Clinical Cancer Research最新文献

{"title":"Quantitative Protein Expression of Antibody-Drug Conjugate Targets in EGFR Mutated and Wild-type Non-Small Cell Lung Cancer.","authors":"Ioannis P Trontzas, Mengni He, Anna Wurtz, Charles J Robbins, Nathaniel Robinson, Katherine Bates, Matthew Liu, Thazin N Aung, Liam Scott, Nay Chan, Sneha Burela, Jacob Schillo, Daniel C Liebler, Salisha Hill, Ryan D Morrison, Ioannis Vathiotis, Konstantinos N Syrigos, Sarah B Goldberg, Katerina Politi, David L Rimm","doi":"10.1158/1078-0432.CCR-24-3347","DOIUrl":"10.1158/1078-0432.CCR-24-3347","url":null,"abstract":"<p><strong>Purpose: </strong>Antibody-drug conjugates (ADC) are a promising approach for the management of patients with non-small cell lung cancer (NSCLC). However, only a small subset of patients derive benefit from these therapies.</p><p><strong>Experimental design: </strong>We used quantitative immunofluorescence assays to measure the levels of four ADC target proteins (HER2, TROP2, HER3, and EGFR) in three NSCLC tissue microarray cohorts stratified according to EGFR mutation [EGFR mutated (n = 83), EGFR wild-type (n = 128), and EGFR unknown (n = 232)]. Assay limits were established by mass spectrometry on standard cell lines.</p><p><strong>Results: </strong>All four targets demonstrated a broad and comparable dynamic range of expression in all three cohorts. High proportions of cases were above the assay limits for all targets. A comparison of target expression showed a significant association of HER2 with EGFR expression and a nonsignificant association with EGFR mutation (P = 0.0005 and 0.14, respectively). TROP2 expression was not associated with EGFR expression or mutation. HER3 demonstrated a significant negative correlation with EGFR mutation but no significant association with EGFR expression (P < 0.0001 and 0.9869, respectively). EGFR expression was significantly associated with EGFR mutation (P = 0.047).</p><p><strong>Conclusions: </strong>ADC targets are highly expressed in NSCLC, implying that the benefit from these agents may be broad. Benefit from these therapies may go beyond mutation status, and fully quantitative approaches may help select patients for ADC targeting. Intertarget correlation may provide an insight on the underlying signaling pathways and/or treatment-related resistant mechanisms. In the future, quantitative immunofluorescence may be a valuable tool to select ADC treatment sequence. See related commentary by Hirsch, p. 2550.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2767-2776"},"PeriodicalIF":10.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12213210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity.","authors":"Timothy A Yap,Mike I Walton,Kyla M Grimshaw,Robert H Te Poele,Paul D Eve,Melanie R Valenti,Alexis K de Haven Brandon,Vanessa Martins,Anna Zetterlund,Simon P Heaton,Kathrin Heinzmann,Paul S Jones,Ruth E Feltell,Matthias Reule,Steven J Woodhead,Thomas G Davies,John F Lyons,Florence I Raynaud,Suzanne A Eccles,Paul Workman,Neil T Thompson,Michelle D Garrett","doi":"10.1158/1078-0432.ccr-25-1021","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1021","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":"2840"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and validation of an ancillary genomic test of malignancy for primary melanocytic tumors","authors":"Ismael A. Vergara, Nigel G. Maher, Alison J. Potter, Elizabeth C. Paver, Jordan W. Conway, Serigne N. Lo, Andrew J. Colebatch, Georgina V. Long, James S. Wilmott, Richard A. Scolyer","doi":"10.1158/1078-0432.ccr-24-1902","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1902","url":null,"abstract":"Purpose: Pathological diagnosis of melanocytic tumors can be difficult and prone to error. More accurate ancillary tools are needed. We present a genomic model for distinguishing benign (nevi) from malignant (melanoma) melanocytic skin tumors. Experimental Design: A DNA-based gene panel was evaluated on 250 nevi and melanomas split into discovery and validation sets. Mutational loads were calculated and a logistic regression model was developed and validated. An independent cohort of 110 borderline melanocytic tumors was analyzed against pathology-based tiers of malignancy and likely pathways of origin. Results: Combining non-BRAF/non-NRAS coding mutational load and non-coding mutational load, we obtained an area under the curve of 95% in the discovery and 96% in the validation cohort. Using a Youden index threshold, the resulting classifier demonstrated &amp;gt;95% specificity and &amp;gt;80% sensitivity in the discovery and validation cohorts. In the cohort of 110 borderline melanocytic tumors, we identified key driver mutations in agreement with the likely pathway of origin. Non-coding mutational load (p=0.02) and melanoma probability (p=0.02) from the genomic model were significantly associated with malignancy estimates in borderline tumors lacking pathway-defining genomic aberrations (conventional tumors). The genomic model estimated a high probability of melanoma in 8/36 (22%) conventional tumors with indeterminate malignancy, with 7/8 showing negative/non-aberrant results on other ancillary diagnostic tests. No malignant behavior based on the genomic model was seen in 4 conventional borderline tumors with &amp;gt;1 year follow-up. Conclusions: This genomic model can become a clinically useful ancillary tool that is highly specific for differentiating melanomas from nevi.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"25 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A First-in-Human Study of Givastomig, a CLDN18.2 and 4-1BB Bispecific Antibody, as Monotherapy in Patients with CLDN18.2-Positive Advanced or Metastatic Solid Tumors","authors":"Geoffrey Ku, Lin Shen, Farshid Dayyani, Jeremy Kratz, Xinjun Liang, Funan Liu, Zhenning Wang, Laura Feller, Eugenia Girda, Hongming Pan, Sunnie Kim, Yanhong Deng, Ting Deng, Tianshu Liu, John Powderly, Kristen Spencer, Reva Schneider, Jordan Berlin, Claire (Cong) Xu, Christoph M. Ahlers, Xuejun Liu, Jou-Ku Chung, Peter Sabbatini, Jinyoung Park, Yangmi Lim, Juyeun Jeon, Yuan Meng, Samuel J. Klempner","doi":"10.1158/1078-0432.ccr-24-4280","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4280","url":null,"abstract":"Purpose: Givastomig is a bispecific antibody that targets CLDN18.2 and conditionally activates local 4-1BB–expressing T cells. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of givastomig in advanced solid tumors. Patients and Methods: 75 patients were enrolled. Escalating givastomig doses of 0.1-18 mg/kg were evaluated in 36 patients with metastatic or advanced solid tumors. An additional 6 patients per cohort with CLDN18.2-positive (defined as membrane intensity score of ≥1+ on ≥1% of tumor cells), advanced or metastatic gastroesophageal carcinoma (GEC) were treated with 5-15 mg/kg givastomig across four cohorts. Fifteen patients with CLDN18.2-positive GEC were then enrolled to the 12 mg/kg dose expansion cohort. Results: No dose-limiting toxicities were reported up to 18 mg/kg, and a maximum tolerated dose was not reached. The most common treatment ‑related adverse events (in ≥10% of patients) were nausea, anemia, fatigue, white blood cell count decrease, vomiting, and increased alanine aminotransferase. Givastomig exposure increased dose proportionally, and soluble 4‑1BB approached a plateau above 5 mg/kg. The 12 mg/kg dose was selected for dose expansion. A 16% objective response rate (ORR) was observed in CLDN18.2-positive GEC above 5 mg/kg (N = 43). CLDN18.2 expression in responders ranged from 11% to 100%. Conclusions: Givastomig demonstrated manageable safety, dose-proportional exposure, and antitumor activity in patients with advanced solid tumors, particularly in CLDN18.2-positive GEC. A givastomig dose range of 5 to 12 mg/kg was chosen to combine with nivolumab and chemotherapy in part 2 of the study in frontline metastatic GEC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IND-Enabling Studies for a TCR-T targeting a pancreatic cancer G12V KRAS mutation","authors":"Sizhen Wang, Guangjie Yu, Yanzhenzi Dai, Chi Gan, Shuyi Qiu, Xiaohui Zhang, Xiaochun Jiang, Ran Wei, Jiongming Yang, Dou Wu, Ling Chen, Lei Huang, Min Li, Yi Xiao, Rongxi Shen, Yimin Chen, Daojun Zhu, Anlong Yao, Yonghao Ouyang, Zhufeng Sun, Xinbo Wang, Hong-Ming Hu","doi":"10.1158/1078-0432.ccr-24-3086","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3086","url":null,"abstract":"Purpose: To develop adoptive T-cell therapy with genetically engineered TCR (TCR-T) that recognizes the KRAS G12V mutation, we performed an IND-enabling preclinical study of a new TCR (051). This TCR was isolated from a pancreatic ductal adenocarcinoma (PDAC) patient carrying the KRAS G12V mutation that could be presented by the HLA-A*11:01 allele, the most common allele of the Chinese population. Experimental Design: In vitro experiments using T cells from health donors transduced with a retroviral vector expressing 051 TCR were performed to determine the TCR specificity and functionality. The tumor reactivity strictly depended on the expression of the G12V mutation and HLA-A*11:01 molecules. The alanine scan experiment did not detect potential “off-target” cross-reactivity against the human genome. Good Laboratory Practice (GLP) studies are carried out to assess the antitumor efficacy, persistence, safety, and toxicities of adoptively transferred human 051 TCR-T cells (IX001) in immunodeficient mice bearing human pancreatic cancer xenografts. Results: After T-cell infusion, a potent antitumor effect was observed with or without IL-2 administration. The analysis of TCR gene integration in host T cells by retrovirus indicated a low risk of developing secondary malignancy. There was no evidence of TCR-T-related toxicity and genotoxicity induced by the retroviral vector. Conclusions: IX001 was safe and highly efficacious in a pancreatic cancer CDX model. Our data support further clinical development of IX001 for HLA-A*11:01 patients with the G12V KRAS mutation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"67 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B7-H3 CAR T-cells are effective against ependymomas, but limited by tumor size and immune response","authors":"Sanya Mehta, Siri Ippagunta, Srinidhi Varadharajan, Alisha Kardian, Nic Laboe, Diana Dinh, Amber B. Jones, Michaela M. Meehl, Jorge Ibañez, Erik Emanus, Tram Dao, Meghan B. Ward, Wilda Orisme, Shannon Lange, Deanna Langfitt, Jeffrey Steinberg, Jason Chiang, Peter Vogel, Heather Sheppard, David W. Ellison, Stephen C. Mack, Giedre Krenciute","doi":"10.1158/1078-0432.ccr-24-3083","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3083","url":null,"abstract":"Purpose: Targeted treatments are desperately needed for ependymomas (EPNs). Chimeric antigen receptor (CAR) T-cells have immense potential to transform patient outcomes. However, CAR T-cell therapy for EPN has been largely understudied. Here, we explore the potential of targeting B7 homolog 3 (B7-H3/CD276) with CAR T-cells to treat pediatric EPN. Experimental Design: We profiled B7-H3 protein expression in 44 pediatric EPN samples by immunohistochemistry. We generated second generation human B7-H3.CAR T-cells and examined their anti-EPN activity in six in vitro and two in vivo xenograft models. We validated findings using HER2-targeted CAR T-cells. In addition, we used murine B7-H3.CAR T-cells to evaluate in vivo antitumor activity in a fully syngeneic supratentorial EPN model. Results: Majority of clinical EPN samples (29/44) stained positive for B7-H3, indicating high but heterogenous expression across patients. In vitro, human B7-H3.CAR T-cells had potent anti-EPN cytolytic activity, expansion, and persistence, which was inversely correlated with upregulation of B7-H3 on CAR T-cells. We found that CAR T-cells favor Th2 phenotypes after repeated exposure to EPN cell lines which may be driven by CCL2 secretion by EPN. In vivo, there was potent and significant antitumor activity in human xenograft EPN models. However, response durability was limited and significantly correlated with degree of tumor burden. In the syngeneic setting, murine B7-H3.CAR T-cell efficacy against EPN was limited and did not extend survival. Conclusions: Our results support ongoing clinical evaluation of B7-H3.CAR T-cells for EPNs and provide model systems for further studying determinants of anti-EPN CAR T-cell treatment efficacy and resistance.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"12 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of Germline Predisposition to Pediatric Thyroid Cancer","authors":"Claudia Harrison, Alise K. Blake, Yin Su, Li Tang, Ninad Oak, Lynn Harrison, Regina Nuccio, Rose B. McGee, Lilyanne Grieve, Arti S. Pandey, Leslie M. Taylor, Manish Kubal, Stacy J. Hines-Dowell, Anthony Sheyn, Zachary Abramson, Melissa Perrino, Sara Federico, Alberto Pappo, Sara Helmig, Kim E. Nichols","doi":"10.1158/1078-0432.ccr-25-0631","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0631","url":null,"abstract":"Purpose: Pediatric thyroid carcinoma is a rare cancer for which germline genetic factors remain incompletely understood. To gain further insight, we examined the prevalence and spectrum of pathogenic variants (PV) in cancer predisposing genes (CPG) in a large cohort of children with thyroid carcinoma at our institution. Experimental Design: This retrospective study included 71 children who presented with thyroid carcinoma as a first (n=52) or subsequent malignant neoplasm (n=19) and underwent germline testing. The objectives were to determine the proportion of patients harboring PV and correlate germline information with clinical features, tumor pathology, and outcome. Results: Eighteen patients (25%; 7 primary and 11 subsequent malignant neoplasm) harbored a PV affecting a CPG. Four of these patients had medullary thyroid carcinoma, while 14 had non-medullary thyroid carcinoma. Children diagnosed with thyroid carcinoma before 11 years of age were significantly more likely to harbor PV (p&amp;lt;0.01), as were children with medullary histology tumors (p&amp;lt;0.05) or a prior cancer history (p&amp;lt;0.001). Both RB1-associated thyroid carcinomas occurred in children who never received prior chemo- or radiation therapy. Seventeen patients remain alive at a median of 3 years since diagnosis (1 month–27 years). Twelve of 18 patients with PV were treated only with thyroidectomy, while six required radioactive iodine or chemotherapy. One patient with MEN2 expired. Conclusions: A substantial proportion of children with thyroid carcinoma harbor a CPG PV. Accordingly, genetic counseling and testing should be considered for all affected children, especially those who are young, have medullary thyroid carcinoma, or a prior cancer history.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FDA Approval Summary: Axatilimab for Adult and Pediatric Patients Weighing at Least 40 Kilograms with Chronic GVHD after Two Prior Lines of Systemic Therapy","authors":"Robert Q. Le, Kamar Godder, Jingyan Wang, Justin S. Collazo, Robyn Konicki, Moran Choe, Monica Feng, Donna Przepiorka, Jonathon Vallejo, Ankit Shah, Jiang Liu, Brenda J. Gehrke, Willie Wilson, Andrea Siegel, Yun Wu, Charles Yuan-Chia Kuo, Melissa Ray, Richard Pazdur, Marc R. Theoret, R. Angelo de Claro","doi":"10.1158/1078-0432.ccr-25-0896","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0896","url":null,"abstract":"On August 14, 2024, the Food and Drug Administration (FDA) approved axatilimab, a colony stimulating factor-1 receptor (CSF-1R)-blocking antibody, for chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy in adult and pediatric patients weighing at least 40 kilograms (kg). Approval was based on the results of the AGAVE-201 Study (NCT04710576), which included a cohort of 79 patients with chronic GVHD treated with axatilimab 0.3 mg/kg administered intravenously every 2 weeks in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) and partial response (PR) according to the 2014 NIH consensus criteria, and the durability of response. The ORR through Cycle 7 Day 1 was 75% (95% CI 64, 84); all responses were PR. The median duration of response was 1.9 months (95% CI: 1.6, 3.5), but 60% (95% CI: 43, 74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions included infection, increased transaminases, decreased phosphate, decreased hemoglobin, musculoskeletal pain, increased lipase, fatigue, increased amylase, increased calcium, increased creatine phosphokinase, increased alkaline phosphatase, nausea, headache, diarrhea, cough, fever, and dyspnea. FDA issued a postmarket requirement to evaluate safety with long-term use.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"643 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical implications and application of molecular testing in the diagnosis and management of thyroid nodules in the Chinese population","authors":"Min Ding, Gaosong Wu, Songtao Zhang, Rongli XIE, Jianming Yuan, Guohui Xiao, Xiaoyue Zhang, Jiaqi Dai, Jian Chen, Sanming Wang, Rui Zhou, Xingchen Li, Jiuzhou Zhao, Fangzheng Ning, Zeyu Wu, Zhiqiang Yin, Jian Fei","doi":"10.1158/1078-0432.ccr-25-0270","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0270","url":null,"abstract":"Purpose: Ultrasound-guided fine-needle aspiration (FNA) biopsy is the gold standard for diagnosing thyroid cancer (TC), but 20%-35% of nodules remain cytologically indeterminate. This study evaluated the value of molecular testing in diagnosing TC and its preoperative risk stratification in the Chinese population. Experimental Design: This multicenter observational study included patients with thyroid nodules admitted to five research centers from January 2021 to June 2023. All samples underwent molecular testing using quantitative polymerase chain reaction (qPCR) or next-generation sequencing (NGS). The study assessed genetic variations in nodules and the diagnostic performance of each test, using stepwise multivariable logistic regression to explore factors affecting lymph node metastases (LNM) and tumor stage. Results: A total of 1984 patients with 2027 thyroid nodules were analyzed. The most common genetic alteration detected was BRAF V600E, followed by TERT promoter and CCDC6-RET fusion. For Bethesda categories II and VI, molecular tests combined with cytology significantly enhanced diagnostic performance, yielding Youden Index values of 0.97 for PCR-8 genes and 0.94 for NGS-28 genes. In cytologically indeterminate nodules, PCR-3 genes and NGS-8 genes exhibited 85% sensitivity and 100% specificity. Independent risk factors for LNM included age (OR=0.97), male sex (OR=1.45), higher TI-RADS grading (OR=1.50), larger tumor size (OR=1.13), and multifocal nodules (OR=1.60). Combined mutations in the 8-gene (OR=6.43) were significant for the advanced tumor stage. Conclusion: Molecular testing substantially improves diagnostic accuracy when integrated with cytology, facilitating the diagnosis of cytologically indeterminate nodules and offering prognostic insights for TC patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"56 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ipatasertib in Patients with Tumors with AKT Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol Z1K","authors":"Carolyn K. McCourt, Zihan Wei, Kevin Kalinsky, Robert Gray, Victoria Wang, Lisa M. McShane, Larry V. Rubinstein, David R. Patton, P. Mickey Williams, Stanley R. Hamilton, Jeremy Force, Anuradha Pakanati, James V. Tricoli, Barbara A. Conley, Carlos Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty","doi":"10.1158/1078-0432.ccr-24-3431","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3431","url":null,"abstract":"Purpose: Activating mutations in AKT genes are rare but play an important role in the commonly dysregulated PI3K/AKT/mTOR signaling pathway. NCI-MATCH (EAY131) is a tumor agnostic platform trial that enrolled patients to targeted therapies based on matching tumor genomic alterations. Subprotocol Z1K evaluated ipatasertib, a pan-AKT inhibitor, in patients with AKT1E17K mutant metastatic tumors. Methods: Patients received ipatasertib 400mg, orally once daily in a 28-day cycle until progression or unacceptable toxicity. Patients with known KRAS, NRAS, HRAS, or BRAF mutations were excluded. Prior PI3K and mTOR inhibitors were allowed. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and toxicity. Results: Thirty-five patients were enrolled, and 29 patients were included in the prespecified primary efficacy analysis. Multiple histologies were enrolled, with breast (n = 18) and gynecologic (n = 7) being the most common. The majority had &amp;gt; 3 lines of therapy (19/29, 65.5%). The ORR was 24.1% (7/29, 90% CI, 11.9%-40.6%) with P &amp;lt; 0.001 against a null rate of 5%. All responses were partial responses. Median response duration was 10.1 months (90% CI, 3.7-10.8). The most common toxicities of any grade included diarrhea (n = 25), nausea (n = 13), and hyperglycemia (n = 9). Grade 3/4 toxicities observed were consistent with reported toxicities for AKT inhibition. Twelve grade 3 events occurred that were thought to be at least possibly related to treatment. Conclusions: The study met its primary endpoint with ipatasertib demonstrating clinically significant activity in heavily pretreated patients with various tumors harboring AKT1E17K mutations.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}