Clinical Cancer Research最新文献

{"title":"A phase II trial of Naxitamab plus stepped-up dosing of GM-CSF for patients with high-risk neuroblastoma in first complete remission","authors":"Brian H. Kushner, Shakeel Modak, Audrey Mauguen, Ellen M. Basu, Kim Kramer, Stephen S. Roberts, Irene Y. Cheung, Nai-Kong V. Cheung","doi":"10.1158/1078-0432.ccr-24-3427","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3427","url":null,"abstract":"Purpose: Naxitamab is a humanized form of the murine anti-GD2 monoclonal antibody (mAb) 3F8. In an international trial, naxitamab+GM-CSF was effective against chemo-resistant high-risk neuroblastoma (HR-NB), leading to approval by the Food and Drug Administration. We now report results with patients in 1st complete remission (CR). Patients and Methods: The primary objective of this phase II protocol 16-1643 (Clinicaltrials.gov NCT03033303) was to assess event-free survival (EFS) of HR-NB patients in 1st CR treated with naxitamab+GM-CSF plus isotretinoin. HR-NB was defined as MYCN-amplified disease (any age) or metastatic disease at age >18 months. Cycles of immunotherapy were administered monthly up to 5 cycles and comprised: 1) subcutaneously-administered priming doses of GM-CSF 250µg/m2/day on days -4-to-0 (Wednesday-Sunday), followed by a step-up to 500µg/m2/day on days +1-to-+5 (Monday-Friday), and 2) naxitamab infused intravenously (30-90”) on days +1, +3, and +5 (Monday-Wednesday-Friday, i.e., 3 doses/cycle). Naxitamab was 3mg/kg/infusion (9mg/kg/cycle, i.e., ~270mg/m2/cycle). Isotretinoin 160mg/m2/day started post-cycle 2, x14 days/course, x6 courses. Results: Fifty-nine HR-NB patients (53 stage 4, 6 stage 3) were enrolled 2/2017-7/2020. At 36 months, EFS/OS were 73%/93%, but 50/59 patients received post-protocol treatment (vaccine and/or DFMO). 6/18 relapses were isolated in the central nervous system (CNS). Longer time from diagnosis to enrollment was a significantly adverse prognostic factor (p=0.04). 21/59 patients took no isotretinoin. Treatment was tolerable allowing outpatient administration. Conclusions: Naxitamab+GM-CSF is a good option to consolidate 1st CR of HR-NB patients, including those who did not undergo ASCT. Efforts to prevent CNS relapse are warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"61 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599827","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":"Adjuvant Aspirin Treatment in PIK3CA Mutated Colon Cancer Patients: The SAKK 41/13 - Prospective Randomized Placebo-Controlled Double-Blind Trial","authors":"Ulrich Güller, Stefanie Hayoz, Daniel Horber, Wolfram Jochum, Sara De Dosso, Dieter Koeberle, Sabina Schacher, Roman Inauen, Michael Stahl, Thierry Delaunoit, Thomas Ettrich, György Bodoky, Pierre Michel, Thibaud Koessler, Karin Rothgiesser, Sandra Calmonte, Markus Joerger","doi":"10.1158/1078-0432.ccr-24-4048","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4048","url":null,"abstract":"Purpose: We assessed the benefit of adjuvant aspirin in resected PIK3CA-mutated colon cancer patients. Patients & Methods: This was a phase III, prospective, randomized, placebo-controlled, double-blind, multicenter, and multinational trial. Patients with resected colon cancer stage II and III harbouring an activating PIK3CA mutation were included. Due to financial constraints, the trial was prematurely closed. Randomization was 2:1 to aspirin 100mg versus placebo daily for 3 years. The primary endpoint was disease-free survival (DFS). Secondary endpoints included the time to disease recurrence (TTR), overall survival, and adverse events (AE). Results: Overall, 1,040 patients were screened for PIK3CA mutations, with 112 randomized to aspirin (N=74) and placebo (N=38). Median age was 66 years and 42.9% were female. After a median follow-up of 4 years, 19 DFS events occurred, including 10 in the aspirin and nine in the placebo arm. The HR for DFS was 0.57 (90%CI: 0.27-1.22), in favor of aspirin (p=0.11). DFS rates at 5 years were 86.5% (90%CI: 77.7%-92.0%) in the aspirin and 72.9% (90%CI: 55.7%-84.3%) in the placebo arm. The HR for TTR was 0.49 (90%CI: 0.21-1.19, p=0.089) in favor of aspirin. No patient experienced aspirin-related serious AEs. Conclusions: The SAKK 41/13 is the first randomized trial to provide clinical evidence of a protective effect of adjuvant aspirin in resected PIK3CA-mutant colon cancer patients, with clinically relevant DFS and TTR improvements. Although results were not statistically significant due to premature study closure, adjuvant aspirin warrants individual consideration in patients with resected PIK3CA-mutant colon cancer stage II and III.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"86 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599820","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":"Emerin Dysregulation Drives the Very-Small-Nuclear Phenotype and Lineage Plasticity that Associates with a Clinically Aggressive Subtype of Prostate Cancer","authors":"Le Zhang, Pai-Chi Teng, Karen A. Cavassani, Jasmine Wang, Catherine Grasso, Joshua Watson, Zijing Chen, Kai-Han Tu, Brenda Salumbides, Krizia Rohena-Rivera, Lilit Gevorkian, Minhyung Kim, Sungyong You, Dolores Di Vizio, Howard M. Sandler, Timothy Daskivich, Neil A. Bhowmick, Michael R. Freeman, Hsian-Rong Tseng, Jie-Fu Chen, Edwin M. Posadas","doi":"10.1158/1078-0432.ccr-24-3660","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3660","url":null,"abstract":"Background: Circulating tumor cells (CTCs) with a very-small-nuclear phenotype (vsnCTCs) in prostate cancer (PCa) are characterized by nuclei smaller than 8.5 μm. Our previous studies established an association between vsnCTCs and visceral metastasis. Reduction of emerin (EMD), a nuclear envelope protein, contributes to PCa metastasis and nuclear shape instability. Here we investigated the correlation between EMD expression and the vsnCTC phenotype and its clinical impact. Methods: We analyzed CTCs from 93 mCRPC patients and categorized them as either vsnCTC+ or vsnCTC- and compared overall survival (OS) and progression-free survival (PFS). C4-2B, 22Rv1, and DU145 with EMD knockdown were developed and characterized by nuclear size and gene expression by GSEA analysis. Abiraterone- and enzalutamide-resistant (Abi-R/Enza-R) C4-2B cells were also characterized by nuclear size and EMD expression. Results: vsnCTC+ patients had significantly worse OS and PFS compared to vsnCTC- patients. EMD expression was markedly reduced in CTCs from vsnCTC+ patients compared to vsnCTC- patients, with a significant positive correlation between EMD expression and CTC nuclear size. EMD knockdown in PCa cells resulted in smaller nuclei, enhanced invasion, and the upregulation of genes associated with lineage plasticity. Additionally, C4-2B Abi-R/Enza-R cells had smaller nuclei and lower EMD expression. vsnCTC+ cells also showed enhanced platinum sensitivity. Conclusions: The presence of vsnCTCs represents a novel hallmark of an aggressive subtype of mCRPC, closely linked to EMD loss and lineage plasticity. These findings highlight the importance of EMD dysregulation in the vsn phenotype, disease progression, and therapeutic resistance in patients with PCa.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589670","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":"DLK1 distinguishes subsets of NF1-associated malignant peripheral nerve sheath tumors with divergent molecular signatures","authors":"Dana K. Mitchell, Kylee Brewster, Stavriani C. Makri, Jaffar Khan, Eric A. Albright, Andrew Horvai, Henry Mang, Qingbo Lu, Shelley A. H. Dixon, Emily White, M. Reza Saadatzadeh, Khadijeh Bijangi-Vishehsaraei, Silpa Gampala, Brooke E. Hickey, Hannah Leffew, Xiaohong Li, Li Jiang, Marisa D. Ciesielski, Waylan K. Bessler, Christopher D. Collier, Aaron Cohen-Gadol, Melissa L. Fishel, Christine A. Pratilas, Karen E. Pollok, Steven P. Angus, Steven Rhodes, D. Wade. Clapp","doi":"10.1158/1078-0432.ccr-24-3029","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3029","url":null,"abstract":"Purpose: MPNST is the leading cause of premature death among individuals with NF1 and the transcriptional aberrations that precede malignant transformation and contribute to MPNST tumorigenesis remain poorly defined. Alterations involving CDKN2A and components of PRC2 have been implicated as early drivers of PNST evolution, but these events do not occur in all MPNST. Accordingly, emerging data has begun to highlight the importance of molecular-based stratification to improve outcomes in patients with NF1-PNST. Experimental design: Here we perform an integrated analysis of multiple, independent datasets obtained from human NF1 patients to gain critical insight into PNST evolution and MPNST heterogeneity. Results: We show that DLK1 is significantly increased in MPNST and provide evidence that DLK1 overexpression may precede histological changes consistent with malignancy. In complementary analyses, we find that serum levels of DLK1 are significantly higher in both mice and humans harboring MPNST compared to those without malignancy. Importantly, while DLK1 expression is increased in MPNST overall, through the integration of multiple, independent datasets we demonstrate that divergent levels of DLK1 expression distinguish MPNST subsets characterized by unique molecular programs and potential therapeutic vulnerabilities. Specifically, we show that overexpression of DLK1 is associated with the reactivation of embryonic signatures, an immunosuppressive microenvironment and a worse overall survival in patients with NF1-MPNST. Conclusions: Collectively, our findings provide critical insight into MPNST tumorigenesis and support prospective studies evaluating the utility of DLK1 tissue and serum levels in augmenting diagnosis, risk assessment and therapeutic stratification in the setting of NF1-PNST.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"29 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589671","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":"The spectrum of IDH- and H3-wildtype high-grade glioma subgroups occurring across teenage and young adult patient populations","authors":"Rita Pereira, Alan Mackay, Yura Grabovska, Amelia Bradley, Tabitha Bloom, James Nicoll, Delphine Boche, John Procter, Mellissa Maybury, Johanna Schagen, Liam Walker, Federico Roncaroli, Konstantina Karabatsou, Olumide Ogunbiyi, Thijs van Dalen, Jai Sidpra, Sabrina Rossi, Evelina Miele, David S. Ziegler, Zhifeng Shi, Thomas S. Jacques, Darren Hargrave, Bassel Zebian, Cristina Bleil, Joseph Yates, Emma Norton, Henry Mandeville, Antonia Creak, Liam Welsh, Lynley Marshall, Fernando Carceller, Sucheta J. Vaidya, Zita Reisz, Safa Al-Sarraj, Angela Mastronuzzi, Andrea Carai, Maria Vinci, Kathreena M. Kurian, Ho-keung Ng, Sebastian Brandner, Chris Jones, Matthew Clarke","doi":"10.1158/1078-0432.ccr-24-1256","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1256","url":null,"abstract":"Background: High-grade gliomas (HGG) occur in any central nervous system (CNS) location and any age. HGGs in teenagers/young adults (TYA) are understudied. This project aimed to characterise these tumours to support accurate patient stratification. Methods: 207 histone/IDH-wildtype tumours from patients aged 13–30 years were collected. DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNPv12.6 R package)) classified cases against reference cohorts. Calibrated scores guided characterisation workflows (RNA-based ArcherDx fusion panel (n=92), whole exome sequencing (WES) (n=107), histological review). Results: 53.4% (n=86) matched paediatric-type subgroups (pedHGG_RTK1A/B/C (31.7%, n=51 PDGFRA, CDKN2A/B, SETD2, NF1 alterations), pedHGG_MYCN (8.1%, n=13, MYCN/ID2 amplifications), and pedHGG_RTK2A/B (7.5%, n=12, TP53, BCOR, ATRX, EGFR alterations)). 18.0% (n=29) classified as adult-type subgroups (GBM_MES (15.5%, n=25, RB1, PTEN, NF1 alterations) and GBM_RTK1/2 (2.5%, n=4, CDK4 amplifications)). 23 cases (14.7%) classified as novel, poorly-characterised subgroups with distinct methylation profiles and molecular features (pedHGG_A/B (n=10 6.2%), HGG_E (n=6 3.7%), HGG_B (n=2 1.0%), GBM_CBM (n=5 3.1%)) with variable histological morphology. 8 cases (5.1%) showed hypermutator phenotypes, enriched in HGG_E, including siblings with constitutional mismatch repair deficiency (CMMRD). TYA HGGs also develop on a background of childhood cancer treatments. Age-distribution comparisons using publicly available methylation/sequencing data (HGG_B (n=19), GBM_CBM (n=35), GBM_MES_ATYP (n=102)), irrespective of age, show HGG_B is TYA-specific (median 29 years) and GBM_CBM and GBM_MES_ATYP show TYA distribution peaks, with GBM_MES_ATYP showing copy number differences and worse survival compared with adult-specific GBM_MES_TYP. Conclusion: TYA HGGs comprise novel methylation subgroups with distinct molecular profiles. Accurate stratification will open opportunities to utilise more effective treatments.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589672","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":"Radiation Dose-Volume Effects on Negative Tumor-Draining Lymph Nodes Impacted T-Cell Activation and Prognosis in Esophageal Cancer with Chemoradiotherapy","authors":"Ihsuan Tseng, Yun Chen, Dashan Ai, Zhengfei Zhu, Weixin Zhao, Min Fan, Ling Li, Hongcheng Zhu, Fangfang Li, Yang Xu, Lu Yu, Zezhou Wang, Junqi Wang, Qi Liu, Jiaying Deng, Shengnan Hao, Qingsong Fan, Jinjun Ye, Jialiang Zhou, Chaoyang Wu, Huarong Tang, Qin Lin, Jiancheng Li, Yunhai Li, Shihong Wei, Hui Luo, Jianzhong Cao, Xiangpeng Zheng, Guang Huang, Yuwei Zheng, Bo Ping, Kuaile Zhao","doi":"10.1158/1078-0432.ccr-24-4123","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4123","url":null,"abstract":"Purpose: Preclinical model found that elective nodal irradiation (ENI) attenuated the efficacy of radiotherapy and radio-immunotherapy. However, limited clinical studies have explored the correlation between radiation dose-volume parameters of negative tumor draining lymph nodes (TDLNs) and T-cell activation/prognosis for cancer patients treated with definitive radio(chemo)therapy. Experimental Design: Patients with locally advanced esophageal cancer undergoing definitive chemoradiotherapy (CRT) were selected from two prospective trials. Dose-volume parameters of TDLN as well as other lymphocyte-related organs at risk (LOARs) and lymphocyte subsets such as CD3-CD19+ B cells, CD8+CD28+ T cells, and activated T cells (CD3+CD8+HLA-DR+) before and at the end of radiotherapy (RT) were collected. Logistic analysis was utilized to correlate dose-volume parameters with reductions in lymphocyte subsets. Prognosis of TDLN irradiation was investigated through Kaplan-Meier analysis and Cox hazards models. Results: Among 512 patients, the median mean dose of TDLN and negative non-TDLN was 25.6 Gy and 15.1 Gy, respectively. Multivariable analyses indicated TDLN V15 >50% was an independent predictor of poorer local-recurrence free survival (HR, 1.31; p=0.029) and distant-metastasis free survival (HR, 1.39; p<0.001), as well as greater reductions in CD3-CD19+ B cells (OR, 1.98; p=0.002), CD8+CD28+ T cells (OR, 3.42; p<0.001) and CD3+CD8+HLA-DR+ T cells (OR, 4.67; p=0.002) post-RT. Conclusions: A higher radiation dose-volume parameter of TDLNs in esophageal cancer patients undergoing CRT was significantly associated with suppression of T-cell activation and a worse prognosis. Limiting the percentage of TDLN V15 may be beneficial for improving the prognosis of CRT with or without PD-1 inhibitors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575251","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":"­­­­­Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma","authors":"Eugenio Morelli, Caroline Fidalgo. Ribeiro, Silvia D. Rodrigues, Claire Gao, Fabio Socciarelli, Domenico Maisano, Vanessa Favasuli, Na Liu, Katia Todoerti, Chandraditya Chakraborty, Yao Yao, Mariateresa Fulciniti, Mehmet Samur, Anil Aktas-Samur, Nicola Amodio, Marcello Turi, Francesca Barello, Johany Penailillo, Cesarina Giallongo, Alessandra Romano, Annamaria Gulla, Kenneth C. Anderson, Giorgio Inghirami, Nikhil C. Munshi, Massimo Loda","doi":"10.1158/1078-0432.ccr-24-2000","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2000","url":null,"abstract":"Purpose: In multiple myeloma (MM), tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis (DNL), in MM metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes. Experimental design: ACC1 expression was evaluated across MM genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed MM cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of ER stress, protein translation, and oxidative damage elucidated underlying mechanisms. Results: ACC1 was overexpressed in MYC-translocated MM. Its inhibition or knockdown reduced MM cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis. Conclusions: ACC1 is a metabolic vulnerability in MYC-driven MM. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for MM.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"87 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575432","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":"Pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer","authors":"Saranya Chumsri, Joseph J. Larson, Emily Liu, Kathleen S. Tenner, Daniel Adams, Morgan T. Weidner, Amanda N. Arnold, Dana L. Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, E. Aubrey Thompson, Edith A. Perez, Keith L. Knutson","doi":"10.1158/1078-0432.ccr-24-3001","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3001","url":null,"abstract":"Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Experimental Design: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic TNBC with ≤ 3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response > 12 months and ongoing even after stopping treatment (5.4 - 69.0 months). Patients with PD-L1-positive tumors (CPS ≥ 10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1-negative tumors. Consistent with preclinical studies, 4 out of 6 patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells (CAMLs) after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575433","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":"Zanubrutinib plus Ixazomib and Dexamethasone in newly diagnosed symptomatic Waldenström macroglobulinemia:a phase II study","authors":"Wenjie Xiong, Yuting Yan, Tingyu Wang, Weiwei Sui, Ying Yu, Tengteng Yu, Rui Lyu, Yi Wang, Wei Liu, Huimin Liu, Gang An, Yan Xu, Wenyang Huang, Dehui Zou, Lugui Qiu, Shuhua Yi","doi":"10.1158/1078-0432.ccr-24-3490","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3490","url":null,"abstract":"Purpose: Waldenström macroglobulinemia (WM) is a rare type of lymphoma, with no optimal treatment. BTK inhibitor have shown promising outcomes, yet achieving deep remission (VGPR or CR) remains challenging and time-limited therapy with proteasome-inhibition has not been reported. We conducted a phase 2 clinical trial (NCT04463953) to evaluate the efficacy and safety of combining zanubrutinib, ixazomib and dexamethasone (ZID) in newly diagnosed WM patients. Patients and Methods: 27 patients were enrolled in the study. Patients received ZID induction therapy for up to six 28-days’ cycles, followed by consolidation therapy up to total 24 cycles. The primary endpoint was the deep remission rate. Results: Overall, 24 of 27 enrolled patients completed induction treatment. One patient (4.2%) achieved CR. 10 patients (41.6%) achieved VGPR. The overall, major and deep remission rates were 100%, 95.8% and 45.8%, respectively. The median time to response was 2 months (range, 1-5). Five of 22 patients had CXCR4 mutation, with no disparity in the deep remission between the patients with/without CXCR4 mutation (40% vs 50%, P=0.594). The median abnormal lymphocyte (7.6% vs 1.6%, P =0.0019) and plasma cells (0.28% to 0.02%, P =0.0306) in bone marrow were significantly reduced after treatment. With a median follow-up of 30.9 months (range, 15-42). The estimated median PFS and OS were 40 months (95% CI:35.5-44.5) and not reached, respectively, with no difference in patients with/without CXCR4mutations. The most common AE was hematological toxicity. Conclusion: ZID regimen might offer deep remission and provided a time-limited BTKi therarpy in WM patients<SPAN style=\"font-weight: 400;\">. </SPAN>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"27 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575434","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":"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>Background: </strong>Antibody-drug conjugates (ADCs) 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>Patients and methods: </strong>We employed quantitative immunofluorescence (QIF) assays to measure the levels of four ADC target proteins (HER2, TROP2, HER3, EGFR) in three NSCLC tissue microarray cohorts stratified according to EGFR mutation (EGFRmut (n=83), EGFRwt (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 assay limits for all targets. Comparison of target expression showed a significant association of HER2 with EGFR expression and a non-significant 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 to select patients for ADC targeting. Inter-target correlation may provide insight on the underlying signaling pathways and/or treatment-related resistant mechanisms. In the future, QIF may be a valuable tool to select ADC treatment sequence.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}