Clinical Cancer Research最新文献

{"title":"Single-cell transcriptomic landscape deciphers intratumoral heterogeneity and subtypes of acral and mucosal melanoma.","authors":"Yunyan Li, Ziyang Cui, Xiaole Song, Yeqing Chen, Cang Li, Junfeng Shi, Wenkang Qian, Guoxin Ren, Jiang Zhou, Chunpu Li, Xiaoqing Ma, Yifan Chen, Dongdong Jia, Yongli Zhang, Zhilin Zhang, Ronghao Zhang, Zhaotian Zhang, Yong Chen, Zhixiang Xu, Wantao Chen, Xiao Miao, Hongmeng Yu, Jianxin Chen, Kai Wang, Colin R Goding, Zhi Wei, Tao Li, Rutao Cui","doi":"10.1158/1078-0432.CCR-24-3164","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3164","url":null,"abstract":"<p><strong>Purpose: </strong>To identify the specific intratumoral and microenvironmental heterogeneity of acral (AM) and mucosal melanoma (MM), we aimed to delineate their distinct cellular compositions, evolutionary trajectories, and subtype-specific therapeutic strategies.</p><p><strong>Experimental design: </strong>Single-cell transcriptomic and genomic landscapes were analyzed across 42 melanoma samples (28 AM, 11 MM, and 3 non-acral cutaneous melanoma [CM]), supplemented by in vitro and in vivo validation. Tumor and stromal cells were profiled using scRNA-seq, whole-exome sequencing, and functional assays, including transwell migration, co-culture systems, and xenograft models.</p><p><strong>Results: </strong>Tumor cells exhibited divergent evolutionary routes, with MM dominated by MGP⁺/PCOLCE⁺ subpopulations showing high epithelial-to-mesenchymal transition (EMT) potential. MM displayed elevated neutrophil infiltration and CXCL3⁺ tumor-associated macrophages, while AM was enriched with PI16⁺ cancer-associated fibroblasts (CAFs) promoting tumor proliferation. Molecular classification revealed MM subtypes: an antigen-presenting subtype linked to favorable outcomes and a proliferative subtype associated with recurrence. TIGIT⁺ Treg cells were enriched in AM, suggesting targeted inhibition potential. Genomic analysis connected BRAF/NRAS mutations to ALDOA⁺ stem-like tumor cells and identified PTGDS as a therapeutic target in triple-WT melanomas.</p><p><strong>Conclusions: </strong>Our study provides a comprehensive comparison of AM and MM, uncovering subtype-specific stromal-immune interactions and molecular programs. The findings highlight actionable targets (e.g., TIGIT in AM, CXCL3⁺ macrophages in MM) and propose a framework for precision therapies, biomarker-driven trials, and risk stratification to improve outcomes in these aggressive melanomas.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794840","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":"Comparing durvalumab, olaparib, and cediranib monotherapy, combination therapy, or chemotherapy in patients with platinum-resistant ovarian cancer with prior bevacizumab: the phase II NRG-GY023 trial.","authors":"Jung-Min Lee, Austin Miller, Peter G Rose, Mariam AlHilli, Christina Washington, Veena S John, Chirag A Shah, Koji Matsuo, Jean Siedel, David S Miller, Elizabeth E Hopp, Andrea O'Shea, John K Chan, Leslie S Bradford, Christopher B Morse, Christa I Nagel, Kerry J Rodabaugh, Elise C Kohn, Kathleen N Moore, Joyce F Liu","doi":"10.1158/1078-0432.CCR-24-3877","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3877","url":null,"abstract":"<p><strong>Purpose: </strong>We assessed the efficacy of anti-PD-L1 durvalumab in combination with olaparib and cediranib (DOC), compared to the standard-of-care chemotherapy (SOC) in platinum-resistant epithelial ovarian cancer (PROC) patients, with prior bevacizumab.</p><p><strong>Patients and methods: </strong>NRG-GY023 was the first, randomized 4-arm superiority phase II trial enrolling high-grade serous/endometrioid or clear cell PROC patients with prior bevacizumab exposure. Patients were randomized 1:2:2:2 to SOC (weekly paclitaxel, topotecan or pegylated liposomal doxorubicin), DOC, durvalumab+cediranib (DC), or olaparib+cediranib (OC). The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. The design had 80% power to detect a hazard ratio (HR) of 0.5 using a one-sided, ⍺=0.1 level test for each comparison to the SOC with a pre-planned interim analysis. Experimental arms with HR estimate (vs SOC)>0.87 could be discontinued.</p><p><strong>Results: </strong>153 patients were enrolled between 4/28/2021, and 2/1/2023. Accrual was permanently closed on 2/1/2023, due to futility. With a data cut-off of 9/9/2024, the median PFS was 3.4, 2.9, 2.5 and 2.8 months, and median OS was 7.5, 8.3, 5.7 and 10.2 months for SOC, DOC, DC and OC, respectively. ORR was 4.3%(95%CI:0.00-0.19), 15.9%(95%CI:0.07-0.29), 11.9%(95%CI:0.05-0.24) and 9.1%(95%CI:0.03-0.20) for SOC, DOC, DC, OC. Compared to SOC, the PFS HR estimates for DOC, DC, OC were 1.003(95%CI:0.56-1.80), 1.108(95%CI:0.63-1.96), and 1.021(95%CI:0.57-1.82). for SOC, DOC, DC, OC, respectively. No new safety signals were observed.</p><p><strong>Conclusion: </strong>In PROC patients with prior bevacizumab, all experimental arms failed to reach the primary objective of improving PFS compared with SOC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794837","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":"Safety and Efficacy of KN046 in combination with KN026 in Patients with advanced HER2-positive Breast Cancer: a Phase II Trial","authors":"Jieqiong Liu, Chuangui Song, Yaping Yang, Xiangcai Wang, Mingli Ni, Xujuan Wang, Lei Chen, Hongwei Yang, Rusen Zhao, Ting Xu, Lin Shen","doi":"10.1158/1078-0432.ccr-24-3888","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3888","url":null,"abstract":"Purpose: Here we reported the results from a phase II trial assessing the safety and efficacy of KN046 in combination with KN026 in HER2-positive metastatic breast cancer patients, who had progressed after prior anti-HER2 combination therapies. Patients and Methods: Female patients with metastatic HER2-positive breast cancer who were previously treated with at least one line of HER2-targeted combination therapy were enrolled from multiple academic hospitals in China to receive KN046 (iv. 5 mg/kg Q3W) plus KN026 (iv. 30 mg/kg Q3W) until progression, unacceptable toxicities or patient withdrawal. Efficacy was evaluated every 6 weeks per RECIST 1.1. The primary endpoint was objective response rate (ORR). Results: A total of 36 patients with the median age of 53 years were enrolled. 30 of 36 patients (83.3%) received ≥3 lines of HER2-targeted combination therapies in the metastatic setting. Thirty-three patients were evaluable for overall response, and all 36 for safety. The ORR was 47.2% ( 95% CI: 30.4-64.5), with two patient achieving CR. The median PFS was 5.6 (95% CI 4.1-13.8) months. 34 of 36 (94.4%) patients experienced TRAEsof any grade, and 10 of 36 (27.8%) patients had experienced ≥grade 3 TRAEs. The most common TRAEs were infusion-related reaction (36.1%), rash (16.7%), alanine aminotransferase increased (13.9%), diarrhea (13.9%), pruritus (13.9%). No treatment-related deaths were observed. Conclusions: The combination of KN046 and KN026, as a chemo free regimen, demonstrated favorable clinical efficacy with comparative toxicities in pre-treated patients with advanced HER2-positive breast cancer.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782397","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":"Integrated metabolomics and spatial transcriptomics of cystic pancreatic cancer precursors reveals dysregulated polyamine metabolism as a biomarker of progression","authors":"Ricardo A. León-Letelier, Yihui Chen, Rongzhang Dou, Ehsan Irajizad, Michele T. Yip-Schneider, Ranran Wu, Rahmah Ejaz, Hamid K. Rudsari, Yaxi Li, Rachelle Spencer, Riccardo Ballarò, Jody Vykoukal, Mark Hurd, Jennifer B. Dennison, Kim-Anh Do, Anirban Maitra, Jianjun Zhang, Samir Hanash, C. Max Schmidt, Johannes F. Fahrmann","doi":"10.1158/1078-0432.ccr-24-2931","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2931","url":null,"abstract":"Purpose: We conducted metabolomics and spatial cell transcriptomics of intraductal papillary mucinous neoplasms (IPMN), recognized pancreatic cancer precursors, to identify oncometabolites that inform upon risk of malignancy of IPMN. Experimental Design: Untargeted metabolomic analyses were performed on cystic fluid from 125 patients with low-grade dysplasia (LG) or high-grade (HG) dysplasia with/without concurrent PDAC (IPMN/PDAC). Predictive performance of individual metabolites for identifying HG or PDAC/IPMN was determined and compared to CA19-9 performance. Data were intersected with metabolic profiles of resected IPMN tissues and murine Kras;Gnas IPMN cell lines as well as spatial and single-cell transcriptomics of IPMN. Results: A total of 388 metabolites were quantified in cystic fluid of which 69 were differential (p-value &amp;lt;0.05) between cases (HG IPMN + IPMN/PDAC) and patients with LG IPMN. Spermidine and spermine biosynthesis and catabolism was identified as the top perturbed metabolic pathway (FDR-adjusted p-value&amp;lt; 0.0001). Increases in cystic fluid spermidine, n-acetylputrescine, acetylspermidine, diacetylspermidine, diacetylspermine, and acetylcadaverine were associated elevated risk of harboring HG or IPMN/PDAC. An OR-rule comprising CA19-9, n-acetylputrescine, acetylspermidine, and diacetylspermine achieved 54.8% sensitivity for detecting HG and IPMNPDAC. CA19-9 alone yielded sensitivity of 11.9% (McNemar Test p-value&amp;lt; 0.001). Polyamines were elevated in IPMNPDAC tissues compared to LG IPMN tissues; spatial and single-cell transcriptomic data revealed transcript levels of polyamine-metabolizing enzymes to be elevated in neoplastic epithelium and tumor-associated macrophages. Conclusion: Cystic fluid polyamines offer utility for determining risk of malignancy of IPMN that is complementary to CA19-9, and that has potential to aid in clinical management of patients with IPMN.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"63 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782409","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 Co-Clinical Trial of Exercise Therapy in Breast Cancer Prevention","authors":"Lee W. Jones, Jessica A. Lavery, Brandon L. Tsai, Chaya S. Moskowitz, Catherine P. Lee, Jenna Harrison, Meghan G. Michalski, Kurtis Stoeckel, Courtenay Graham, Neil M. Iyengar, Umeshkumar Bhanot, Irina Linkov, Mala Jain, Maxine S. Jochelson, Mara Monetti, Victoria L. Seewaldt, Melissa L. Pilewskie, Patrick Pribil, Chenghao Zhu, Jaron Arbet, Debra A. Mangino, Paul C. Boutros","doi":"10.1158/1078-0432.ccr-24-4298","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4298","url":null,"abstract":"Purpose. We conducted a mouse–human co-clinical trial to evaluate the biological efficacy of exercise therapy in breast cancer prevention. Materials and methods. In a phase 1 randomized trial, 75 nonexercising women at high-risk of breast cancer were allocated to receive (1:1 ratio): usual care or one of three exercise therapy dose regimens: 75, 150, or 300 minutes/week for 24 consecutive weeks. Biological efficacy was evaluated by changes in breast epithelial cell proliferation (Ki67). Correlative proteomic analysis of paired tissue and plasma samples was also performed. A corresponding preclinical study tested the dose-response of exercise therapy on breast tumor latency. Results. Change in Ki67 was not different between groups (global p-value = 0.2). Among participants with paired Ki67 measures, the mean (s.d) change in Ki67 was: –1.26 (4.32) for 75 minutes/week, –1.74 (5.04) for 150 minutes/week, –0.45 (5.16) for 300 minutes/week, and 3.40 (5.53) for usual care (global p-value = 0.04). Only 150 minutes/week associated with significant reductions in Ki67 compared with usual care (Bonferroni-adjusted p-value 0.03). The “response rate” (reduction in Ki67) was 29% for usual care compared with 52% for 150 minutes/week. Proteomics revealed marked reduction in genes involved in epithelial mesenchymal transition in tissues of responding patients. In the preclinical study, only 150 minutes/week significantly delayed tumor latency compared with control (Benjamini- Hochberg-adjusted p-value 0.02). Conclusion. Exercise therapy is a promising strategy for early interception of breast cancer in high-risk women.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782411","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":"BCL-XL Protects ASS1-Deficient Cancers from Arginine Starvation-Induced Apoptosis.","authors":"Prashanta Kumar Panda, Ana Carolina Paschoalini Mafra, Alliny C S Bastos, Li Cao, Maria Serra Bonet, Caitlyn B Brashears, Ethan Yang Chen, Heather M Benedict-Hamilton, William Ehrhardt, John Bomalaski, Carina Dehner, Leonard C Rogers, Toshinao Oyama, Brian A Van Tine","doi":"10.1158/1078-0432.CCR-24-2548","DOIUrl":"10.1158/1078-0432.CCR-24-2548","url":null,"abstract":"<p><strong>Purpose: </strong>Argininosuccinate synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, such as PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis.</p><p><strong>Experimental design: </strong>The effects of ADI-PEG20 on cell-cycle regulation, apoptosis, and BCL-XL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions among BCL-XL, BAX, and BAK. In vitro synergy was determined, and in vivo efficacy was modeled.</p><p><strong>Results: </strong>Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell-cycle progression but did not induce significant cell death. BCL-XL was found to bind to BAX and BAK, preventing the initiation of apoptosis despite arginine starvation. Inhibition of BCL-XL allowed proapoptotic BAX and BAK to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo.</p><p><strong>Conclusions: </strong>The study identifies BCL-XL as a key factor limiting the efficacy of arginine starvation therapies. Combining BCL-XL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in phase 1 clinical trials for ASS1-deficient cancers.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1333-1345"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078563","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":"FDA Approval Summary: Nadofaragene Firadenovec-vncg for Bacillus Calmette-Guérin-Unresponsive Non-Muscle-Invasive Bladder Cancer.","authors":"Laronna Colbert, Yuxia Jia, Anurag Sharma, Jiang Hu, Zhenzhen Xu, Daniel L Suzman, Asha Das, Peter Bross, Paul G Kluetz, Lola A Fashoyin-Aje","doi":"10.1158/1078-0432.CCR-24-2812","DOIUrl":"10.1158/1078-0432.CCR-24-2812","url":null,"abstract":"<p><p>On December 16, 2022, the FDA approved the adenoviral vector-based gene therapy nadofaragene firadenovec-vncg (brand name Adstiladrin) for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). The product represents the first approved adenoviral vector-based gene therapy and the first approved gene therapy for bladder cancer. Determination of efficacy was based on results from Study rAd-IFN-CS-003 (Study CS-003), a single-arm trial in 98 evaluable patients with BCG-unresponsive NMIBC with CIS who received intravesical instillations of the gene therapy product (75 mL of nadofaragene firadenovec at 3 × 1011 viral particles per mL) once every 3 months. The major efficacy outcome measures were complete response (CR) at any time and duration of response. Fifty subjects experienced CR 3 months after the initial treatment (CR = 51%; 95% confidence interval, 40.7; 61.3%), of whom 46% remained in response for ≥12 months. The median duration of response was 9.7 months (range: 3-52+). Common adverse reactions included instillation site discharge, fatigue, bladder spasm, micturition urgency, hematuria, chills, pyrexia, and dysuria. The approval of nadofaragene firadenovec provides a new therapy option for patients with BCG-unresponsive NMIBC with CIS who are ineligible for cystectomy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1182-1185"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863530","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":"Endothelial Cell pY397-FAK Expression Predicts the Risk of Breast Cancer Recurrences after Radiotherapy in the SweBCG91-RT Cohort.","authors":"Rebecca J G Drake, Amalia H Landén, Erik Holmberg, Axel Stenmark Tullberg, Fredrika Killander, Emma Niméus, Alexander Jordan, Jennifer McGuinness, Per Karlsson, Kairbaan Hodivala-Dilke","doi":"10.1158/1078-0432.CCR-24-2939","DOIUrl":"10.1158/1078-0432.CCR-24-2939","url":null,"abstract":"<p><strong>Purpose: </strong>Identifying biomarkers of radiotherapy (RT) response is important for optimizing the treatment of early breast cancer. In this study, we tested the interaction between endothelial cell (EC) expression of phospho-Tyr397-FAK (pY397-FAK) and adjuvant-RT on clinical outcomes after breast-conserving surgery (BCS) within a randomized study. Preclinical data suggest an enhanced effect of RT on low EC_pY397-FAK expression.</p><p><strong>Experimental design: </strong>We analyzed tissue microarrays from the Swedish Breast Cancer Group 91 Radiotherapy (stage I-II, lymph node-negative) breast cancer cohort, consisting of 1,178 patients randomly assigned to receive either BCS alone or BCS plus adjuvant-RT. Tissue microarray sections were immunostained for pY397-FAK, CD31, α-smooth muscle actin, and pan-cytokeratin. HALO analysis scored mean pY397-FAK intensity in CD31+ ECs, pan-cytokeratin-positive tumor epithelial cells, and α-smooth muscle actin + mural/stromal cells per core. For 822 patients, multivariable Cox regression analysis was performed for the primary and secondary 5-year endpoints, locoregional recurrence and all recurrence, respectively, as dependent variables and RT and EC_pY397-FAK as independent variables.</p><p><strong>Results: </strong>EC_pY397-FAK expression was not predictive for the primary endpoint locoregional recurrence (P = 0.098), but the direction of the RT effect was in line with preclinical findings. For the secondary endpoint all recurrence, there was a significant interaction (P = 0.026) between EC_pY397-FAK and RT. Without RT, higher EC_pY397-FAK expression resulted in a lower risk for all recurrence (HR = 0.74 per SD; 95% confidence interval = 0.57-0.96; P = 0.026).</p><p><strong>Conclusions: </strong>Within the first 5 years following BCS, patients with low EC_pY397-FAK expression derive greater benefit from RT than patients with high EC_pY397-FAK expression. However, without RT, low EC_pY397-FAK expression is associated with a higher risk of recurrence.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1323-1332"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188427","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":"Intratumoral or Subcutaneous MK-2118, a Noncyclic Dinucleotide STING Agonist, with or without Pembrolizumab, for Advanced or Metastatic Solid Tumors or Lymphomas.","authors":"Jason J Luke, Randy F Sweis, J Randolph Hecht, Reva Schneider, Mark N Stein, Talia Golan, Timothy A Yap, Anuradha Khilnani, Mo Huang, Runchen Zhao, Thomas Jemielita, Sandip Pravin Patel","doi":"10.1158/1078-0432.CCR-24-2824","DOIUrl":"10.1158/1078-0432.CCR-24-2824","url":null,"abstract":"<p><strong>Purpose: </strong>We evaluated the noncyclic dinucleotide stimulator of IFN genes agonist MK-2118 ± pembrolizumab in participants with advanced solid tumors or lymphomas.</p><p><strong>Patients and methods: </strong>This first-in-human study (NCT03249792) enrolled participants with refractory, advanced solid tumors or lymphomas. Participants received intratumoral (IT) MK-2118 100 to 20,000 μg (arm 1), IT MK-2118 900 to 15,000 μg plus intravenous (IV) pembrolizumab 200 mg every 3 weeks (arm 2), or subcutaneous (SC) MK-2118 5,000 to 150,000 μg plus IV pembrolizumab 200 mg every 3 weeks (arm 4); arm 3 (visceral injection of MK-2118) was not pursued. IT dosing used an accelerated titration design and modified toxicity probability interval method; SC dosing (arm 4) was started subsequent to arms 1 and 2. The primary objectives were safety/tolerability. MK-2118 pharmacokinetics was a secondary endpoint; objective responses and biomarkers were exploratory endpoints.</p><p><strong>Results: </strong>A total of 140 participants were enrolled (arm 1, n = 27; arm 2, n = 57; arm 4, n = 56). Grade 3/4 treatment-related adverse events occurred in 22%, 23%, and 11% of participants, respectively, but no maximum tolerated dose was identified up to MK-2118 20,000, 15,000, and 150,000 μg across the three arms. Dose-dependent increases in MK-2118 systemic exposure were observed following IT and subcutaneous administration. Objective responses were seen in 0%, 6%, and 4% of participants, respectively. IT MK-2118 led to dose-dependent changes in stimulator of interferon genes-based blood RNA expression levels, IFNγ, IFNγ-induced protein 10, and IL6; SC MK-2118 did not generate dose-related immune responses.</p><p><strong>Conclusions: </strong>IT MK-2118 ± pembrolizumab and SC MK-2118 plus pembrolizumab had manageable toxicity and limited antitumor activity. IT but not SC administration demonstrated systemic immune effects.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1233-1242"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022360","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":"Anlotinib versus Placebo as Adjuvant Therapy for Localized High-Grade Soft-Tissue Sarcomas: A Phase II, Double-Blinded, Randomized Controlled Trial.","authors":"Chunmeng Wang, Xianglin Hu, Lingge Yang, Yu Xu, Biqiang Zheng, Jilong Yang, Zhichao Liao, Zhengwang Sun, Shengjian Zhang, Lin Yu, Yan Yan, Yong Chen, Tomohiro Fujiwara, Jianrong Zhang, Ilia N Buhtoiarov, Yangbai Sun, Wangjun Yan","doi":"10.1158/1078-0432.CCR-24-2531","DOIUrl":"10.1158/1078-0432.CCR-24-2531","url":null,"abstract":"<p><strong>Purpose: </strong>We aimed to investigate the efficacy and safety of anlotinib as adjuvant targeted therapy for completely resected localized high-grade soft-tissue sarcomas (STS).</p><p><strong>Patients and methods: </strong>Patients with localized high-grade STS after complete resection were randomly assigned in a 1:1 ratio to receive either oral 12 mg anlotinib or placebo once daily on days 1 to 14 every 21 days as a cycle, with up to six cycles until disease relapse, unmanageable toxicity, or death. The efficacy and safety were analyzed. This trial was the first trial exploring adjuvant targeted therapy for STS (NCT03951571).</p><p><strong>Results: </strong>Between June 2019 and November 2023, 88 patients were randomly assigned to receive anlotinib (n = 44) or placebo (n = 44). With a median follow-up of 30.95 months, the 1- and 2-year disease-free survival rates were 88% and 77% in the anlotinib group compared with 64% and 58% in the placebo group, respectively. Compared with patients treated with surgery alone, patients receiving adjuvant anlotinib combined with surgery had a reduced risk of disease recurrence [HR, 0.47; 95% confidence interval (CI), 0.22-1.00; P = 0.0445]. Based on the tumor histology, the reduced risk of disease recurrence with anlotinib versus placebo was observed in patients with myxofibrosarcoma (HR, 0.54; 95% CI, 0.17-1.65; P = 0.2698) and undifferentiated pleomorphic sarcoma (HR, 0.58; 95% CI, 0.12-2.87; P = 0.4971). Four patients discontinued anlotinib: two for proteinuria/hematuria (2/44, 5%) and two for poor healing of surgical wound (2/44, 5%).</p><p><strong>Conclusions: </strong>Compared with surgery alone, adjuvant anlotinib following surgery reduces the incidence of disease relapse in localized high-grade STS, with acceptable toxicity.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1194-1203"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363759","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}