or at all; risks of unexpected costs, delays, or other unexpected hurdles; risks that Nuvalent may not be able to nominate drug candidates from its discovery programs; the direct or indirect impact of public health emergencies or global geopolitical circumstances on the timing and anticipated timing and results of Nuvalent's clinical trials, strategy, and future operations; the timing and outcome of Nuvalent's planned interactions with regulatory authorities; and risks related to obtaining, maintaining, and protecting Nuvalent's intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Nuvalent's Annual Report on Form 10-K for the fiscal year ended December 31, 2023, as well as any prior and subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Nuvalent's views only as of today and should not be relied upon as representing its views as of any subsequent date. Nuvalent explicitly disclaims any obligation to update any forward-looking statements. SOURCE Nuvalent, Inc.