Clinical Cancer Research最新文献

{"title":"FDA-AACR Strategies for Optimizing Dosages for Oncology Drug Products: Selecting Optimized Dosages for Registrational Trials","authors":"Stacy S. Shord, Cong Chen, Jin Y. Jin, Scott Van Wart, Sarah K. Martin, Brad A. Davidson, Jiang Liu, Patricia M. LoRusso, Geoffrey R. Oxnard","doi":"10.1158/1078-0432.ccr-25-0098","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0098","url":null,"abstract":"The maximum tolerated dose has historically been the recommended phase two dose, and this dosage has typically been evaluated in registrational clinical trials for oncology drugs. With the emergence of targeted therapies, this approach may lead to the investigation of unnecessarily high dosages that elicit additional toxicity without added benefit. The utilization of innovative trial designs and model-informed approaches during clinical development can potentially lead to more informed dosage selection. Exposure-response analyses, clinical utility index, and other model-informed approaches have been successfully applied to understand preliminary activity and safety data for various classes of modern oncology drugs, providing insight to support the proposed dosage(s) for the registrational trial. Seamless trial designs have also played an important role in dosage selection by leveraging pre-planned flexibilities and statistical procedures to increase efficiency during the conduct of trials. Critically, both approaches can be fit for purpose, allowing for adaptation and the usage of the totality of relevant clinical and nonclinical data. Despite this, the evaluation of maximum tolerated dose remains prevalent in registrational trials. This article, the third in a series of three describing best-practice approaches to dosage optimization in oncology drug development, highlights successful applications of and relevant considerations for innovative trial designs and model-based approaches to aid the selection of better optimized dosages for evaluation in registrational clinical trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203656","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":"Checkpoint Blockade Combinations in High Tumor Mutational Burden/Load Tumors: Insights from the Atezolizumab + Bevacizumab and Nivolumab + Ipilimumab Cohorts in DRUP.","authors":"Karlijn Verkerk,Soemeya F Haj Mohammad,Laurien J Zeverijn,Birgit S Geurts,Ilse A C Spiekman,Florentine A J Verbeek,Hans Timmer,Maud A van Maren,V van der Noort,Miguel Parra Martinez,Paul Roepman,Anne M L Jansen,Wendy W J de Leng,Serena Marchetti,Kim Monkhorst,Henk M W Verheul,Hans Gelderblom,Emile E Voest","doi":"10.1158/1078-0432.ccr-25-2260","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2260","url":null,"abstract":"PURPOSETo evaluate the efficacy of atezolizumab plus bevacizumab (atezo+beva) in tumors with high tumor mutational burden (TMB; number of mutations per megabase), and nivolumab plus ipilimumab (nivo+ipi) in tumors with high TMB or tumor mutational load (TML; total number of non-synonymous mutations across the genome).PATIENTS AND METHODSPatients with treatment-refractory, solid tumors were treated in the Drug Rediscovery Protocol (2023-509152-33-00). Patients with microsatellite stable tumors harboring a TML of 200-1000, or TMB of 11-24 (Oncomine) or 15-39 (TSO500) were eligible for nivo+ipi. Similar patients with a panel-independent TMB ≥16 received atezo+beva. Clinical benefit (CB; confirmed objective response or stable disease ≥16 weeks) was the primary endpoint. Whole-genome and RNA-sequencing were performed on pre-treatment tumor biopsies.RESULTSAmong 25 evaluable patients with 14 different tumor types treated with atezo+beva, the CB-rate (CBR) was 60% (95% confidence interval [CI], 39-79), with an objective response rate (ORR) of 24% (95% CI, 9-45) and median duration of response (mDoR) of 25.0 months (95% CI, 13.8-NA). In the nivo+ipi cohort the CBR was 50% (95% CI, 29-71) and ORR 37.5% (95% CI, 19-59) among 24 evaluable patients with 13 distinct tumor types. The mDoR was not reached after a median follow-up of 36 months. In both cohorts, responses were only observed in patients with TMB >20, and TMB and (clonal) TML were significantly correlated with response. Various markers of adaptive immune infiltration were associated with longer progression-free survival.CONCLUSIONSAtezo+beva and nivo+ipi showed durable responses in patients with TMB >20, underscoring their tumor-agnostic efficacy in this patient population.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194703","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":"Increased Peripheral T Stem Cell-like Memory Features in Patients with Advanced Solid Tumors Treated with Tumor-Targeting IL-12 Immunocytokine Therapy.","authors":"Meghali Goswami, Carolina Celades, Christine M Minnar, Asma S Khelifa, Lisa K Poppe, Dara Bracken-Clarke, Nicole J Toney, Megan T Lynch, Jennifer L Marté, Sofia R Gameiro, James L Gulley, Jeffrey Schlom, Renee N Donahue","doi":"10.1158/1078-0432.CCR-25-1490","DOIUrl":"10.1158/1078-0432.CCR-25-1490","url":null,"abstract":"<p><strong>Purpose: </strong>T-cell stemness is important for antitumor immunity. The presence in tumor-draining lymph nodes and tumor of stem-like memory T (TSCM) cells and T cells expressing the transcription factor T-cell factor 1 (TCF1), critical in T-cell self-renewal, is associated with improved response to immune checkpoint inhibitors.</p><p><strong>Experimental design: </strong>We studied the effects of the tumor-targeting immunocytokine PDS01ADC (NHS-IL12) on peripheral T-cell stemness in murine hosts and in patients with advanced solid tumors. TSCM and expression of the murine T-cell stemness markers stem cell antigen 1 (Ly6a) and Tcf7 were evaluated in naïve and tumor-bearing mice receiving murine PDS01ADC (NHS-muIL12). Peripheral blood from patients treated in a clinical trial with PDS01ADC was analyzed for TSCM and expression of TCF1 on T-cell subsets.</p><p><strong>Results: </strong>NHS-muIL12 treatment in naïve mice increased stem cell antigen 1-positive peripheral T cells with stem-like phenotypes and promoted tumor infiltration of CD8+ T cells displaying increased stemness. In patients with advanced solid tumors, PDS01ADC treatment increased peripheral CD8+ and CD4+ TSCM frequencies and effector memory T cells expressing TCF1, with greater increases associated with disease control. Most peripheral TSCM cells were negative for PD-1 and TIGIT throughout treatment, suggesting their quiescence and self-renewal capacity. Expanded TCF1-negative effector memory CD8+ T cells expressed PD-1 with increased intensity of granzyme B, indicating an activated, cytotoxic state.</p><p><strong>Conclusions: </strong>PDS01ADC treatment in patients with advanced solid tumors boosts peripheral T cells with stem-like characteristics, correlating with disease stabilization. Further studies combining PDS01ADC with other immunotherapies to synergize with this peripheral burst of T-cell stemness are warranted.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4159-4173"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyamine Depletion by D,L-α-Difluoromethylornithine Inhibits Ewing Sarcoma Metastasis by Inducing Ferroptosis.","authors":"Rachel Offenbacher, Kyle W Jackson, Masanori Hayashi, Jinghang Zhang, Da Peng, Yuqi Tan, Tracy Murray Stewart, Paul Ciero, Jackson Foley, Robert A Casero, Patrick Cahan, David M Loeb","doi":"10.1158/1078-0432.CCR-24-1778","DOIUrl":"10.1158/1078-0432.CCR-24-1778","url":null,"abstract":"<p><strong>Purpose: </strong>Despite decades of clinical trials, no progress has been made in improving the survival of patients with Ewing sarcoma who either present with metastatic disease or suffer a metastatic relapse. In our preclinical models, we found differential levels of polyamines in tumors that metastasize compared with tumors that do not, leading us to investigate the potential for D,L-α-difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, to prevent Ewing sarcoma metastasis.</p><p><strong>Experimental design: </strong>The effect of DFMO on Ewing sarcoma cell lines in vitro was studied by measuring proliferation, sphere formation, and clonogenic growth in soft agar. The effect in vivo was investigated using our orthotopic implantation/amputation model of metastasis. Transcriptomic changes were evaluated by RNA sequencing.</p><p><strong>Results: </strong>DFMO causes a cell cycle arrest and inhibits both sarcosphere formation and clonogenic growth in soft agar. In vivo, DFMO slows primary tumor growth and inhibits metastasis. RNA sequencing demonstrated gene expression patterns consistent with induction of ferroptosis caused by polyamine depletion, which was validated in vitro by demonstrating that DFMO treatment induces lipid peroxidation, and ferrostatin-1 and liproxstatin-1 allow sphere formation even in the presence of DFMO.</p><p><strong>Conclusions: </strong>DFMO slows the growth of Ewing sarcoma cells in vitro, with a profound impact on sphere formation and clonogenic growth, and affects all aspects of Ewing sarcoma tumorigenesis, including tumor initiation, tumor growth, and metastasis, probably through induction of ferroptosis mediated by polyamine depletion. Our results provide preclinical justification to test the ability of DFMO to prevent metastatic recurrence in patients with Ewing sarcoma.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4196-4210"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surgical and Blood-Based Minimal Residual Disease in Patients with Ovarian Cancer after First-line Therapy: Clinical Outcomes and Translational Opportunities.","authors":"Anne Knisely, Yibo Dai, Graham L Barlow, Sanghoon Lee, Barrett Lawson, Helen Clark, Bryan Fellman, Ying Yuan, Wei Lu, Idania Carolina Lubo Julio, Rossana N Lazcano, Manoj Chelvanambi, Brenda Melendez, Bharat Singh, Bhavana Singh, Khalida Wani, Jianfeng Chen, Chih-Chen Yeh, Jianjun Gao, Sean Barnes, Ou Shi, Khaja B Khan, Alejandra G Serrano, Lorena I Gomez-Bolanos, Carly Bess Scalise, Samantha K Cheung, Punashi Dutta, Sharlene Velichko, Adam C ElNaggar, Minetta C Liu, Roni N Wilke, Jeffrey How, Lois M Ramondetta, David M Boruta, Gwyn Richardson, Aaron Shafer, Shannon N Westin, Travis Sims, Anil K Sood, Pedro T Ramirez, Alexander J Lazar, Pamela T Soliman, Karen Lu, Cara L Haymaker, Luisa M Solis Soto, Jennifer A Wargo, Rachel Grisham, Kai W Wucherpfennig, Linghua Wang, Amir A Jazaeri","doi":"10.1158/1078-0432.CCR-25-0512","DOIUrl":"10.1158/1078-0432.CCR-25-0512","url":null,"abstract":"<p><strong>Purpose: </strong>Minimal residual disease (MRD) after first-line treatment of advanced-stage ovarian cancer remains a long-standing barrier to cure. We investigated the prognostic and translational value of MRD detection by second-look laparoscopy (SLL) and ctDNA at the completion of first-line therapy.</p><p><strong>Experimental design: </strong>Patients with high-grade epithelial ovarian cancer who had a complete clinical response to first-line therapy and underwent SLL and plasma collection for ctDNA were included. Progression-free survival (PFS) and overall survival (OS) were estimated based on MRD and clinicopathologic status. Spatial transcriptomics (GeoMx and Visium) and proteomics (CODEX) profiling were performed on serial samples from select patients.</p><p><strong>Results: </strong>Forty of 95 (42.1%) patients had surgically detected MRD, which was associated with worse PFS (median PFS 7.4 vs. 23.8 months; P < 0.001) and OS (median OS 33.9 vs. not reached; P < 0.001). SLL positivity was an independent negative prognostic factor for OS (HR, 4.40; 95% confidence interval, 1.37-14.21; P = 0.013) in multivariable analysis. Among 44 patients who underwent SLL and had ctDNA testing, 34% (15/44) were ctDNA-positive, which was associated with worse PFS (6.4 vs. 28.1 months; P < 0.001) and OS (32.4 months vs. not reached; P = 0.008). We demonstrated the feasibility of spatial multiomics in studying MRD and their ability to provide hypothesis-generating observations, implicating the upregulation of the hypoxia signaling pathway, expression of multiple druggable targets (CDK6, GLS, MSLN, ERBB2), and immune exclusion in MRD lesions.</p><p><strong>Conclusions: </strong>Approximately half of patients in clinical remission after first-line therapy have assessable MRD, which can inform prognosis, therapeutic target discovery, and clinical trials.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4122-4135"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D3-GPC2-directed CAR T cells are safe and efficacious in preclinical models of neuroblastoma and small cell lung cancer.","authors":"Anna Maria Giudice,Stephanie Matlaga,Sydney L Roth,Whitney Gladney,David Groff,Ted J Hofmann,Guillem Pascual-Pasto,Brendan McIntyre,Vincent Zecchino,Dan Martinez,Timothy T Spear,Adam J Wolpaw,Charles-Antoine Assenmacher,Enrico Radaelli,Jenny Pogoriler,Bruce Pawel,David Barrett,Stephan A Grupp,John M Maris,Kristopher R Bosse","doi":"10.1158/1078-0432.ccr-25-0089","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0089","url":null,"abstract":"BACKGROUNDWe previously identified glypican 2 (GPC2) as a cell surface MYCN-regulated neuroblastoma oncoprotein and developed a D3-GPC2 antibody that specifically binds a conformational, tumor-specific epitope conserved between mouse and human.EXPERIMENTAL DESIGNHere we sought to further validate GPC2 as an immunotherapeutic target and develop Investigational New Drug application-enabling data to support the clinical translation of D3-GPC2 chimeric antigen receptor (CAR) T cells.RESULTSImmunohistochemistry validated that GPC2 is widely expressed on human neuroblastomas and flow cytometry showed high levels of cell surface GPC2 on neuroblastoma cellular models. Second-generation D3-GPC2 CAR T cells with either a 4-1BB or CD28 co-stimulatory domain were selectively activated and induced potent neuroblastoma cell cytotoxicity in several complementary in vitro co-incubation assays. Conversely, no measurable cytotoxicity or D3-GPC2 CAR T cell activation was observed in co-incubation studies with nine primary human normal tissue cell lines. Moreover, GPC2 CAR T cells induced significant regression of GPC2-expressing neuroblastoma xenografts. No GPC2 CAR-related toxicities were noted, including in comprehensive mouse necropsies performed after GPC2 CAR T cell administration. Finally, to explore the potential broader clinical impact of GPC2 CAR T cells we showed that they are also potently cytotoxic to preclinical models of GPC2-expressing small cell lung cancers.CONCLUSIONSThese data validate GPC2 as a bona fide CAR T cell target in neuroblastoma and other cancers. The safety and preliminary efficacy of GPC2 CAR T cells are being tested in a first-in-human phase 1 clinical trial for children with relapsed/refractory neuroblastoma (NCT05650749).","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"65 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194766","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":"Organ preservation via immunotherapy-based total neoadjuvant therapy in early low rectal cancer (TORCH-E): a multicenter, open-label, single-arm, phase 2 study.","authors":"Fan Xia,Yajie Chen,Di Zhou,Juefeng Wan,Lijun Shen,Yaqi Wang,JinLuan Li,Hui Zhang,Yan Wang,Wang Yang,Menglong Zhou,Ruiyan Wu,Shujuan Zhou,Yikuan Chen,Dakui Luo,Wenchao Gu,Peng Lian,Junjie Peng,Fangqi Liu,Yiqun Sun,Lei Wang,Sanjun Cai,Zhen Zhang,Xinxiang Li","doi":"10.1158/1078-0432.ccr-25-0975","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0975","url":null,"abstract":"PURPOSEOrgan preservation (OP) can be preferred in low-lying rectal cancer to reduce morbidity from radical surgery. Immunotherapy-based total neoadjuvant therapy (iTNT) showed remarkable tumor regression and facilitated OP in locally advanced rectal cancer. This study evaluated the efficacy and safety of iTNT, comprising short-course radiotherapy (SCRT) followed by CAPOX and Toripalimab, in enabling OP for early low rectal cancer.PATIENTS AND METHODSTORCH-E was a multicenter, single-arm phase 2 trial enrolling patients with T2-3bN0 rectal adenocarcinoma ≤5 cm from anal verge. Patients received SCRT (25Gy/5Fx) followed by four cycles of CAPOX plus Toripalimab. Good responders were eligible for watch-and-wait (WW) or local excision (LE), total mesorectal excision (TME) was recommended for poor responders or those with high-risk features post-LE. The primary endpoint was complete response (CR), including clinical complete response (cCR) with WW and pathological CR (pCR). Secondary endpoints included OP rate, adverse effects, and quality of life.RESULTSFrom December 2022 to March 2024, 33 patients were enrolled, with 75.8% staged as T3. After iTNT, 16 patients achieved cCR and adopted WW. pCR was observed in 8/8 LE and 5/9 TME patients. The most common grade 3-4 adverse event was thrombocytopenia (27.3%). After a median follow-up of 24.1 months, four local regrowth and one metastatic recurrence occurred. Total CR rate was 72.7%, and OP rate was 60.6%.CONCLUSIONSAs an exploratory trial, TORCH-E demonstrated a promising iTNT approach achieving high CR rate, enabling OP through WW and selective LE in early low rectal cancer, warranting subsequent randomized validation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"24 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194765","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":"Tumor-Agnostic AKT Inhibition: Is It Time to AKT?","authors":"Ricardo Dahmer Tiecher,Alison M Schram","doi":"10.1158/1078-0432.ccr-25-2640","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2640","url":null,"abstract":"Basket trials of AKT-mutated tumors show that pan-AKT inhibitors are active in hormone receptor-positive breast cancer. There is mounting evidence for AKT inhibition in other tumor types, although small sample sizes limit evaluation of the tumor-agnostic potential for AKT inhibition. Emerging AKT1 E17K-specific molecules may improve tolerability and efficacy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"24 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194767","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":"Final Results from a First-in-Human Phase 1 Study of the Dual Isocitrate Dehydrogenase (IDH) 1/2 Inhibitor, LY3410738, in Advanced Solid Tumors Harboring IDH1 or IDH2 Mutations.","authors":"James J Harding,Do-Youn Oh,Teresa Macarulla Mercade,Lipika Goyal,Andreas Varkaris,Lola Jade Palmieri,Masafumi Ikeda,Shunsuke Kondo,Li-Yuan Bai,Makoto Ueno,Li-Tzong Chen,Kyriakos P Papadopoulos,Rachna T Shroff,Sani H Kizilbash,Antoine Hollebecque,Jorge Adeva,Rasha Cosman,Tomoya Yokota,Joon Oh Park,Anita Turk,Chih-Yi Liao,Taroh Satoh,Mitesh J Borad,Anthony El-Khoueiry,Nilofer Azad,Kurt A Jaeckle,Herbert H Loong,Wei-Peng Yong,Mark H Bender,Sunoj Chacko Varughese,Deepa Sachdeva,David B Radtke,Ivelina Gueorguieva,Anna M Szpurka,Hsiao-Rong Chen,Hui Liu,Xiaojian Xu,Jordi Rodon","doi":"10.1158/1078-0432.ccr-25-0174","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0174","url":null,"abstract":"BACKGROUNDIsocitrate dehydrogenase (IDH) 1/2-isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated (mIDH1/mIDH2) neoplasms. However, primary and secondary resistance limits their therapeutic potential. LY3410738, an oral, brain penetrant, dual mIDH1/mIDH2 isoform-selective inhibitor was designed to overcome resistance.METHODSThis global, multicenter, open-label, phase 1 study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose-escalation) for advanced solid tumors in combination with cisplatin-gemcitabine for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose-expansion) (NCT04521686). Primary objectives were the maximum tolerated dose (MTD), recommended phase 2 dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and circulating tumor DNA (ctDNA) were assessed.RESULTSOverall, 119 patients received LY3410738 alone (N=94) or in combination with cisplatin-gemcitabine (N=19) or durvalumab (N=6). No dose-limiting toxicities (DLTs) were observed; the MTD was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1%, and disease control rates of 56.9% and 63.0%, were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one DLT in the durvalumab cohort. LY3410738 plus cisplatin-gemcitabine demonstrated a response rate of 42.1%, median DOR of 8.1 months, median PFS of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma.CONCLUSIONSLY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus cisplatin-gemcitabine exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"53-54 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194764","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":"Rewiring antitumor immunity: targeting CLDN18.2 with conditional 4-1BB activation.","authors":"Giulia Pretelli,Elena Garralda","doi":"10.1158/1078-0432.ccr-25-2554","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2554","url":null,"abstract":"Claudin 18.2 has emerged as a validated target in solid tumors, spurring next-generation therapies. Bispecific antibodies linking Claudin 18.2 to conditional 4-1BB activation offer a novel approach to enhance T cell function. By confining co-stimulation to the tumor microenvironment, they aim to boost efficacy while limiting systemic toxicity.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182587","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}