Investigational New Drugs最新文献

{"title":"Comparative efficacy of CLDN18.2-directed regimens in advanced gastric/gastroesophageal junction adenocarcinoma: a meta-analysis of single-arm trials.","authors":"Yue Yuan, Hongkai Yan, Qinhang Wu","doi":"10.1007/s10637-026-01635-x","DOIUrl":"https://doi.org/10.1007/s10637-026-01635-x","url":null,"abstract":"<p><strong>Objective: </strong>To compare the efficacy and safety of different Claudin (CLDN)18.2-directed regimens in advanced gastric/gastroesophageal junction adenocarcinoma.</p><p><strong>Methods: </strong>PubMed, Web of Science, CNKI, and Wanfang databases were searched up to June 2026. Single-arm trials evaluating CLDN18.2-targeted gastric/gastroesophageal junction adenocarcinoma therapies were included. Meta-analysis was performed to pool objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and safety outcomes.</p><p><strong>Results: </strong>Ten studies (710 patients) were included. The pooled mPFS was 4.19 months (95% CI 2.90-5.49), the pooled ORR was 30.3% (95% CI 14.8%-48.1%), and the pooled DCR was 78.5% (95% CI 61.2%-92.1%). Subgroup analyses by treatment type revealed substantial efficacy differences. Zolbetuximab monotherapy showed limited activity (mPFS 1.84 months, ORR 4.8%, DCR 37.9%), which improved markedly when combined with chemotherapy (mPFS 6.61 months, ORR 63.7%, DCR 95.6%). Antibody-drug conjugates (ADCs) achieved notable efficacy in pretreated patients (mPFS 5.31 months, ORR 36.7%, DCR 84.3%). Chimeric antigen receptor T-cell (CAR-T) therapy demonstrated substantial anti-tumor activity (mPFS 5.80 months, ORR 54.2%, DCR 96.1%), but the evidence was based on a single study and should be considered preliminary.</p><p><strong>Conclusion: </strong>Zolbetuximab plus chemotherapy is the preferred strategy for patients eligible for chemotherapy. ADCs represent a viable option for patients with chemotherapy resistance or intolerance. Zolbetuximab monotherapy has limited efficacy and should be used sparingly. CAR-T showed promising activity but remains investigational.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parthenolide enhances imatinib activity in gastrointestinal stromal tumor models through stress-associated apoptosis.","authors":"Chuang-Ming Zheng, Longyi Piao, Zhenggen Piao, Chun-Hua Zheng, Dongyuan Xu, Xi-Hui Li, Pengcheng Wei, Cho Park, Toufeng Jin","doi":"10.1007/s10637-026-01631-1","DOIUrl":"https://doi.org/10.1007/s10637-026-01631-1","url":null,"abstract":"<p><p>Imatinib remains a mainstay of treatment for gastrointestinal stromal tumors (GISTs), yet responses may be incomplete or short-lived. We examined whether parthenolide (PTL) enhances imatinib activity in GIST models and characterized the cellular changes associated with combined treatment. Public GIST transcriptomic datasets were analyzed as hypothesis-generating resources. GIST-T1 and GIST-882 cells were treated with PTL, imatinib, or their combination. Cell growth, migration, colony formation, apoptosis, reactive oxygen species, mitochondrial function and ultrastructure, ER-stress-associated proteins, and autophagy-associated markers were assessed. Antitumor activity was further examined in a GIST-T1 xenograft model. PTL and imatinib each inhibited GIST cell growth in a concentration-dependent manner. At the selected concentrations, the combination produced greater and more sustained suppression of cell viability, migration, and colony formation than either monotherapy. TUNEL staining and Annexin V-FITC/PI analysis showed increased apoptosis, accompanied by lower Bcl-2 expression and a higher Bax/Bcl-2 ratio. Combined treatment also increased DCF fluorescence, reduced mitochondrial membrane potential, caused mitochondrial ultrastructural abnormalities, increased p-IRE1α/IRE1α and CHOP, and altered PINK1, LC3B, and Beclin-1. In vivo, the combination showed the slowest mean tumor growth and the lowest endpoint tumor weight, without greater body weight loss than imatinib alone. PTL enhanced imatinib activity in imatinib-responsive GIST models. This effect was accompanied by apoptotic, oxidative, mitochondrial, ER stress-associated, and autophagy-associated changes; however, their causal relationships remain to be established.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-human phase I study of DT-9081, a selective EP4 receptor antagonist, in advanced solid tumors.","authors":"Rachel Galot, Zahra Castel-Ajgal, Nuria Kotecki, Christiane Jungels, Jean-Pierre Delord, Iphigenie Korakis, Samira El-Farouk, Claire Jouffroy-Zeller, Anne Quesnel, Carolina Duarte, Abdelkrim Taamma, Thomas Maurin, Lola Lecru, Antoine Mousson, Orphée Blanchard, Anne-Laure Blayo, Nathalie Lenne, Stephan Schann, Xavier Leroy, Jean-Marie Cuillerot, Christophe Le Tourneau, Jean-Pascal Machiels","doi":"10.1007/s10637-026-01636-w","DOIUrl":"https://doi.org/10.1007/s10637-026-01636-w","url":null,"abstract":"<p><p>DT-9081 is a selective antagonist of the prostaglandin E2 receptor EP4, developed to counteract tumor-driven immunosuppression. This first-in-human phase I study aimed at determining the dose-limiting toxicity/maximum tolerated dose (DLT/MTD) of DT-9081 and identifying the recommended phase II dose (RP2D) in patients with advanced solid tumors. This open-label, dose-escalation study enrolled patients with advanced (unresectable, recurrent or metastatic) solid tumors refractory to standard therapies. DT-9081 was administered orally once daily across six sequential dose cohorts (25-600 mg, daily). Primary objectives were safety and determination of the RP2D. Secondary objectives included efficacy, pharmacokinetics (PK) characterization, and pharmacodynamic (PD) assessment. Twenty-nine patients were treated. One dose-limiting toxicity (grade 3 increased hepatic enzymes) was observed at the 50 mg dose level. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (55.2%), decreased appetite (24.1%), nausea (20.7%), vomiting (20.7%), and asthenia (20.7%). Most TEAEs were grade 1-2. Grade ≥ 3 DT-9081-related adverse events occurred in 2 (6.9%) patients (grade 3 diarrhea and grade 3 increased hepatic enzymes). DT-9081 exhibited dose-proportional PK with sustained plasma exposure exceeding preclinical IC50 thresholds at higher dose levels. Pharmacodynamic analyses demonstrated dose-dependent reversal of EP4-mediated suppression of TNF-α production, confirming target engagement. Based on integrated safety, PK, and PD data, 600 mg once daily was selected as the RP2D, despite the absence of meaningful clinical activity. MTD was not reached and pharmacodynamic activity was consistent with EP4R antagonism. These findings support further clinical development of DT-9081, including evaluation in immunotherapy-based combination regimens.EUCT Number: 2024-516206-28-00;NCT05582850.Study registration date: 10/10/2022.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of LGALS3 polymorphisms on chemotherapy-induced peripheral neuropathy in patients with metastatic pancreatic cancer treated with gemcitabine and nab-paclitaxel: an exploratory biomarker analysis of the GENESECT study.","authors":"Masahiro Hatori, Daiki Tsuji, Kyoka Nagai, Rei Arafune, Takashi Yokokawa, Kazuyoshi Kawakami, Wataru Suzuki, Naoki Shibata, Naoki Sasahira, Masato Ozaka, Masakazu Yamaguchi, Tomonobu Uchino, Kunihiko Itoh","doi":"10.1007/s10637-026-01632-0","DOIUrl":"https://doi.org/10.1007/s10637-026-01632-0","url":null,"abstract":"<p><p>Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting factor and determinant of treatment continuation in patients receiving anticancer drugs. CIPN often persists even after treatment discontinuation and negatively impacts patients' quality of life. At present, the risk factors for CIPN development remain unclear. This study aimed to exploratively examine the association between genetic polymorphisms and CIPN in Japanese patients with metastatic pancreatic cancer treated with gemcitabine and nab-paclitaxel (GnP) as first-line chemotherapy. This exploratory analysis of the GENESECT dataset included 65 patients with metastatic pancreatic cancer who received GnP therapy. The association of 14 genetic polymorphisms with CIPN was analyzed by multivariate Firth logistic regression with Benjamini-Hochberg correction for multiple comparisons. The Kaplan-Meier curves among genetic polymorphisms were analyzed using log-rank test to compare the cumulative dosage of nab-paclitaxel until CIPN ≥ grade 2. Results were considered significant at p < 0.05. The AA and AC variants of LGALS3 rs4652 tended to be associated with CIPN ≥ grade 2 (adjusted odds ratio (OR), 0.248; 95% confidence interval (CI), 0.055-1.02, p = 0.053), and a cumulative dose of nab-paclitaxel ≥ 1625 mg/m² (median) was significantly associated (adjusted OR, 6.72; 95% CI, 2.02-27.0, p = 0.002). Patients with AA and AC variants of LGALS3 rs4652 tended to have larger median cumulative dosages of nab-paclitaxel until the development of CIPN ≥ grade 2 (4050 mg/m² vs. 1600 mg/m², p = 0.073). LGALS3 rs4652 may represent a promising candidate biomarker that requires prospective validation.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Qishen Yiqi Dripping Pills ameliorate doxorubicin-induced cardiotoxicity: a study based on bioinformatics and experimental verification.","authors":"Jiangtao Wang, Jian Yu, Dong Cao, Bohua Ma, Huihua Shen, Juan Liu, Yuan Yuan, Rui Wang, Wu Li","doi":"10.1007/s10637-026-01634-y","DOIUrl":"https://doi.org/10.1007/s10637-026-01634-y","url":null,"abstract":"<p><p>Qishen Yiqi Dripping Pills (QSYQ) have shown promising therapeutic effects on cardiovascular diseases. Recent studies have reported their potential in mitigating doxorubicin-induced cardiotoxicity (DIC), but the primary active ingredients and specific mechanisms remain unclear. A total of 2740 differentially expressed genes (DEGs) were screened out. GSEA results were mainly enriched in Glycolysis, Apoptosis, Cellular Senescence, PI3K/Akt Signaling Pathway, TGF Beta Signaling Pathway, etc. Weighted gene co-expression network analysis yielded 1520 key module genes, and 1134 DIC-related genes were obtained by intersecting with DEGs. A total of 130 active ingredients and 943 target genes of QSYQ were obtained, and 50 common targets were identified after intersecting with DIC-related genes. The top 5 active ingredients were DFV, quercetin, Vestitone, formononetin and (6aR,11aR)-9,10-dimethoxy-6a,11a-dihydro-6H-benzofurano[3,2-c]chromen-3-ol. GO and KEGG enrichment analyses showed a close relationship with the HIF-1 signaling pathway and its upstream and downstream components. Three key genes identified were EP300, JUN, and CREBBP. Receiver operating characteristic analysis demonstrated good diagnostic value for these key genes, and their DOX-induced expression alterations were reversed by QSYQ (limited experimental evidence). Notably, the experimental validation of JUN showed a trend opposite to that observed in the bioinformatics analysis. Molecular docking revealed good binding capabilities of the primary active ingredients with the key genes. QSYQ may alleviate DIC through EP300, JUN, and CREBBP, providing new evidence for the use of QSYQ in ameliorating DIC.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of SHP2 enhances the effects of selective receptor tyrosine kinase inhibitors in untreated preclinical models of RET-mutated thyroid cancer.","authors":"Wenjun Xie, Mengrang Tian, Weike Ma, Ying Sun, Linfei Hu, Yu Zeng, Xing Chen, Xianhui Ruan, Xiangqian Zheng, Ming Gao","doi":"10.1007/s10637-026-01633-z","DOIUrl":"https://doi.org/10.1007/s10637-026-01633-z","url":null,"abstract":"<p><p>RET rearrangements and activating point mutations are major oncogenic drivers in thyroid cancer. Although selective RET inhibitors such as selpercatinib (LOXO-292) and pralsetinib (BLU-667) induce significant clinical responses, adaptive resistance frequently arises through reactivation of MAPK signaling. The molecular mechanisms underlying sustained ERK activation in residual RET-mutated thyroid cancer cells remain incompletely defined. Here, we investigated whether SHP2 mediates adaptive ERK reactivation following RET inhibition. RET-mutated thyroid cancer cell lines (TPC-1 and TT) were treated with selective RET inhibitors alone or in combination with the SHP2 inhibitor SHP099. RET inhibition initially suppressed ERK phosphorylation and was followed by compensatory transcriptional upregulation of multiple receptor tyrosine kinases, including MET, EGFR, FGFR2, and PDGFRB, together with ERK reactivation. Pharmacologic inhibition or knockdown of SHP2 attenuated this adaptive MAPK response and sustained ERK suppression. Combined targeting of RET and SHP2 significantly reduced cell proliferation in vitro and produced marked tumor growth inhibition in a TPC-1 xenograft model without significant loss of body weight. These findings support SHP2 as an important mediator of adaptive ERK reactivation following RET inhibition. Dual blockade of RET and SHP2 produces more durable MAPK pathway suppression and enhances antitumor efficacy in the models tested, providing a rationale for further evaluation of this combination in RET-altered thyroid cancer.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells.","authors":"Ludovica Taglieri, Giovanna Rubinacci, Anna Giuffrida, Simone Carradori, Susanna Scarpa","doi":"10.1007/s10637-026-01617-z","DOIUrl":"10.1007/s10637-026-01617-z","url":null,"abstract":"","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"337"},"PeriodicalIF":3.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical and clinical evaluation of futibatinib in combination with binimetinib in patients with advanced cancer.","authors":"Jordi Rodon, Bert O'Neil, Christopher Lim, Natraj R Ammakkanavar, Carlos Torrado, Kazuaki Matsuoka, Hiroshi Hirai, Akihiro Miura, Bailey Anderson, Leah Jin, Nanae Hangai, Amanda Long, Volker Wacheck, Lee Rosen","doi":"10.1007/s10637-026-01618-y","DOIUrl":"10.1007/s10637-026-01618-y","url":null,"abstract":"<p><strong>Introduction: </strong>KRAS-mutant NSCLC resistance to MEK inhibitors (MEKi) is related to compensatory upregulation of fibroblast growth factor receptor (FGFR) signaling. Futibatinib is a potent, covalent FGFR1-4 inhibitor approved for locally advanced/metastatic cholangiocarcinoma with FGFR2 fusions. We conducted a bench-to-bedside study evaluating futibatinib plus the MEKi binimetinib preclinically, followed by a Phase Ib trial of patients with advanced cancer.</p><p><strong>Methods: </strong>The effect of futibatinib ± MEKi on cell signaling and proliferation of KRASmt NSCLC lines (A549, LU99) were assessed in vitro. In a Phase Ib study, patients with advanced cancer who had exhausted standard therapies received futibatinib QD plus binimetinib BID orally following a \"3 + 3\" dose-escalation design. Primary objective was to establish the recommended Phase 2 dose (RP2D) based on safety. Secondary endpoints included pharmacokinetics and anti-tumor activity.</p><p><strong>Results: </strong>In vitro, MEKi with futibatinib resulted in additive or synergistic anti-tumor activity in KRASmt NSCLC lines. Twenty-three patients received futibatinib with binimetinib at 4 dose levels. The most prevalent adverse events were reversible retinopathies in 20 patients, including 2 DLTs and limiting dose escalation beyond futibatinib 16 mg QD plus binimetinib 15 mg BID (MTD). There were no relevant drug-drug interactions between binimetinib and futibatinib. One patient harboring an FGFR2 fusion had a partial response. No RP2D could be defined as the MTD was below active dose levels of binimetinib.</p><p><strong>Conclusion: </strong>Despite additive anti-tumor activity for FGFR and MEK inhibition in KRASmt NSCLC lines, the trial was stopped after dose escalation, as no RP2D was identified for futibatinib/binimetinib due to reversible retinopathies. Trial register number. NCT04965818. Trial registration date. 20-September-2021.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"295-304"},"PeriodicalIF":3.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147963708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I trial of the anti-IL23 monoclonal antibody tildrakizumab, in combination with abiraterone acetate, for the treatment of metastatic castration-resistant prostate cancer.","authors":"Khobe Chandran, Christina Guo, Simon Pacey, Guillermo Villacampa, Ruth Matthews, Toby Prout, Joan Fernandes, Alison Turner, Mona Parmar, Ruth Riisnaes, Ana Ferreira, Suzanne Carreira, Claudia Bertan, Mateus Crespo, Ines Figueiredo, Wei Yuan, Denisa Bogdan, Florence Raynaud, Ruth Ruddle, Bianca Calì, Martino Maddalena, Arianna Calcinotto, Christina Yap, Adam Sharp, Andrea Alimonti, Johann De Bono, Alec Paschalis","doi":"10.1007/s10637-026-01619-x","DOIUrl":"10.1007/s10637-026-01619-x","url":null,"abstract":"<p><strong>Background: </strong>Interleukin-23 (IL23) has been reported to drive androgen receptor (AR) and JAK2-STAT3 signaling, promoting treatment resistance and disease progression in advanced prostate cancer (PC). We evaluated the safety, tolerability, and antitumor activity of the anti-IL23 monoclonal antibody tildrakizumab in combination with the AR pathway inhibitor (ARPI) abiraterone acetate (AA) in men with ARPI-resistant metastatic castration-resistant PC (mCRPC).</p><p><strong>Methods: </strong>mCRPC patients of ECOG performance status (PS) ≤ 2, who had previously progressed on first-line ARPI therapy, were treated with tildrakizumab (100 mg, 300 mg, 600 mg; 4-weekly) in combination with AA (YonsaTM, 500 mg daily). The primary objective was to determine the recommended phase 2 dose. Secondary endpoints were elucidation of pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.</p><p><strong>Results: </strong>No dose limiting toxicities (DLTs) were observed, nor any grade ≥ 3 adverse effects (AEs). The most common treatment-related AEs attributable to tildrakizumab were grade 1-2 fatigue (n = 3/12; 25.0%) and grade 1 nausea (n = 2/12; 16.7%). PK analyses showed no obvious drug-drug interactions. Overall, no objective responses were observed. Median progression free survival (PFS) was 3.7 months (n = 10; 95% CI 1.6-not reached) with median overall survival (OS) of 9.7 months (n = 10; 95% CI 6.9-not reached).</p><p><strong>Conclusions: </strong>Tildrakizumab and abiraterone acetate combination therapy is well tolerated but did not show clinical efficacy in this small, unselected, cohort of ARPI-resistant mCRPC patients. Further study into the causes of primary resistance to IL23 targeting in mCRPC, and development of biomarkers of downstream IL23-IL23R activity, are now needed to translate IL23 blockade into the clinic.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"285-294"},"PeriodicalIF":3.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147948542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 1 study of PF-07260437, a B7-H4 × CD3 bispecific T-cell engager, in patients with advanced or metastatic breast, ovarian, and endometrial cancer.","authors":"Fengting Yan, Marcia Cruz-Correa, Jennifer Specht, Edward Wenge Wang, Jinyu Lu, Hatem Soliman, Amy Jackson-Fisher, Szu-Yu Tang, Sibo Jiang, Christophe Le Corre, Meng Li, David Sommerhalder","doi":"10.1007/s10637-026-01614-2","DOIUrl":"10.1007/s10637-026-01614-2","url":null,"abstract":"<p><p>B7-H4 is overexpressed in various cancers, making it a promising target for cancer immunotherapy. This phase 1, open-label, first-in-human study in patients with advanced/metastatic breast, ovarian and endometrial cancer evaluates the safety, pharmacokinetics (PK), and anti-tumour activity of PF-07260437, a novel B7-H4xCD3 bispecific T-cell engager. Enrolled patients received escalating doses of PF-07260437 (with/without priming dose) subcutaneously every two weeks, with a starting dose of 100 µg. Primary objectives included determination of maximum tolerated dose (MTD)/recommended dose for expansion (RDE), safety and tolerability. Secondary objectives included PK parameters and immunogenicity. Bayesian logistic regression model (BLRM) was used to guide dose escalation. Thirty patients with advanced/metastatic breast, ovarian and endometrial cancer received the study treatment during dose escalation; all were female (median age, 61.0 [41-75] years). Four patients (13.3%) experienced DLTs (alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, cytokine release syndrome). Overall, 29 (96.7%) patients experienced 202 treatment-related TEAEs (no grade 4/5 TEAEs); no TEAE resulted in study discontinuation. No objective response was observed. Disease control rate (DCR) was 33.3% (95% CI: 17.3%, 52.8%). PF-07260437 ≥ 300 μg resulted in exposures in the theoretic efficacious range, with a transient increase in serum cytokines levels following the first dose. The study was terminated by the Sponsor based on the overall assessment of the observed clinical safety, preliminary efficacy, pharmacokinetic and pharmacodynamic data. The MTD was not reached. PF-07260437 was tolerable in patients with breast, ovarian, and endometrial cancers with manageable TEAEs. TRIAL REGISTRATION NUMBER: NCT05067972. REGISTRATION DATE: 5 October, 2021.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"305-316"},"PeriodicalIF":3.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}