Investigational New Drugs最新文献

{"title":"Evaluation of the anti-leukemia activity and underlying mechanisms of the novel perinucleolar compartment inhibitor CTI-2 in acute myeloid leukemia.","authors":"Anran Li, Mingmin Yu, Yue Zhao, Shuangshuang Wu, Guan Wang, Liping Wang","doi":"10.1007/s10637-025-01516-9","DOIUrl":"https://doi.org/10.1007/s10637-025-01516-9","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a malignant clonal hematological tumor originating from immature myeloid cells and is the most prevalent type of leukemia in adults. Traditional chemotherapy regimens based on cytarabine and anthracycline agents are associated with a high relapse rate. Therefore, investigation of novel targeted therapies is crucial for improving AML treatment outcomes. In this study, we found that CTI-2, a novel inhibitor of perinucleolar compartment (PNC), has potential anti-AML activity with a favorable safety profile. CTI-2 induced a greater degree of apoptosis in FLT3-ITD mutant AML cells compared to AML cells with wild-type FLT3 mainly through the intrinsic apoptotic pathway. Furthermore, MK2 and Pim-1 were identified as potential targets of CTI-2 through molecular docking analysis. CTI-2 decreased both the overall expression level and the phosphorylation of c-Myc, which are regulated by MK2 and Pim-1, respectively. Notably, CTI-2 exhibited a more substantial inhibitory effect on c-Myc in FLT3-ITD mutant cells, which may contribute to the enhanced efficacy of CTI-2 in this specific subset of AML. In summary, we have conducted a preliminary investigation into the anti-AML activity and underlying mechanisms of CTI-2. These results provide clues for the targeting of PNC in the treatment of AML.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199289","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":"Rucaparib induces mitochondrial fragmentation and apoptosis in prostate cancer cells by targeting Drp1.","authors":"Xiaodong Lu, Yishu Lin, Hao Tang, Zhigang Chen, Kewei Tang","doi":"10.1007/s10637-025-01586-9","DOIUrl":"https://doi.org/10.1007/s10637-025-01586-9","url":null,"abstract":"<p><p>Mitochondrial dynamics, particularly the balance between fission and fusion, are critical in regulating cellular metabolism, apoptosis, and cancer progression. Dysregulation of this balance contributes to tumor survival and therapeutic resistance in castration-resistant prostate cancer (CRPC). Rucaparib, a clinically approved poly (ADP-ribose) polymerase (PARP) inhibitor, is primarily known for its role in DNA damage repair; however, its impact on mitochondrial function remains largely unexplored. In this study, we demonstrate that Rucaparib induces significant cytotoxicity and apoptosis in PC-3 CRPC cells in a time- and concentration-dependent manner, characterized by increased Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 activation. Mechanistically, Rucaparib disrupts mitochondrial integrity by reducing mitochondrial membrane potential (MMP), inhibiting Complex IV activity, and depleting ATP levels. Confocal imaging and biochemical assays reveal that Rucaparib triggers mitochondrial fragmentation by promoting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and enhancing its translocation to mitochondria. This process is accompanied by elevated intracellular Ca²⁺ levels and activation of calcium/calmodulin-dependent protein kinase II (CaMKII), suggesting a Ca²⁺/CaMKII/Drp1 signaling axis. Importantly, pharmacological inhibition of CaMKII with KN-93 reverses Drp1 mitochondrial translocation, restores mitochondrial morphology, and partially rescues ATP production, confirming the functional role of CaMKII in Rucaparib-induced mitochondrial dysfunction. These findings uncover a previously unrecognized mechanism of Rucaparib action beyond DNA repair inhibition, highlighting its ability to target mitochondrial dynamics and bioenergetics through Ca²⁺/CaMKII/Drp1 signaling. Our results provide new insights into the multifaceted anticancer mechanisms of Rucaparib and suggest that modulation of mitochondrial fission may offer a promising therapeutic avenue for CRPC.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102962","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":"Phase I results on the efficacy, safety and pharmacokinetics of lurbinectedin and irinotecan in advanced solid tumors.","authors":"Alejandro Falcón, Santiago Ponce, Gregory M Cote, Ana Gil, Jessica J Lin, Bruno Bockorny, Julia Martínez, Carmen Kahatt, Sara Martinez, Pablo Zubiaur, Mariano Siguero, Martin Cullell-Young, Javier Jiménez, Jon Zugazagoitia, Luis Paz-Ares","doi":"10.1007/s10637-025-01583-y","DOIUrl":"https://doi.org/10.1007/s10637-025-01583-y","url":null,"abstract":"<p><p>Lurbinectedin and irinotecan showed synergistic antitumor activity when combined in preclinical studies, and have non-completely overlapping toxicity profiles. A two-stage phase I/II trial was designed to evaluate the combination. The first (dose escalation) stage of the trial assessed two schedules, lurbinectedin on Day (D)1 plus irinotecan on D1,D8 or D1 every three weeks in 83 patients with relapsed advanced solid tumors. Two recommended doses (RDs) were defined for lurbinectedin on D1 plus irinotecan on D1,D8: lurbinectedin 2.0 mg/m² plus irinotecan 75 mg/m², and lurbinectedin 3.0 mg/m² plus irinotecan 40 mg/m², both with primary growth factor prophylaxis. No RD was defined for lurbinectedin on D1 plus irinotecan on D1. Lurbinectedin on D1 plus irinotecan on D1,D8 q3wk showed a manageable safety profile at the RDs, with most common toxicities being myelosuppression, fatigue and gastrointestinal disorders. No toxic deaths occurred. Thirteen confirmed partial responses and 24 disease stabilizations ≥ 4 months were found at all dose levels, including the RDs. Compared to other tumor types, antitumor activity was higher in small cell lung cancer (SCLC), soft tissue sarcoma (synovial), endometrial carcinoma, glioblastoma and pancreatic adenocarcinoma. No major pharmacokinetic interaction was found between lurbinectedin and irinotecan. The second (expansion) stage of the trial is evaluating the RD of lurbinectedin 2.0 mg/m² plus irinotecan 75 mg/m² with primary growth factor prophylaxis in selected advanced solid tumors. An ongoing phase III trial is also evaluating the combination in second-line SCLC after prior platinum-containing chemotherapy. Trial registration number: NCT02611024 (Nov 20, 2015).</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080577","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":"Comparative analysis of the effects of PSPH and PHGDH inhibitors on tumor cell proliferation.","authors":"Yanbing Wang, Longze Sha","doi":"10.1007/s10637-025-01581-0","DOIUrl":"https://doi.org/10.1007/s10637-025-01581-0","url":null,"abstract":"<p><p>Serine metabolism plays a pivotal role in supporting the rapid proliferation of tumor cells, with PHGDH recognized as a key rate-limiting enzyme and therapeutic target. However, whether its antitumor effects rely exclusively on serine metabolism remains controversial. In this study, we compared the effects of PHGDH and PSPH inhibitors on serine metabolism and cell proliferation in the breast cancer cell lines HCC-70 and BT-20. While two PSPH inhibitors markedly reduced cellular serine M + 3 levels, they failed to effectively inhibit cell proliferation. In contrast, PHGDH inhibitors exhibited robust antiproliferative activity under both serine-deprived and serine-supplemented conditions. Furthermore, supplementation with α-ketoglutarate, a downstream metabolite of PHGDH, partially reversed this inhibitory effect. These findings indicate that the antitumor activity of PHGDH inhibition cannot be solely attributed to blockade of serine biosynthesis, but rather arises from the coordinated disruption of multiple metabolic pathways. This provides new insights into the potential of metabolic targeting strategies for cancer therapy.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040152","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":"Association of different approvals with Chinese Society of Clinical Oncology recommendation levels for solid tumor drugs: a cross-sectional analysis.","authors":"Lirong Zhang, Hongbin Yi, Liping Kuai, Sheng Han, Hong Sun, Jiaqin Cai, Xiaoxia Wei","doi":"10.1007/s10637-025-01584-x","DOIUrl":"https://doi.org/10.1007/s10637-025-01584-x","url":null,"abstract":"<p><p>In China, many solid tumor drugs have been approved via the accelerated approval (AA) pathway. We extracted data regarding indications for solid tumor-treating drugs approved by the National Medical Products Administration (NMPA) between 2015 and 2023, along with their corresponding Chinese Society of Clinical Oncology (CSCO) guideline recommendation levels and inclusion data. Descriptive statistics, Fisher's exact tests, and t-tests were used to examine associations between NMPA approval pathways and CSCO guideline recommendation levels. The study included 92 solid tumor drugs comprising 191 indications. Sixty-three indications were approved via the regular approval (RA), and 128 were approved via the AA. One hundred fifty-seven indications obtained CSCO guideline recommendation level I, 28 obtained level II, and 6 obtained level III. No significant difference in the recommendation level was observed between the approval pathways. The average time for the indications approved via the RA to obtain the recommendation level was 2.03 months before NMPA approval. The average time for the indications approved via the AA to obtain the level was 6.66 months after NMPA approval. Compared with initial levels, 57 indications had their recommendation levels upgraded. Most indications obtain the CSCO guideline recommendation level I, with similar likelihoods across obtaining different approval pathways. Indications approved via the RA tended to obtain the CSCO guideline recommendation earlier than those via the AA. Given the limitations in data completeness and CSCO guideline coverage, these findings should be interpreted with caution. Clearer criteria for evaluating recommendation levels and standardizing rating procedures will enable CSCO guidelines to better support clinicians and patients.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023266","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":"Targeting the Keap1/Nrf2 axis in cancer: molecular mechanisms and pharmacological interventions.","authors":"Yangchen Xia, Ziyang Xu, Xun Yuan, Qian Chu","doi":"10.1007/s10637-025-01578-9","DOIUrl":"https://doi.org/10.1007/s10637-025-01578-9","url":null,"abstract":"<p><p>The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is the first-line regulator of a plethora of cytoprotective pathways, such as inflammation, redox metabolism, and proteostasis. Besides its protective role in oxidative stress, several recent advances suggested that the Nrf2 pathway is extensively involved in cancer pathogenesis and confers a survival advantage and malignant transformation. Therefore, pharmacological inhibition of Nrf2 is a potential therapeutic approach for cancer that is related to oxidative stress and inflammation. In this review, we first describe the molecular regulatory mechanisms of Nrf2 and its biological function in cancer. Then, we discuss the recent progress of blocking Nrf2 activity, comprising novel chemical molecules, and the advance in preclinical or clinical trials in cancer therapy.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000533","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":"Targeting the TRIB3-MYC axis in cancer: mechanistic insights and therapeutic disruption strategies.","authors":"Emadeldin M Kamel, Sulaiman A Alsalamah, Ahmed A Allam, Noha A Ahmed, Faris F Aba Alkhayl, Al Mokhtar Lamsabhi","doi":"10.1007/s10637-025-01582-z","DOIUrl":"https://doi.org/10.1007/s10637-025-01582-z","url":null,"abstract":"<p><p>The oncogenic transcription factor MYC drives proliferation, metabolism, and therapy resistance in the majority of human cancers, yet its large, nuclear protein-protein interface has long frustrated direct drug discovery. A pivotal breakthrough was the identification of Tribbles pseudokinase 3 (TRIB3) as a high-affinity scaffold that binds the helix-loop-helix/leucine zipper region of MYC, blocks the E3-ubiquitin-ligase, UBE3B, from tagging critical lysines, and thereby prolongs MYC protein half-life while enhancing MYC-MAX transcriptional output. This review integrates structural, biochemical, and in vivo data to show how genetic deletion or pharmacological eviction of TRIB3 collapses MYC levels, silences its gene program, and suppresses tumor growth in B-cell lymphomas and selected solid tumors. We detail two distinct solid-tumor circuits: (i) inducible TRIB3 overload in KRAS- or EGFR-mutant lung adenocarcinoma that triggers lethal paraptosis when mTOR is inhibited by everolimus plus ginsenoside Rh2; (ii) VHL-controlled UBE3B abundance in breast carcinoma, where loss of VHL renders tumors dependent on TRIB3 shielding for sustained MYC signaling. Emerging therapeutics include helix-mimetic and stapled peptides such as PCM4, fragment-derived small molecules that target a unique Glu344-centered pocket on TRIB3, and PROTAC degraders that either eliminate TRIB3 or hijack it to destroy MYC. When combined with DNA-damaging agents, BET or CDK7 inhibitors, or ligase-restoring strategies, these disruptors produce marked synergy in preclinical models. Remaining translational challenges-efficient intracellular delivery, biomarker-guided patient selection, and off-target surveillance-are increasingly tractable thanks to advances in peptide formulation, AI-accelerated screening, and established regulatory paths for targeted degraders. Collectively, current evidence positions the TRIB3-MYC interface as a druggable Achilles' heel and a realistic gateway to long-sought direct MYC blockade in the clinic.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992417","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":"A phase 1b/2 study of intermittent talazoparib plus temozolomide in patients with metastatic castration-resistant prostate cancer and no mutations in DNA damage response genes.","authors":"Karen A Autio, Christos E Kyriakopoulos, Paul Palyca, Han Xiao, Hamid Emamekhoo, Daniel Danila, Mehrin Jan, Victoria Catharine, Elyn Riedel, Michael Devitt, A Douglas Laird, Howard I Scher","doi":"10.1007/s10637-025-01580-1","DOIUrl":"https://doi.org/10.1007/s10637-025-01580-1","url":null,"abstract":"<p><p>As monotherapy, PARP inhibitors have little cytotoxic effect in tumors without homologous recombinant repair (HRR) alterations. Supported by preclinical models, we hypothesized that the PARP inhibitor talazoparib in combination with temozolomide chemotherapy could induce DNA damage leading to cell death and tumor response in patients with metastatic castration-resistant prostate cancer (mCRPC) without HRR alterations. In this phase 1b/2 trial (NCT04019327; registration date July 11, 2019), patients with progressive mCRPC without HRR mutations who failed at least one androgen receptor signaling inhibitor were enrolled in escalating doses of intermittent talazoparib plus temozolomide to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) in Phase 1b. Phase 2 used a composite endpoint of overall response per RECIST v1.1, 50% decline in prostate-specific antigen (PSA), and/or circulating tumor cells (CTC) conversion from ≥ 1 cell/7.5 mL to 0. Sixteen patients were enrolled across 4 dose levels. The most common adverse events were thrombocytopenia, neutropenia, anemia, fatigue, and nausea. In phase 1b, one patient receiving talazoparib 1 mg and temozolomide 75 mg/m² had a dose-limiting toxicity (grade 3 neutropenic fever, grade 4 thrombocytopenia). The RP2D was talazoparib 1 mg once daily (QD) (D1-6) and temozolomide 75 mg/m² QD (D2-8) in 28D cycles. The phase 2 portion was terminated early. Across dose levels, three (18.8%) patients met the efficacy endpoint. Hematologic toxicity was dose-limiting in this combination strategy using intermittent dosing of talazoparib and temozolomide in patients with mCRPC without HRR alterations. The risk/benefit profile did not support further evaluation.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992394","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":"Advanced strategies to overcome multidrug resistance in cancer therapy: progress in P-glycoprotein inhibitors, drug delivery, and personalized medicine.","authors":"Ankitha Harish, N Deepika, Vedamurthy Joshi, Prakash S Goudanavar","doi":"10.1007/s10637-025-01562-3","DOIUrl":"https://doi.org/10.1007/s10637-025-01562-3","url":null,"abstract":"<p><p>Multidrug resistance (MDR) appears to be a major challenge in cancer treatment, frequently leading to suboptimal clinical results and treatment failure. A transmembrane efflux pump called P-glycoprotein (P-gp) is essential to multidrug resistance because it actively transports various chemotherapeutic drugs out of cancer cells, lowering their intracellular concentrations and efficacy. To improve treatment approaches, it is essential to comprehend the structural and functional dynamics of P-glycoprotein and the genetic and epigenetic processes controlling its expression. From the early-generation drugs with poor clinical outcomes to the creation of new medications with enhanced selectivity, potency, and safety profiles, this article thoroughly summarizes the development of P-glycoprotein inhibitors. Enhancing medication bioavailability and overcoming P-glycoprotein-mediated efflux may be possible through the integration of sophisticated drug delivery methods, such as micellar formulations, liposomes, nanoparticles, and polymer-based carriers. Meanwhile, the rise of personalized medicine provides a revolutionary way to manage multidrug resistance through identifying biomarkers, genetic and proteomic characterization, and medication modification for each patient. Advanced tactics such as RNA interference, CRISPR-mediated gene editing, immunotherapeutic therapies, and tumor microenvironment modulation significantly broaden the options to counter multidrug resistance. While highlighting current difficulties, case studies and clinical examples also illustrate translational achievements. In addition to highlighting recent advancements, the present research points out important constraints and suggests potential paths for more potent, focused multidrug resistance cancer treatments.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954370","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":"Safety and efficacy of semi-dose venetoclax plus azacitidine in unfit acute myeloid leukemia patients in China: a real-world single-center study.","authors":"Xian Li, Xin-Yi Zhu, Xi-Bin Xiao, Xiao-Hong Zhang, Wei-Qin Wang, Wen-Bin Qian","doi":"10.1007/s10637-025-01579-8","DOIUrl":"https://doi.org/10.1007/s10637-025-01579-8","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) carries a poor prognosis in elderly or medically unfit patients, with median overall survival (OS) of only 7-8 months for those ineligible for intensive chemotherapy. While venetoclax (VEN) combined with azacitidine (AZA) has become a standard therapy, real-world evidence indicates that Asian patients experience higher VEN exposure and toxicity with the standard 400 mg/day dose. This retrospective study aimed to evaluate the efficacy and safety of a reduced-dose regimen (VEN 200 mg/day + AZA) in frail/elderly Chinese AML patients deemed unfit for intensive therapy. We analyzed 14 patients (13 newly diagnosed, 1 relapsed; median age 71.5 years) treated at Zhejiang University Hospital (May 2020-May 2024). All had ECOG status ≥ 3 (64.3%) or comorbidities (71.4%), and 57.1% were classified as adverse-risk by ELN 2022 criteria. Treatment comprised AZA (75 mg/m², days 1-7) and VEN (200 mg/day, days 1-28, in absence of CYP3A4 inducer). Response to treatment was evaluated by bone marrow biopsy for minimal residual disease (MRD). Toxicity was graded per CTCAE v5.0. Survival and trough VEN concentrations were analyzed using Kaplan-Meier and descriptive statistics. All patients (100%) achieved CR/CRi, with a median time to MRD negativity of 1.45 months. Median OS was not reached (> 24.6 months), with 2-year OS and EFS rates of 61.5% and 53.8%, respectively. Adverse-risk patients (42.9%) showed 50.0% survival beyond 21.8 months. Trough VEN concentrations (median 487.7 ng/mL) exceeded therapeutic thresholds (~ 500 ng/mL), confirming adequate exposure. Hematologic toxicity was reduced versus historical full-dose data: grade ≥ 3 thrombocytopenia (21.4% vs. 24-89.5%), febrile neutropenia (35.7% vs. 42.9-78.9%), and anemia (50.0% vs. 70-100%). No VEN dose modifications, tumor lysis syndrome, or 60-day mortality occurred. The semi-dosed VEN-AZA regimen (200 mg/day) demonstrated unprecedented efficacy (100% CR/CRi, median OS > 24.6 months) and a favorable safety profile in frail Chinese AML patients. Reduced toxicity without compromised efficacy supports its use in this population, likely due to optimized pharmacokinetics in Asian patients. These findings challenge the necessity of standard VEN dosing and highlight 200 mg/day as a viable, potentially superior strategy for this demographic.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954476","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}