Clinical Cancer Research最新文献

{"title":"Concordance between tumor tissue and plasma DNA genotyping in the NCI-MATCH trial (EAY131)","authors":"Mohamed A. Gouda, Filip Janku, Ying Yuan, Leylah M. Drusbosky, Alice P. Chen, Xiaofeng Zheng, Keyur Patel, Stanley R. Hamilton, Mark Routbort, James V. Tricoli, P. Mickey Williams, A. John Iafrate, Jeffrey Sklar, Brent Coffey, Richard F. Little, Carlos L. Arteaga, Peter J. O'Dwyer, Keith T. Flaherty, Lyndsay N. Harris, Funda Meric-Bernstam","doi":"10.1158/1078-0432.ccr-24-3531","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3531","url":null,"abstract":"Purpose: Liquid biopsies with circulating tumor DNA (ctDNA) analysis are increasingly being utilized as a non-invasive approach to identify actionable genomic alterations in advanced/metastatic cancers. Herein, we report the correlation between ctDNA analysis of plasma samples collected from patients enrolled in the NCI-MATCH trial and tumor tissue-based sequencing. Patients and Methods: We analyzed plasma samples collected from patients enrolled on 16 subprotocols of NCI-MATCH who had plasma samples collected within 90 days before starting treatment. Concordance was defined as the detection of the same gene alteration leading to patient enrollment in NCI-MATCH in both tissue and plasma. Results: We included 300 patients who were enrolled in NCI-MATCH. Most patients (81%, n=243) were enrolled based on central tissue testing and had contemporaneous tissue and plasma samples. The tissue alteration of interest was detected in the plasma of 81.1% (n=197) of patients. Lower rates of detection of the tissue alteration of interest were observed in samples from 57 patients who were enrolled based on outside designated laboratory testing (56.1%, n=32) and had non-contemporaneous tissue and plasma samples. Variations in concordance rates were observed with different alteration types, by maximum plasma variant allelic frequency, and based on tumor biopsy site. Conclusions: The tumor tissue alteration of interest was detected in the plasma of 81% of patients who were enrolled in the NCI-MATCH trial based on central tissue testing and had contemporaneous tissue and plasma samples. This suggests a potential role for liquid biopsy in patients’ enrollment in trials evaluating biomarker-driven anticancer therapies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097165","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":"Phase II study of perioperative Avelumab plus chemotherapy for patients with resectable gastric cancer or gastroesophageal junction cancer – the MONEO Study","authors":"Maria Alsina, Guillermo Villacampa, Carlos de Andrea, Ana Vivancos, Mariano Ponz-Sarvise, Virginia Arrazubi, Paula Jimenez-Fonseca, Marc Diez, Enrique Sanz-Garcia, Eva Martínez, Raquel Guardeño, Mariona Calvo, Cristina Bugés, Federico Longo, Víctor Navarro, Eduardo García-Galea, Alena Gros, Maria C. Ochoa, Alvaro Lopez-Janeiro, Sandra Sanchez-Gregorio, Claudia Herrero, Ibone Labiano, Maria Vila-Casadesús, Dario López, Raluca Alexandru, Susana Muñoz, Josep Tabernero, Ignacio Melero","doi":"10.1158/1078-0432.ccr-25-0369","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0369","url":null,"abstract":"Purpose: Immune checkpoints inhibitors (ICIs) combined with chemotherapy have provided successful results in patients with gastric and gastroesophageal junction (G/GEJ) cancers in the metastatic setting. Similar strategies have been explored in earlier stages. Here, we present final results of the phase II MONEO trial, which evaluated the addition of avelumab to neoadjuvant chemotherapy. Patients and methods: Patients with untreated, resectable G/GEJ adenocarcinoma received neoadjuvant treatment with four cycles of avelumab plus the FLOT4 regimen, followed by surgery. Upon postoperative recovery, patients underwent four additional adjuvant cycles of the same combination, followed by avelumab monotherapy for up to one year. The primary endpoint was pathological complete response (pCR) rate. Sequential flow cytometry and cytokine determination were performed in peripheral blood, along with multiplex tissue immunofluorescence and RNA sequencing (RNA-seq) in tumor specimens. Results: Forty patients were enrolled, achieving a pCR rate of 21.1% (95% CI: 10.0–37.0). Major pathological response rate was 28.9%, more pronounced in those patients with tumors expressing programmed cell death protein 1 (PD-L1) before treatment as measured by combined positive score (CPS cut-off 10; 33.3% vs. 21.1%). Results propose several potential biomarkers considering tumor immune infiltrate, circulating immune cells, and cytokines. Eighty percent of patients experienced treatment-related grade ≥3 adverse events. Conclusions: The combination of avelumab plus the FLOT4 regimen showed relatively modest efficacy in resectable G/GEJ adenocarcinoma. Better results were observed in PD-L1 CPS ≥10% tumors. Exploratory biomarker analyses provide insights that may help to identify candidates most likely to benefit from chemoimmunotherapy as a neoadjuvant treatment.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097164","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":"Validation of guidelines for genetic investigation of myeloid neoplasms with germline predisposition: results from a prospective cohort study","authors":"Bianca Tesi, Anna Robelius, Berivan Baskin, Vladimir Lazarevic, Stefan Deneberg, Martin Höglund, Linda Fogelstrand, Johanna Ungerstedt, Tatjana Pandzic, Magnus Tobiasson, Hege Gravdahl. Garelius, Ekaterina Kuchinskaya, Fredrik Persson, Helena Ågerstam, Helene Hallböök, Thoas Fioretos, Jessika Nordin, Anna Norberg, Ann-Charlotte Thuresson, Sören Lehmann, Claes Ladenvall, Gisela Barbany, Lovisa Vennström, Elisabeth Ejerblad, Lucia Cavelier, Jörg Cammnega, Martin Jädersten, Eva Hellström-Lindberg, Panagiotis Baliakas","doi":"10.1158/1078-0432.ccr-24-4251","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4251","url":null,"abstract":"Purpose: In a multicenter prospective cohort-study we assessed the diagnostic yield of the Nordic guidelines for germline investigation in myeloid neoplasms (MN) and mapped the spectrum of inherited and somatic variants. Experimental Design: Eighty-five patients (acute myeloid leukemia (AML): n=38; myelodysplastic syndromes (MDS): n=26; thrombocytopenia: n=14; other: n=7) fulfilling the Nordic criteria for germline investigation: (1) medical history (MH) or family history (FH) suggestive of a germline condition; (2), relevant findings from the somatic diagnostic work-up (CytoMol), were recruited. The genetic analysis included enhanced whole-exome sequencing (WES, n=69) or sequencing of specific variants of interest (n=16). Results: Pathogenic or likely pathogenic (P/LP) germline variants were identified in 35% of patients (30/85). The diagnostic yield varied from 6% (1/16) in the FH group to 52% (17/33) in the CytoMol group. Germline DDX41 P/LP variants were the most frequent finding (13/30, 43% of all positive cases), almost exclusively found within the CytoMol group (12/13). Seven variants of unknown significance (VUS) were also detected (TERT n=2; DDX41, RTEL1, ETV6, PARN and SAMD9: n=1). Five patients carried a P/LP variant in genes associated with another hereditary cancer syndrome (BRCA1 n=3; PALB2 n=1; CHEK2; n=1). Survival analysis showed a trend for longer survival among patients with AML and confirmed or suspected germline predisposition that underwent allogeneic stem cells transplantation (allo-HSCT). Conclusions: The implementation of the Nordic guidelines in a prospective Swedish cohort, results in a high overall diagnostic yield (35%), proving the feasibility and utility of these or similar guidelines in a clinical setting.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"121 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097166","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":"Capecitabine maintenance therapy in patients with residual nasopharyngeal carcinoma: a single-arm, phase 2 trial","authors":"Xun Cao, Zhuo-Ying Luo, Hao-Yang Huang, Jia-Yu Zhou, Xi Chen, Ying-Ying Huang, Liang-Ru Ke, Lu-Jun Han, Yue Xia, Wei-Xiong Xia, Lin-Quan Tang, Shan-Shan Guo, Xiang Guo, Xing Lyu","doi":"10.1158/1078-0432.ccr-24-4132","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4132","url":null,"abstract":"Purpose: Patients with residual nasopharyngeal carcinoma after receiving standard-of-care treatment have poor prognoses. In this trial, we aimed to assess the efficacy and safety of capecitabine maintenance therapy in patients with residual nasopharyngeal carcinoma. Patients and Methods: This open-label, single-arm, phase 2 trial was conducted at Sun Yat-sen University Cancer Center. We recruited patients aged 18–70 years with an ECOG performance-status score of 0–1, histopathological, cytological confirmed nasopharyngeal carcinoma (without distant metastasis), who had residual disease after receiving definitive treatment. Patients received 1 year of capecitabine maintenance therapy. The primary endpoint was 2-year progression-free survival. Results: Between January 1, 2019, and December 30, 2022, 111 patients were recruited and commenced capecitabine maintenance therapy for 1 year. After a median follow-up duration of 34.8 months (IQR 30.5–45.2), progression-free survival was 92% at 1-year; 86% at 2 years; and 81% at 3 years. Adverse events were reported in 97.3% of patients. Hand-foot syndrome was the most common adverse event (59.5%). In addition, 28.7% of patients experienced grade 3 treatment-related adverse events, the most common of which was hand-foot syndrome (7.2%); no grade 4–5 adverse events were recorded. 72.1% of patients received the full dosage of capecitabine. 76.6% of patients completed the 1-year capecitabine maintenance therapy. Conclusions: The anti-tumor efficacy of capecitabine maintenance therapy is promising, and the safety profile is manageable in patients with residual nasopharyngeal carcinoma after receiving standard-of-care treatment.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"75 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097161","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":"Clinicogenomic characterization of inflammatory breast cancer","authors":"Nolan Priedigkeit, Beth Harrison, Robert Shue, Melissa E. Hughes, Yvonne Li, Alinés Lebrón-Torres, Gregory J. Kirkner, Liam F. Spurr, Marie Claire. Remolano, Sarah Strauss, Janet Files, Anne-Marie Feeney, Libby Grant, Ayesha Mohammed-Abreu, Ana Garrido-Castro, Romualdo Barroso Sousa, Brittany Bychkovsky, Faina Nakhlis, Jennifer R. Bellon, Tari A. King, Eric P. Winer, Neal Lindeman, Bruce E. Johnson, Lynette Sholl, Deborah Dillon, Beth Overmoyer, Sara M. Tolaney, Andrew D. Cherniack, Nancy U. Lin, Filipa Lynce","doi":"10.1158/1078-0432.ccr-24-2081","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2081","url":null,"abstract":"Background: Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC to non-IBC cases. Patients and Methods: We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors, 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, 1,552 metastases). Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV), tumor mutational burden (TMB), and exploratory survival outcomes were compared between IBC and non-IBC. Results: The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment in TP53 SNVs in IBC, particularly in HER2+ and hormone receptor-positive (HR+) disease. TMB did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment in NOTCH pathway alterations. TP53, CCND1 and RB1 alterations were associated with poor outcomes in IBC. Conclusion: This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC; highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations—beyond bulk sequencing of the somatic genome—are required to better understand the biology driving this aggressive disease.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067158","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":"Unravelling the tumor microenvironment and PD-L1 expression across tissue type in high-grade serous ovarian cancer in the NeoPembrOV/GINECO phase II randomized trial","authors":"Laetitia Collet, Maude Ardin, David Venet, Justine Berthet, Sarah Ghamry-Barrin, Isabelle Treilleux, Jean-Christophe Noel, Marianne Leheurteur, Jérôme Meunier, Leïla Bengrine Lefevre, Mathilde Martinez, Frank Priou, Frédéric Selle, Pierre-Alexandre Just, Guillaume Bataillon, Françoise Rothé, Christos Sotiriou, Christophe Caux, Bertrand Dubois, Isabelle Ray-Coquard, Olivia Le Saux","doi":"10.1158/1078-0432.ccr-24-2712","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2712","url":null,"abstract":"Purpose: To describe PD-L1 expression across tissue types and its associated tumor microenvironment (TME) and to investigate how it impacts its predictive value for response to pembrolizumab in treatment-naïve ovarian cancer (OC) patients included in the NeoPembrOV phase II trial (NCT03275506). Methods: PD-L1 expression was assessed for 85 patients (56 on metastasis, 29 on tubo-ovary) using tumor proportion score (TPS) and immune cell (IC) score, considering positivity if ≥ 1% and high expression if ≥ 5%. RNA sequencing and multiplex immunofluorescence were conducted. The Australian Ovarian Cancer Study (AOCS) was used as an external validation cohort. Results: PD-L1 was primarily expressed by tumor cells (TCs) in tubo-ovaries and by ICs in metastases. IC-score assessed on the metastases was associated with a longer PFS in the pembrolizumab arm compared to the control arm. Compared to tubo-ovaries, metastases were enriched in T and B cells as well as in GZMBCD8 cytotoxic T cell signatures. In metastases, IC-score was associated with immune infiltration and overexpression of additional immune checkpoints such as IDO1, LAG3, ICOS while TPS was associated with cell proliferation, immune infiltration and interferon-gamma pathways. In tubo-ovaries, TPS was associated with pathways linked to cell proliferation and antigen presentation but depleted in activated immune pathways, and CD274 expression was correlated with hypoxia and PI3K/Akt/mTOR signaling. Discussion: Distinct PD-L1 expression patterns across tissue type are associated with different biological pathways and TME in OC impacting PD-L1 predictive value. Our results provide novel insights in HGSC biology for tailoring immunotherapy in OC patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066785","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 single arm phase 2 trial of doxorubicin plus zalifrelimab (anti-CTLA-4 antibody) and balstilimab (anti-PD-1 antibody) in advanced/metastatic soft tissue sarcomas","authors":"Breelyn A. Wilky, Katherine A. Julian, Alessandra Maleddu, Anne C. Mailhot, Chelsey R. Cartwright, Dexiang Gao, Cristiam Moreno Tellez, Lindsey E. Kemp, Nicholas R. Therrien, Sumra S. Chaudhry, Jeffrey D. Rytlewski, Qierra R. Brockman, Eduardo Davila, Anthony D. Elias","doi":"10.1158/1078-0432.ccr-25-0618","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0618","url":null,"abstract":"Purpose: Doxorubicin is standard chemotherapy for metastatic soft tissue sarcomas (STSs) but also enhances innate/adaptive immune responses by inducing immunogenic cell death. Most STSs are immune “cold” tumors that do not respond to immune checkpoint inhibitors (ICIs) blocking PD-1 and CTLA-4. We hypothesized that concurrent doxorubicin would improve tumor immunogenicity and boost efficacy of ICIs in STS. Patients and Methods: We conducted a single arm, phase 2 trial of doxorubicin plus zalifrelimab (anti-CTLA-4 antibody) and balstilimab (anti-PD-1 antibody) for advanced/metastatic STS patients without prior doxorubicin or ICIs (NCT04028063). The study was a Simon minimax two-stage design to accrue 28 patients evaluable for primary endpoint of progression-free survival rate at six months (PFS6mo) by RECIST 1.1. The study aimed to improve PFS6mo by 20% over historical null rate of 43.4% with doxorubicin monotherapy. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and adverse events (AEs). Results: PFS6mo for 28 evaluable patients was 46.4% [95% CI 27.5-66.1] and not superior to null rate, with median PFS of 25.3 weeks [95% CI 24.0-42]. Best ORR was 33.3% [95% CI 17.3-52.8] with DCR of 80.0% [95% CI 61.4-92.3], including STS types unlikely to respond to doxorubicin or ICIs alone. Grade 3/4 treatment-related AEs occurred in 45% of patients, with immune-mediated AEs requiring immunosuppression in 9%. Conclusions: Although the study did not meet the predefined endpoint for PFS improvement, promising signals of efficacy warrant future investigation including response/resistance biomarkers to inform patient selection.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066783","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":"Innovative Therapeutic Strategies Targeting the Network Architecture of Glioblastoma","authors":"Julius Beichert, Dirk C. Hoffmann, Frank Winkler, Miriam Ratliff","doi":"10.1158/1078-0432.ccr-25-0018","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0018","url":null,"abstract":"Recent discoveries concerning the network architecture of glioblastoma, including tumor microtubules (TMs) and neuron-glioma synapses, have underscored critical pathways that sustain tumor growth, enhance resistance, and integrate glioblastoma with the surrounding neural environment. This review explores emerging therapeutic strategies targeting these pathways, including inhibitors of gap junctions, AMPA receptors, and glutamate signaling, which are currently being tested in clinical trials. By consolidating these advances, this review seeks to bridge the gap between neurobiology, cancer neuroscience, and oncology, proposing novel approaches to overcome resistance and improve patient outcomes. The insights derived from this comprehensive review hold the potential to significantly influence the future management of glioblastoma.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"122 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066784","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":"Porustobart (HBM4003) plus toripalimab as second-line therapy in patients with advanced hepatocellular carcinoma: a multicenter, open-label, phase I study","authors":"Ningning Zhang, Tian Liu, Ming Luo, Jihui Hao, Shukui Qin, Yanqiao Zhang, Gang Wang, Yajin Chen, Jingdong Zhang, Shanzhi Gu, Junqi Niu, Guijie Xin, Ge Yu, Yabing Guo, Chongyuan Xu, Jun Yao, Jie Shen, Aibing Xu, Shuwen Zhang, Di Yang, Meijuan Gao, Ruixuan Luo, Yebo He, Fei Zheng, Nan Cao, Xiaolu Tao","doi":"10.1158/1078-0432.ccr-24-3412","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3412","url":null,"abstract":"Purpose: To evaluate porustobart (HBM4003), a novel anti-CTLA-4 monoclonal antibody, combined with toripalimab as second-line therapy in advanced HCC. Patients and Methods: This phase I study included two cohorts of patients with advanced HCC: cohort 1 included patients who were anti-PD-1/PD-L1 naïve and had received first-line anti-VEGFR- tyrosine kinase inhibitor; cohort 2 included patients who had failed prior first-line anti-PD-1/PD-L1 and anti-VEGF/VEGFR therapies. Porustobart (0.45 mg/kg) and toripalimab (240 mg) were administered every 21 days. The primary endpoint was the objective response rate (ORR). Results: Totally, 16 patients were enrolled in cohort 1 and 12 in cohort 2. In the 26 patients with evaluable efficacy data, ORR was 23.1% (95% CI 9.0-43.6). Cohort 1 exhibited an ORR of 40.0%, while cohort 2 presented no objective response. The median progression-free survival was 4.2 months, with 5.7 months for cohort 1 and 3.8 for cohort 2. Biomarker exploration revealed higher abundance of intratumoral Tregs in responders before treatment, and a substantial elevation of CD4+Ki67+ and CD8+Ki67+ T cells after treatment. For safety, treatment-emergent adverse events were reported in 27 (96.4%) patients, treatment-related adverse events (TRAEs) were reported in 25 patients (89.3%), among whom 13 (46.5%) had grade ≥3 TRAEs. Serious adverse events (SAEs) were observed in 12 patients (42.9%), and treatment-related SAEs were observed in 9 (32.1%) patients. Conclusions: The combination of porustobart and toripalimab shows promising efficacy as a second-line therapy in anti-PD-1/PD-L1 naïve patients with advanced HCC and a manageable safety profile. Trial Registration: ClinicalTrials.gov identifier: NCT05149027.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"29 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066787","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":"Phase I/II Study of Tifcemalimab, an Anti-B and T-lymphocyte Attenuator Antibody, in Combination with Toripalimab in Previously Treated Advanced Lung Cancer","authors":"Ying Cheng, Jie Wang, Yan Yu, QiMing Wang, Runxiang Yang, Bing Xia, Chong Li, Dongqing Lv, Tienan Yi, Liang Han, Xiao-Qing Liu, Xi-Cheng Wang, Wei Zhang, Man Su, Minjie Shen, Jing Xu, Bang.an Peng","doi":"10.1158/1078-0432.ccr-25-0022","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0022","url":null,"abstract":"Purpose: Tifcemalimab is a recombinant humanized IgG4k monoclonal antibody targeting B and T-lymphocyte attenuator (BTLA). Co-blockade of BTLA and programmed death-1 pathways improved outcomes in non-clinical models. This phase I/II trial evaluated the safety and preliminary efficacy of tifcemalimab plus toripalimab in advanced lung cancer. Patients and Methods: Eligible patients with pathologically confirmed advanced non-small cell lung cancer (NSCLC) without sensitive epidermal growth factor receptor variation and anaplastic lymphoma kinase fusion who failed standard treatment including one programmed death-(ligand) 1 inhibitor, or refractory extensive-stage small cell lung cancer (SCLC) received tifcemalimab (200 mg) and toripalimab (240 mg) every 3 weeks intravenously until disease progression or intolerable toxicity. Simon’s two-stage optimal design was used in expansion part. The primary endpoints included safety and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Results: Totally, 24 patients with NSCLC and 43 with SCLC were enrolled (median age of all patients, 60.0 years). All patients with NSCLC and 14 (32.6%) with SCLC had received previous immunotherapy. Fifty-five (82.1%) patients experienced treatment-related adverse events (AEs), and 5 (7.5%) patients reported grade ≥3 immune-related AEs. For NSCLC, ORR was 4.3%, and disease control rate (DCR) was 47.8%; median progression-free survival (PFS) and overall survival (OS) was 1.5 and 18.9 months, respectively. For SCLC, ORR and DCR were 35.0% and 55.0%, respectively; median duration of response, PFS, and OS were 5.7, 2.8, and 12.3 months, respectively. Conclusions: Tifcemalimab plus toripalimab showed promising antitumor activities with acceptable safety, especially, in advanced refractory SCLC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066786","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}