PRISM: PRecIsion in SCLC Via a Multicohort Study: Randomized Phase II Studies Evaluating Maintenance Durvalumab With or Without Biomarker-Directed Therapy for Extensive Stage Small Cell Lung Cancer (ES-SCLC)

This phase II trial tests how well biomarker tests on patients tumor tissue works in selecting personalized treatments for patients with extensive stage small cell lung cancer (ES-SCLC). Biomarker tests look for certain features in cancer cells that may give doctors more information about what is driving cancer and how to treat it. Based on the biomarker test results, study doctors can determine the subtype of ES-SCLC that study treatments can target. This study also tests different types of maintenance treatment for ES-SCLC with drugs durvalumab, saruparib, ceralasertib or monalizumab. Maintenance treatment is given after initial treatment and is given to help keep the cancer under control and prevent it from getting worse. Immunotherapy with monoclonal antibodies, such as durvalumab and monalizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Saruparib is a PARP inhibitor. PARP is a protein that helps repair damaged deoxyribonucleic acid (DNA). Blocking PARP may prevent cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Ceralasertib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for tumor cell growth. Giving biomarker selected personalized maintenance treatment with durvalumab, saruparib, ceralasertib or monalizumab may work better in treating patients with ES-SCLC.

开始日期2025-09-08

申办/合作机构

SWOG

[+1]

NCT06732401

/ Recruiting临床3期IIT

A Randomized Phase III Trial of Checkpoint Blockade in Lung Cancer Patients in the Adjuvant Setting Based on Pathologic Response Following Neoadjuvant Therapy (CLEAR)

This phase III trial compares the effect of adding AZD6738 to durvalumab versus durvalumab alone to increase time without cancer in patients with non-small cell lung cancer, following treatment with chemotherapy and surgery. AZD6738 may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Adding AZD6738 to durvalumab may increase time without cancer in patients with non-small cell lung cancer, following treatment with chemotherapy and surgery.

开始日期2025-08-07

申办/合作机构

National Cancer Institute

NCT06929260

/ Recruiting临床1期

A Phase I, Open-label, Fixed-sequence Study to Evaluate the Effect of Ceralasertib on Pharmacokinetics of Drug X, Drug Y and Drug Z in Participants With Advanced Solid Tumours

The study aims to assess the effect of ceralasertib on the pharmacokinetics (PK) of Drug X, Drug Y and Drug Z in participants with advanced solid tumours.

开始日期2025-05-21

申办/合作机构

AstraZeneca PLC

[+1]

100 项与 Ceralasertib 相关的临床结果

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100 项与 Ceralasertib 相关的转化医学

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100 项与 Ceralasertib 相关的专利（医药）

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253

项与 Ceralasertib 相关的文献（医药）

2025-11-01·CANCER LETTERS

Nuclear cGAS mediated replication stress and mitotic catastrophe can overcome gemcitabine resistance

Review

作者: Park, Soon Young ; Brody, Jonathan R ; Rames, Matthew J ; Poire, Alfonso ; Sears, Rosalie C ; Jeong, Bo Young ; Mills, Gordon B ; Sheng, Yuhan ; Ozmen, Tugba Y ; English, Isabel A ; Jeong, Kang Jin

Gemcitabine, a ribonucleotide reductase (RNR) inhibitor, is active in pancreatic ductal carcinoma (PDAC) patients, but unfortunately has a limited impact on long term outcomes. Gemcitabine induces nucleotide deficiency, DNA damage including single stranded DNA (ssDNA) and replication stress (RS). DNA damage can activate cyclic GMP-AMP synthase (cGAS), leading to genome instability, micronucleus generation, and immune activation. In model systems, gemcitabine resistance can be overcome by combination treatment with the ataxia telangiectasia and Rad3-related inhibitor (ATRi; AZD6738) that blocks S and G2 checkpoints, although underlying mechanisms remain to be fully elucidated. We show that cells with low basal RS are resistant to gemcitabine, which could be overcome by combination treatment with AZD6738 through elevation of RS, phospho-RPA32 exhaustion, and mitotic catastrophe in PDAC cell models. Gemcitabine induces nuclear cGAS accumulation independent of STING-mediated immune activation. The binding of nuclear cGAS to γH2AX at double strand DNA breaks (DSBs) plays a pivotal role in RS activation and mitotic catastrophe in gemcitabine and AZD6738 treated cells.

2025-09-01·JCO Precision Oncology

Multicenter Phase II Study of Olaparib and the ATR Inhibitor Ceralasertib in Metastatic Castration-Resistant Prostate Cancer (TRAP)

Article

作者: Heath, Elisabeth I. ; Tsung, Irene ; Smith, Simon ; Devitt, Michael E. ; Dean, Emma ; Reichert, Zachery R. ; Palmbos, Phillip ; Braun, Thomas M. ; Caram, Megan E.V. ; Cackowski, Frank ; Smith, David C. ; Chinnaiyan, Arul M. ; Alumkal, Joshi J. ; Shah, Neel ; Nguyen, Charles B. ; Yentz, Sarah ; Vaishampayan, Ulka

PURPOSE:

Preclinical studies suggest the combination of the poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) inhibitor olaparib and the ataxia telangiectasia–mutated and Rad3-related (ATR) inhibitor ceralasertib has synergistic antitumor activity in homologous recombination proficient (HRP) and homologous recombination repair gene mutation (HRRm) patients. This study aims to determine the efficacy of olaparib plus ceralasertib in metastatic castration-resistant prostate cancer (mCRPC) with and without HRRm.

PATIENTS AND METHODS:

Thirty-five HRP and 12 HRRm PARP inhibitor–naïve patients with mCRPC progressing on ≥1 line of therapy or previous androgen receptor pathway inhibitor were enrolled. Patients received olaparib (300 mg twice daily) and ceralasertib (160 mg once daily, days 1-7) in 28-day cycles. HRRm was defined as biallelic inactivation of BRCA2 or BRCA1 , monoallelic inactivation of ATM , or germline inactivation of any of these genes. The primary end point was disease response rate (dRR; confirmed prostate-specific antigen decline ≥50% and/or complete/partial radiographic response by RECIST v1.1) in HRP patients. Secondary end points included dRR in HRRm patients, progression-free survival (PFS), and safety/toxicity. Two-stage designs were used.

RESULTS:

Four of 35 (11%; 95% CI, 3.2 to 26.7) HRP and four of 12 HRRm patients responded. Median PFS was 8.2 months (95% CI, 5.3 to not reached) for HRP patients. Thirty-six percent of patients had ≥grade 3 toxicity, most commonly from anemia. Limitations include small, single-arm, nonrandomized trial design.

CONCLUSION:

Combining ceralasertib with olaparib had limited activity in patients with HRP mCRPC. HRRm response rate was not greater than previous single-agent PARP inhibitor clinical trials.

2025-08-01·CANCER CELL

KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant non-small cell lung cancer

Article

作者: Arrechedera, Claudio ; Galan-Cobo, Ana ; Hughes, Adina ; Iyer, Sonia ; Conway, James ; Valge-Archer, Viia ; Young, Lucy ; Critchlow, Susan E ; Karmokar, Ankur ; Lau, Alan ; Byers, Lauren A ; Qian, Yu ; Cosaert, Jan ; Barrett, J Carl ; Kong, Yifan ; Keshvani, Caezaan ; Heymach, John V ; Karimi, Amirali ; Poteete, Alissa ; Vokes, Natalie I ; Sargeant, Rebecca ; Ramkumar, Kavya ; Do, Minh Truong ; Floc'h, Nicolas ; Wang, Jing ; Barry, Simon T ; Molkentine, David ; Paula, Alvaro G ; Schlacher, Katharina ; Pisegna, Marlese ; de Toma, Ilario ; Cho, Sungnam ; Shen, Li ; Milo, Marta ; McGrail, Daniel J ; Hernandez, Sharia ; Kar, Gozde ; Keddar, Mohamed Reda ; Solanki, Anisha

KRAS mutations frequently co-occur with alterations in STK11/LKB1 and/or KEAP1, defining an aggressive subset of lung cancers resistant to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA damage response-based therapies, the impact of KEAP1 alterations remains unknown. We demonstrate that KEAP1-NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi), particularly in the setting of increased replication stress associated with LKB1 loss. ATRi shows enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC) models and synergizes with gemcitabine. ATRi also enhances antitumor immunity and mitigates the immunosuppressed phenotype of LKB1/KEAP1-deficient tumors. In the HUDSON trial, LKB1/KEAP1-deficient NSCLC patients demonstrate enhanced benefits to the ATRi ceralasertib plus durvalumab. These findings suggest that alterations in the KEAP1-NRF2 pathway and/or LKB1 are associated with enhanced sensitivity to ATRi and could serve as biomarkers for predicting response to ATRi combination regimens.

项与 Ceralasertib 相关的新闻（医药）

2025-07-31

·ioncology

2025 ESMO丨一文纵览，肺癌领域口头报告亮点全捕捉！

点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标”ESMO 2025 微专辑扫描二维码可查看更多内容2025年欧洲肿瘤内科学会年会（ESMO 2025）将于10月17~21日在德国柏林盛大举行。作为全球肿瘤学领域最具影响力的学术盛会之一，本届大会将集中呈现肿瘤诊疗领域的突破性研究进展。目前，大会官网已公布除LBA（Late-breaking Abstract）摘要外的全部入选研究标题，其中肺癌领域近30项研究成果入选口头报告，5项研究成果来自中国。《肿瘤瞭望》特将肺癌领域入选优选口头报告（Proffered Paper session）和迷你口头报告（Mini Oral session）的相关研究标题进行整理，以飨读者。非小细胞肺癌（NSCLC）迷你口头专场摘要号：921MO英文标题：Phase 1 Global Study of Iza-Bren (BL-B01D1), an EGFR x HER3 Bispecific Antibody-drug Conjugate (ADC), in Patients with Metastatic or Unresectable Non-Small Cell Lung Cancer (NSCLC) and Other Solid Tumors中文标题：Iza-Bren（BL-B01D1，一种 EGFR×HER3 双特异性抗体偶联药物）在转移性或不可切除非小细胞肺癌及其他实体瘤患者中的Ⅰ期全球研究讲者：Helena A. Yu（美国）摘要号：1787MO英文标题：Updated results from the phase III ALINA study of adjuvant alectinib vs chemotherapy (chemo) in patients (pts) with early-stage ALK+ non-small cell lung cancer (NSCLC)中文标题：阿来替尼辅助治疗对比化疗治疗早期ALK阳性NSCLC患者的III期ALINA 研究更新结果讲者：Rafal Dziadziuszko（波兰）摘要号：1817MO英文标题：Molecular residual disease (MRD) analysis from the LAURA study of osimertinib (osi) in unresectable (UR) stage III EGFR-mutated (EGFRm) NSCLC中文标题：奥希替尼治疗不可切III期EGFR突变NSCLC的LAURA研究的微小残留病灶（MRD）分析讲者：Edurne Arriola Aperribay （西班牙）摘要号：1818MO英文标题：Surgery versus radiotherapy after induction therapy with serplulimab combined with chemotherapy for unresectable stage IIIB-IIIC non-small cell lung cancer: a randomized controlled, open-label, phase 2 trial中文标题：不可切除IIIB-IIIC期NSCLC接受斯鲁利单抗联合化疗诱导治疗后进行手术与放疗的比较：一项随机对照、开放标签、II 期试验讲者：Suyu Wang（上海市肺科医院）摘要号：1845MO英文标题：Prospective observational study of brigatinib after alectinib in ALK-positive, non-small cell lung cancer: efficacy and biomarker analyses from Cohort A of the WJOG11919L/ABRAID trial中文标题：阿来替尼治疗后布格替尼用于ALK 阳性非小细胞肺癌的前瞻性观察研究：WJOG11919L/ABRAID 试验A队列的疗效和生物标志物分析讲者：Yuichi Ozawa（日本）摘要号：1846MO英文标题：Intracranial efficacy of olomorasib, a second-generation KRAS G12C inhibitor, in patients with KRAS G12C-mutant NSCLC who have active, untreated brain metastases中文标题：第二代 KRAS G12C 抑制剂olomorasib对 KRAS G12C 突变型非小细胞肺癌（NSCLC）患者颅内疗效的研究讲者：Philippe Cassier（法国）摘要号：1847MO英文标题：Activity of Zipalertinib Against Active Central Nervous System (CNS) Metastases in Patients With Non-Small Cell Lung Cancer (NSCLC) Harboring EGFR Exon 20 Insertion (Ex20ins)/Other Uncommon Mutations中文标题：Zipalertinib对携带EGFR外显子20插入（ex 20ins）突变/其他非常见突变的NSCLC患者活动性中枢神经系统（CNS）转移的活性讲者：Kadoaki Ohashi（日本）摘要号：1848MO英文标题：Phase 2 Study of Firmonertinib in Patients with Previously Treated Advanced/Metastatic Non-Small Cell Lung Cancer (mNSCLC) with EGFR Exon 20 Insertion (Ex20ins) Mutations中文标题：Firmonertinib用于既往治疗过的携带 EGFR 外显子 20 插入突变的晚期 / 转移性非小细胞肺癌患者的 Ⅱ 期研究讲者：程颖教授（吉林省肿瘤医院）摘要号：1849MO英文标题：Updated overall survival analysis from the phase 2 PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC)中文标题：恩考芬尼联合binimetinib治疗BRAF V600E突变转移性非小细胞肺癌（mNSCLC）患者的2期PHAROS研究的更新总生存分析讲者：Melissa L. Johnson （美国）摘要号：1850MO英文标题：TeLuRide-005: Phase 2 Study of EIK1001, a Toll-Like Receptor 7/8 (TLR7/8) Co-Agonist with Pembrolizumab (pembro)+Chemotherapy (chemo) as First-Line (1L) Therapy in Stage 4 Non-Small Cell Lung Cancer (NSCLC)中文标题：TeLuRide-005：EIK1001（一种Toll样受体7/8[TLR7/8]协同激动剂）联合帕博利珠单抗（pembro）+化疗（chemo）作为4期非小细胞肺癌（NSCLC）一线（1L）治疗的2期研究讲者：Dan Costin（美国）摘要号：1851MO英文标题：Pembrolizumab plus chemotherapy (PEM + CT) versus pembrolizumab (PEM) as first-line therapy for advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50%: Open-label, phase 3, randomized trial (PAULIEN)中文标题：帕博利珠单抗联合化疗（PEM + CT）对比帕博利珠单抗（PEM）作为PD-L1 TPS≥50% 的晚期非小细胞肺癌一线治疗：开放标签、3 期、随机试验（PAULIEN）讲者：Ilias Houda （荷兰）摘要号：1852MO英文标题：KEYMAKER-U01 Substudy 01A: Investigational Agents + Pembrolizumab (Pembro) And Chemotherapy (Chemo) in Untreated Stage IV Non–Small-Cell Lung Cancer (NSCLC)中文标题：KEYMAKER-U01 子研究 01A：研究药物 + 帕博利珠单抗联合化疗用于初治 Ⅳ 期非小细胞肺癌讲者：Charu Aggarwal （美国）优选口头专场摘要号：1513O英文标题：Long-term follow-up GDFATHER-01 trial: GDF-15 neutralization combined with nivolumab can enable deep, long-term remission in heavily pretreated, anti-PD1/-L1 relapsed/refractory non-squamous non-small cell lung cancer (NSCLC), urothelial cancer (UC) and hepatocellular cancer (HCC)中文标题：GDFATHER-01研究长期随访：中和性抗GDF-15抗体联合纳武利尤单抗可使经多线抗PD-1/PD-L1治疗的复发/难治性非鳞状非小细胞肺癌、尿路上皮癌和肝细胞癌患者获得深度、长期缓解讲者：Ignacio Melero（西班牙）小细胞肺癌（SCLC）及其他迷你口头专场摘要号：922MO英文标题：Updated ongoing Phase I/II clinical trial results of AMT-116, a first-in-class anti-CD44v9 antibody-drug conjugate (ADC), in patients with advanced solid tumors中文标题：首创抗CD44v9抗体偶联药物AMT-116 治疗晚期实体瘤患者的Ⅰ/Ⅱ期临床研究更新结果讲者：宋正波教授（浙江省肿瘤医院）摘要号：1517MO英文标题：Emerging survival plateaus with botensilimab and balstilimab: Pan tumor data from a large phase 1b trial of advanced solid tumors中文标题： botensilimab与balstilimab出现生存平台期：一项大型1b期晚期实体瘤试验的泛肿瘤数据讲者：Michael Gordon（美国）摘要号：2758MO英文标题：Updated results from a phase 1/2 study of gocatamig for small cell lung cancer (SCLC) and other neuroendocrine cancers中文标题：Gocatamig 用于小细胞肺癌及其他神经内分泌肿瘤的 Ⅰ/Ⅱ 期研究更新结果讲者：Himisha Beltran（美国）摘要号：2759MO英文标题：DAREON®-8: a Phase I trial of first-line obrixtamig plus standard of care (SoC) in extensive-stage small cell lung carcinoma (ES-SCLC)中文标题：DAREON®-8：一线obrixtamig联合标准治疗（SoC）治疗广泛期小细胞肺癌（ES-SCLC）的I期试验讲者：Solange Peters（瑞士）摘要号：2760MO英文标题：Intracranial activity of ifinatamab deruxtecan (I-DXd) in patients (pts) with extensive-stage (ES) small cell lung cancer (SCLC) and baseline (BL) brain metastases (BM): Primary analysis of IDeate-Lung01中文标题：Ifinatamab deruxtecan（I-DXd）在广泛期（ES）小细胞肺癌（SCLC）且基线（BL）有脑转移（BM）患者中的颅内活性：IDeate-Lung01的主要分析讲者：Pedro F. Simoes da Rocha （西班牙）摘要号：2761MO英文标题：Chemo-immunotherapy followed by Durvalumab and Ceralasertib in treatment naive patients with extensive-stage small cell lung cancer中文标题：化疗联合免疫治疗后序贯Durvalumab和Ceralasertib用于初治广泛期小细胞肺癌患者讲者：Muhammad Furqan（美国）摘要号：2762MO英文标题：Patterns of disease progression (PD) and efficacy associated with tumour burden from the Phase 3 IMforte study of lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in ES-SCLC中文标题：芦比替定（lurbi）+阿替利珠单抗（atezo）作为一线（1L）维持治疗（tx）在广泛期小细胞肺癌（ES-SCLC）中的疾病进展（PD）模式及与肿瘤负荷相关的疗效：3期IMforte研究讲者：Luis Paz-Ares（西班牙）摘要号：2762MO英文标题：Patterns of disease progression (PD) and efficacy associated with tumour burden from the Phase 3 IMforte study of lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in ES-SCLC中文标题：芦比替定（lurbi）+阿替利珠单抗（atezo）作为一线（1L）维持治疗（tx）在广泛期小细胞肺癌（ES-SCLC）中的疾病进展（PD）模式及与肿瘤负荷相关的疗效：3期IMforte研究讲者：Luis Paz-Ares（西班牙）优选口头专场摘要号：2757O英文标题：Tarlatamab with first-line chemoimmunotherapy for extensive stage small cell lung cancer (ES-SCLC): DeLLphi-303 study中文标题：Tarlatamab联合一线化疗免疫疗法治疗广泛期小细胞肺癌（ES-SCLC）：DeLLphi-303研究讲者：Martin Wermke（德国）摘要号：108O英文标题：Thymic health is associated with immunotherapy outcomes in patients with cancer.中文标题：胸腺健康与癌症患者的免疫治疗结局相关讲者：Simon Bernatz（美国）摘要号：659O英文标题：Molecular diagnosis and management of leptomeningeal metastases with evolving therapeutic paradigm in advanced lung cancer中文标题：晚期肺癌软脑膜转移的分子诊断及治疗模式演变下的管理讲者：郑媚美教授（广东省人民医院）摘要号：914O英文标题：HRS-7058, a KRAS G12C inhibitor (G12Ci), in advanced solid tumors with KRAS G12C mutation: a phase 1, multi-center, first-in-human study中文标题：HRS-7058（一种 KRAS G12C 抑制剂）在携带 KRAS G12C 突变的晚期实体瘤患者中的 Ⅰ 期、多中心、首次人体研究讲者：黄鼎智教授（天津市肿瘤医院）摘要号：915O英文标题：KRAS G12D inhibitor HRS-4642 in patients with KRAS G12D-mutant advanced solid tumors: a phase 1 trial中文标题：KRAS G12D 抑制剂 HRS-4642 在 KRAS G12D 突变晚期实体瘤患者中的 Ⅰ 期试验讲者：周彩存教授（上海同济大学附属东方医院）摘要号：917O英文标题：DS-3939, a tumor-associated mucin 1 (TA-MUC1)–directed antibody–drug conjugate (ADC), in patients (pts) with advanced/metastatic (adv/met) solid tumors: Initial results from a first-in-human (FIH) study中文标题：DS-3939（一种靶向TA-MUC1的抗体偶联药物）在晚期 / 转移性实体瘤患者中的首次人体研究初步结果讲者：Manish R. Patel（美国）摘要号：1786O英文标题：External validation of AI for early-stage lung cancer recurrence prognosis using CT radiomics中文标题：使用 CT 放射组学对早期肺癌复发预测的人工智能进行外部验证讲者：Ann Valter（爱沙尼亚）排名不分先后，按照摘要类别划分；如有遗漏或任何问题，请后台留言（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。

抗体药物偶联物临床2期临床3期临床结果

2025-07-28

·BioArt

Cancer Cell | ATR抑制剂破局：KRAS突变肺癌免疫耐药新解

撰文 | 咸姐非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因之一，其中KRAS突变是最常见的致癌驱动事件之一。然而，KRAS突变肿瘤的异质性极高，其临床行为和治疗反应往往受到共突变基因的显著影响。KEAP1是肺腺癌（LUAD）中第三大常见的肿瘤抑制基因突变，常与KRAS突变共存，而STK11/LKB1的缺失也频繁出现在KRAS突变肿瘤中，三者共突变（KLK）形成一种高度侵袭性的分子亚型，这类患者的中位生存期显著缩短，且对免疫检查点抑制剂（ICB）和标准化疗的响应率极低，成为肺癌治疗领域的“硬骨头”【1】。KEAP1-NRF2通路是细胞抗氧化应激的核心调控轴，KEAP1突变会导致NRF2的持续激活，进而扰乱细胞氧化还原平衡，促进肿瘤存活并介导化疗耐药。STK11/LKB1作为肿瘤抑制基因，其缺失导致细胞周期失控、代谢重编程及免疫微环境抑制，同时与KEAP1/NRF2通路协同作用，进一步加剧肿瘤的恶性表型【2,3】。DNA损伤应答（DDR）是一个复杂的DNA修复网络，能够保护细胞DNA免受持续的内外源性损伤。共济失调毛细血管扩张症突变蛋白（ATM）和ATM与Rad3相关蛋白（ATR）是其中的两个关键组分，分别负责启动同源重组（HR）修复以应对DNA双链断裂和复制相关DNA损伤。基因组不稳定性是癌症的重要特征，许多肿瘤存在DDR通路缺陷，导致它们对DNA损伤更加敏感，并更依赖于剩余完整的DDR通路组分的功能。因此，抑制DDR蛋白已成为癌症治疗的一种重要策略【4】。近年来，DDR通路抑制剂，尤其是ATR抑制剂（ATRi），在癌症治疗中显示出潜力，ATRi可通过阻断CHK1激活，加剧DNA损伤，但其在KLK亚型肿瘤中的疗效及潜在机制尚未系统探索。近日，来自美国得克萨斯大学安德森癌症中心的John V. Heymach团队在Cancer Cell上在线发表了文章KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant non-small cell lung cancer，发现同时存在STK11/LKB1和KEAP1基因改变的KRAS突变型NSCLC对ATR-CHK1信号通路存在依赖性，对ATRi敏感性显著增强。当ATRi与吉西他滨（gemcitabine）化疗或ICB联用时，可进一步增强抗肿瘤活性，并有效逆转由这些基因改变导致的ICB耐药现象，其中联合使用ATRi ceralasertib和PD-L1抑制剂durvalumab的方案正在进行III期临床试验验证。这些发现提示，LKB1和KEAP1可作为预测性生物标志物，用于筛选可能对ATRi单药治疗、或与化疗/免疫治疗等联合方案产生应答的患者群体。本文研究人员首先利用20种人NSCLC细胞系筛选ATRi（Ceralasertib和Berzosertib）的敏感性，发现携带STK11/LKB1和/或KEAP1共突变的细胞对ATRi高度敏感，且IC50值显著低于野生型细胞，而LKB1 和/或 KEAP1 的突变与细胞周期检查点的失调以及细胞凋亡的异常有关，从而可能使得细胞对ATRi的敏感性更高。值得一提的是，在LKB1和KEAP1缺失的细胞中观察到的增强敏感性至少部分（但并非完全）取决于KRAS突变的存在，这与最近报道的临床数据相一致，这些数据表明STK11/LKB1和KEAP1突变对免疫治疗效果的影响会受到KRAS突变状态的影响。随后，研究人员利用CRISPR-Cas9 技术在Kras 突变型小鼠原代细胞系（LKR13，K）中构建LKB1、KEAP1单缺失及双缺失的同源细胞系（K、KL、KK、KLK），体外实验结果证实LKB1或KEAP1单独缺失即可增强ATRi的抗肿瘤效果，而KLK细胞的敏感性最高，表现为最低的IC50值、最明显的克隆形成能力抑制以及最显著的凋亡诱导。不过，LKB1和/或KEAP1的缺失对PARP或ATM抑制的敏感性则几乎没有影响。与此同时，研究人员评估了Ceralasertib在Kras突变型LKB1和/或KEAP1缺陷型同种异体小鼠模型以及患者来源的异种移植（PDX）模型中的抗肿瘤活性，与体外实验结果一致，KL或KK小鼠肿瘤对Ceralasertib的敏感性显著高于K肿瘤，表现为肿瘤生长抑制更明显、生存期延长；而KLK肿瘤对ATR抑制的敏感性最高，肿瘤体积缩小最显著，生存获益最大。进一步地，研究人员检测了ATR抑制后DNA损伤标志物（γ-H2AX、53BP1、RAD51）和ATR-CHK1通路激活状态，证实LKB1缺失导致基础DNA损伤增加，而KEAP1缺失则通过激活ATR-CHK1通路形成代偿性修复。而在KRAS突变小鼠模型（K、KL、KK、KLK）中观察到KLK细胞表现出最高的ATR通路活性和DNA损伤敏感性。对临床肺腺癌（LUAD）患者队列（ICON和TCGA）的蛋白组学分析显示，LKB1缺失肿瘤基础DNA损伤水平更高，KEAP1缺失肿瘤则呈现ATR-CHK1通路过度激活，二者协同增强对ATR抑制的依赖性。为了评估有效的联合治疗方法，研究人员探讨了其他遗传毒性药物如PARPi （olaparib）或临床可用的化疗是否可以增强ATR抑制的抗肿瘤作用。体外和体内实验均显示，STK11/LKB1和KEAP1突变时，PARP+ATR抑制不存在明显的协同效应，表明在这种情况下，ATR-CHK1 通路是更具治疗意义的DDR靶点。与之相反，化疗药物Gemcitabine与ATRi Ceralasertib联用可产生显著的协同效应，显著降低细胞活力并协同诱导DNA损伤（γ-H2AX升高、ATR-CHK1通路过度激活）。体内小鼠实验证实，LKB1 和 KEAP1 的缺失增强了对Gemcitabine的敏感性，且低剂量Gemcitabine与ATRi联合使用为 LKB1 和/或 KEAP1 缺陷型肿瘤提供了特异且强大的抗肿瘤活性，肿瘤退缩更明显、生存期进一步延长，野生型肿瘤则未显示协同效应。与此同时，研究人员在免疫治疗耐药的LKB1/KEAP1缺失小鼠模型（KL、KLK）中测试Ceralasertib联合抗PD-1抗体，发现Ceralasertib单药显著延长生存期，联合治疗则进一步提升中位生存期。此外，对已完成II期HUDSON试验的268例免疫治疗耐药NSCLC患者进行回顾性分析发现，其中72例携带STK11/KEAP1变异的患者接受Durvalumab+Ceralasertib治疗后，中位无进展生存期达6.0个月，显著优于其他联合方案，且总生存期呈现改善趋势。这些数据表明ATRi可能是一种有效的治疗手段，尤其对伴有或不伴有LKB1缺失的KEAP1缺陷型肿瘤。将ATRi与ICB联用，或可缓解KLK肿瘤中常见的免疫治疗耐药现象。此外，研究结果提示KRAS突变状态可能影响Ceralasertib的治疗获益程度。进一步地，研究人员通过FACS免疫表型分析发现，未经治疗的LKB1/KEAP1缺失小鼠肿瘤（KL/KLK）呈现典型的免疫冷肿瘤特征：CD8+和CD4+ T细胞浸润显著减少，抑制性髓系细胞比例升高，且抗原提呈细胞（APC）功能受损；经Ceralasertib单药或联合抗PD-1治疗后，肿瘤微环境发生显著重塑——CD8+ T细胞浸润增加、记忆T细胞扩增，髓系细胞向iNOS+抗肿瘤表型极化，同时STING-IFN信号通路激活。这些数据证明ATRi能够至少部分逆转由LKB1和KEAP1缺失导致的免疫抑制表型改变，而这些免疫微环境的改善很可能是Ceralasertib联合PD-(L)1抑制剂在PD-(L)1耐药肿瘤（特别是携带STK11和/或KEAP1基因改变的NSCLC）中发挥抗肿瘤作用的关键机制。综上所述，本研究揭示KRAS突变NSCLC中，STK11/LKB1和KEAP1共突变通过DNA损伤修复缺陷与ATR-CHK1通路代偿激活，形成对ATR抑制剂的合成致死敏感性。临床前模型证实，ATR抑制剂（如Ceralasertib）联合Gemcitabine或PD-1抗体，可显著抑制肿瘤生长并逆转免疫抑制微环境。HUDSON试验亚组分析进一步显示，此类患者接受ATR抑制剂联合免疫治疗后生存期明显延长。研究提出将LKB1/KEAP1缺失作为生物标志物，指导ATR抑制剂精准治疗，为免疫治疗耐药的KRAS突变肺癌提供了突破性策略。原文链接：https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00261-2制版人：十一参考文献1. Skoulidis, F., et al. (2015). Co-occurring Genomic Alterations Define Major Subsets of KRAS Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities. Cancer Discov. 5, 860–877.2. Sitthideatphaiboon, P., et al. (2021). STK11/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition. Clin. Cancer Res. 27, 1720–1733.3. Shorning, B.Y., and Clarke, A.R. (2016). Energy sensing and cancer: LKB1 function and lessons learnt from Peutz-Jeghers syndrome. Semin. Cell Dev. Biol. 52, 21–29.4. O’Connor, M.J. (2015). Targeting the DNA Damage Response in Cancer. Mol. Cell 60, 547–560.学术合作组织（*排名不分先后）战略合作伙伴（*排名不分先后）·转载须知【原创文章】BioArt原创文章，欢迎个人转发分享，未经允许禁止转载，所刊登的所有作品的著作权均为BioArt所拥有。BioArt保留所有法定权利，违者必究。BioArtMedPlants人才招聘近期直播推荐

免疫疗法临床3期

2025-07-14

·BioSpace

AstraZeneca’s Baxdrostat Pushes Blood Pressure Lower in Phase III Trial

iStock, HuiLiu The drug came to AstraZeneca through its acquisition of CinCor Pharma in 2023, with the hopes of beefing up its cardiovascular and kidney disease pipelines. AstraZeneca’s $1.3 billion gamble on CinCor may be paying off, after baxdrostat, an aldosterone synthase inhibitor it got in the deal, achieved a “statistically significant and clinically meaningful” drop in blood pressure in a late-stage trial, according to a company press release Monday. The results are from the Phase III BaxHTN trial, comparing patients with uncontrolled or treatment-resistant hypertension on two different doses—1 mg or 2 mg—to patients who received placebo. All patients either received baxdrostat or placebo on top of standard of care. AstraZeneca originally took on baxdrostat via the $1.3 billion acquisition of CinCor Pharma in 2023 . The deal also involved regulatory milestones involving baxdrostat that could kick the total value up to $1.8 billion—a gamble for shareholders as baxdrostat had flunked a previous Phase II trial run by CinCor after failing to reduce blood pressure in patients with uncontrolled hypertension. Data from a subgroup, however, kept hopes alive that the drug could address the condition. AstraZeneca did not go into specific details of the results, only saying that both doses met the primary endpoint, which was the difference in seated systolic blood pressure (SBP) after 12 weeks. The trial also met secondary endpoints in specific patient subpopulations and other measures of hypertension. AstraZeneca said that the drug was “generally well tolerated with a favorable safety profile.” AstraZeneca plans to reveal more details at the European Society of Cardiology Congress in August 2025. Baxdrostat works by blocking aldosterone synthase, a protein responsible for synthesizing aldosterone, a steroid involved in sodium retention and maintaining homeostatic blood pressure in the body. AstraZeneca is also testing baxdrostat in a Phase III trial in combination with dapagliflozin for treating chronic kidney disease progression in patients with both kidney disease and high blood pressure. Baxdrostat is part of a spate of drugs that AstraZeneca is hoping will help the company hit $80 billion in revenue by 2030, according to analysts at Leerink Partners, writing in a note to investors in April. Those also include ceralasertib, currently in a Phase I trial for solid tumors; gefurulimab for treating myasthenia gravis; and efzimfotase alfa, currently in Phase III trials for hypophosphatasia.

临床3期临床结果临床2期并购临床1期

100 项与 Ceralasertib 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D11787	-	-	DB14917

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期非小细胞肺癌	临床3期	美国	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	中国	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	日本	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	阿根廷	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	澳大利亚	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	比利时	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	巴西	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	加拿大	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	法国	AstraZeneca PLC	2022-09-15
晚期非小细胞肺癌	临床3期	德国	AstraZeneca PLC	2022-09-15

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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


NCT05061134 (MONETTE, CTgov)	临床2期	局部晚期黑色素瘤	194	Durvalumab+Ceralasertib	蓋選夢遞衊範襯積餘醖 = 願鹹鹹糧積簾構鏇壓膚膚齋簾壓網築築構醖壓 (鏇襯遞窪觸鏇鹽獵鑰淵, 鏇蓋範鏇獵糧遞膚糧鏇 ~ 鬱廠衊壓鑰齋積鑰鹽簾) 更多	-	2025-05-21
ASH2024	N/A	慢性粒单核细胞白血病 \| 骨髓增生异常综合征	-	Ceralasertib 160mg BID 7on/7off	壓顧簾鏇襯鏇構繭憲醖(衊齋選構獵築餘壓襯顧) = n=1, grade 3 or higher AEs with 7on/7off dosing 願遞齋艱齋憲蓋衊膚鑰 (蓋壓餘築鹹鏇願齋遞膚 ) 更多	-	2024-12-07
				Ceralasertib 160mg BID 14on/14off
NCT03787680 (CTgov)	临床2期	转移性去势抵抗性前列腺癌	49	Olaparib+AZD6738 (Cohort 1 (DRPro))	鏇選顧蓋顧壓鏇遞齋夢 = 憲餘構繭壓鏇醖鬱艱繭簾積壓窪鹽蓋衊選構製 (醖範糧鹹蓋構鏇鬱製齋, 夢構構糧遞窪構鏇製製 ~ 鑰簾餘窪鏇鹹淵鑰鏇襯) 更多	-	2024-08-12
				Olaparib+AZD6738 (Cohort 2 (DRDef))	膚積醖艱簾夢觸齋願遞(繭鏇鬱積餘糧夢鹽齋衊) = 齋餘襯憲遞選餘膚鬱築築艱醖觸獵齋壓願艱憲 (艱窪壓選獵構夢願壓積, 製積餘鬱餘觸衊衊蓋築 ~ 鹽艱築襯遞淵鹽憲餘鏇) 更多
NCT04564027 (PLANETTE, CTgov)	临床2期	晚期恶性实体瘤 \| 晚期癌症	54	Ceralasertib (Cohort A (aST): 160 mg of Ceralasertib)	願鹽鑰獵網齋遞醖鑰鑰 = 餘遞遞壓顧獵夢鹹淵鬱製築廠繭遞憲艱膚糧衊 (壓遞範艱艱鏇衊網構壓, 廠糧構繭憲衊願膚艱願 ~ 齋簾醖網餘壓鏇製襯艱) 更多	-	2024-06-25
				Ceralasertib (Cohort B (mCRPC): 160 mg of Ceralasertib)	壓廠鹹鬱遞網鹹糧鏇簾 = 窪範蓋蓋網蓋醖鹽艱蓋鏇窪範繭選鑰鹽糧襯壓 (鹹獵憲膚蓋膚憲衊鹹憲, 鏇鹽願衊鏇鏇艱壓齋鹽 ~ 遞鬱鹽鏇壓憲範淵鹽鑰) 更多
NCT03462342 (CAPRI, ASCO2024)	临床2期	铂敏感性卵巢上皮癌 genomic instability \| HRD positive \| LOH	37	Ceralasertib 160mg	鬱艱獵襯鏇鹹壓蓋繭選(繭蓋襯遞範築鑰獵蓋顧) = 網網蓋蓋獵獵壓窪衊範窪窪構築淵願壓鬱顧顧 (鏇網鹽構鏇選餘壓構醖 ) 更多	积极	2024-05-24
NCT04564027 (PLANETTE, AACR2024) 人工标引	临床2期	实体瘤 \| 转移性去势抵抗性前列腺癌 ATM	45	Ceralasertib 160 mg BIDCeralasertib 160 mg BID	鹹齋顧簾選鹽蓋窪範獵(壓餘觸範憲衊夢齋築艱) = 憲醖願築膚觸醖築膚齋繭鏇艱鏇鏇蓋襯齋網獵 (艱築範糧積鬱顧遞鑰選, 1.9 ~ 17.9) 更多	不佳	2024-04-05
				Ceralasertib (mCRPC)	鹹齋顧簾選鹽蓋窪範獵(壓餘觸範憲衊夢齋築艱) = 窪構艱顧鬱鹹積顧製壓繭鏇艱鏇鏇蓋襯齋網獵 (艱築範糧積鬱顧遞鑰選, 0.8 ~ 26.8) 更多
NCT03334617 (HUDSON, Pubmed) 人工标引	临床2期	晚期非小细胞肺癌 PD-L1 Expression	268	Durvalumab-ceralasertib	淵餘糧鏇廠窪糧構夢積(簾鏇艱蓋膚選夢鏇憲範) = 糧製齋選鑰廠構鑰窪鹹鏇製鹹範鏇糧窪壓夢遞 (壓鹽製積窪鹽淵蓋構膚 ) 更多	积极	2024-03-01
				Durvalumab-olaparibdanvatirsenoleclumab	淵餘糧鏇廠窪糧構夢積(簾鏇艱蓋膚選夢鏇憲範) = 淵顧顧膚鹽廠遞壓齋遞鏇製鹹範鏇糧窪壓夢遞 (壓鹽製積窪鹽淵蓋構膚 ) 更多
NCT02223923 (PATRIOT, Pubmed) 人工标引	临床1期	难治恶性实体肿瘤 Gene \| ARID1A Positive	67	Ceralasertib 20-240 mg BD	醖鹹遞願壓構糧積範範(築獵膚遞選網廠夢獵鏇) = 鬱鑰築醖構構構顧齋淵網簾夢積鏇憲鹽鹹觸築 (廠鹽蓋蓋蓋襯鏇窪壓鹽 ) 更多	积极	2024-01-16
NCT02664935 (WCLC2023) 人工标引	临床2期	晚期非小细胞肺癌 RAS Mutations	31	Ceralasertib+Durvalumab (KRASmut patients received previous ICB)	繭壓憲淵壓獵築膚遞夢(醖網鬱範願網糧窪憲觸) = 鬱顧觸觸網餘窪蓋廠鹽製簾觸簾鬱鹽鏇觸鹹鹽 (壓製積鏇鬱蓋蓋築衊淵 ) 更多	积极	2023-09-10
				Ceralasertib+Durvalumab (ICB exposed KRAS wild-type patients)	繭壓憲淵壓獵築膚遞夢(醖網鬱範願網糧窪憲觸) = 觸選廠膚窪顧糧鑰鹽顧製簾觸簾鬱鹽鏇觸鹹鹽 (壓製積鏇鬱蓋蓋築衊淵 ) 更多
NCT05450692 (LATIFY, ASCO2023)	临床3期	转移性非小细胞肺癌 \| 局部晚期非小细胞肺癌二线 \| 三线	580	Ceralasertib + Durvalumab	築鬱簾範襯鑰蓋襯餘鏇(襯繭艱鹹廠蓋繭獵構艱) = 鏇繭艱鏇憲簾築淵齋顧窪壓製獵觸遞顧膚範廠 (醖鹽願廠鹹艱積夢膚構, 14.1–20.3) 更多	-	2023-05-31