Clinical Cancer Research最新文献

{"title":"Cabozantinib plus Atezolizumab in Advanced, Progressive Endocrine Malignancies: A multi-cohort, Basket, Phase II Trial (CABATEN/GETNE-T1914).","authors":"Jaume Capdevila,Jorge Hernando,Javier Molina-Cerrillo,Marta Benavent Viñuales,Rocio Garcia-Carbonero,Alex Teulé,Ana Custodio,Paula Jimenez-Fonseca,Carlos Lopez,Cinta Hierro,Alberto Carmona-Bayonas,Vicente Alonso,Marta Llanos,Isabel Sevilla,Alejandro Garcia-Alvarez,Teresa Alonso-Gordoa,Inmaculada Gallego Jiménez,Beatriz Antón-Pascual,Andrea Modrego Sánchez,Enrique Grande","doi":"10.1158/1078-0432.ccr-25-2143","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2143","url":null,"abstract":"BACKGROUNDMultikinase inhibitors (MKIs) have shown efficacy in endocrine neoplasms and synergism with immune-checkpoint inhibitors (ICI) has been noted in other tumors.PATIENTS AND METHODSThis is a prospective, multi-center, open-label, Simon 2 stage optimal design, phase II study including patients with advanced and refractory endocrine and neuroendocrine neoplasms in 6 cohorts: lung well-differentiated neuroendocrine tumors (lungNET), anaplastic thyroid cancer (ATC), adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PPGL), well-differentiated gastroenteropancreatic NET (GEP-NET), and grade 3 extrapulmonary neuroendocrine neoplasms (G3 EP-NEN). Patients received atezolizumab 1200 mg IV Q3W plus cabozantinib 40 mg/day PO until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR) by RECIST 1.1.RESULTSFrom October 2020 to December 2022, 93 patients were included. ORR was 14.3% (95% CI:1.8-42.8) in ATC (N=14); 8.3% (95% CI:1.0-27.0) in ACC (N=24); 15.4% (95% CI:1.9-45.5) in PPGL (N=13) and 16.7% (95% CI: 4.7-37.4) in GEP-NET (N=24). LungNET and G3 EP-NEN had no responses. Duration of response (DoR) was 20.4 months in ATC; 13.1 months in ACC; 12.2 months in PPGL and 15.8 months in GEP-NET. Survival rates at 12 months in ATC and ACC were 47.6 %and 47.6 % respectively. No unexpected toxicity was observed.CONCLUSIONCabozantinib and atezolizumab were safely administered and showed promising ORR and preliminary long-term survival rates were observed in aggressive and pretreated ACC and ATC, which warrants further investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"311 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043526","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":"Atezolizumab monotherapy window preceding combined neoadjuvant chemo- and immune therapy in triple negative breast cancer (TNBC) - the neoMono trial.","authors":"Hans-Christian Kolberg,Johannes Schumacher,Ramona Erber,Michael Braun,Peter A Fasching,Eva-Maria Grischke,Christian Schem,Michael P Lux,Mustafa Deryal,Oliver Hoffmann,Bernhard Heinrich,Georg Kunz,Kristina Lübbe,Petra Krabisch,Arndt Hartmann,Philip Räth,Sabine Kasimir-Bauer,Cornelia Kolberg-Liedtke","doi":"10.1158/1078-0432.ccr-25-1288","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1288","url":null,"abstract":"INTRODUCTIONExploratory data suggest a benefit of an immune-checkpoint inhibitor (ICI) monotherapy window in early TNBC. The neoMono trial prospectively analyzed whether the addition of an atezolizumab monotherapy window prior to neoadjuvant atezolizumab and chemotherapy improves pCR rates in early TNBC.METHODSNeoMono is a phase 2 randomized multicenter trial that recruited patients with primary TNBC larger than 10 mm. Neoadjuvant treatment consisted of neoadjuvant atezolizumab and chemotherapy, in arm A preceded by atezolizumab monotherapy two weeks before combination therapy. This study used a Bayesian trial design.RESULTSA total of 359 patients were included. Overall, pCR rates in study arms A and B were similar (ITT population: 65.7% and 69.0%, respectively). In an exploratory analysis pCR rates in PD-L1-positive tumors were 91.5% in arm A and 82.2% in arm B. The corresponding pCR rates in the PD-L1-negative group were 56.1% in arm A and 64.5% in arm B. In patients with low-risk TNBC (cT1c AND cN0) pCR rates in the PD-L1-positive group were 100.0% in arm A and 90.0% in arm B, the corresponding pCR rates in the PD-L1 (IC)-negative group were 65.9% and 76.3 %, respectively.CONCLUSIONThe neoMono trial demonstrated the highest pCR rates reported in a phase II/III trial in TNBC, particularly in the case of PD-L1 positivity. While no significant impact of an ICI monotherapy window on the pCR rate in the unselected ITT population could be demonstrated, our data reinforce the use of combinations of neoadjuvant chemotherapy and ICI in this indication.CCR-25-2186R1.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"35 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032147","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":"Extracellular matrix-myCAF signatures correlate with resistance to neoadjuvant aPD-L1 immune checkpoint inhibition with durvalumab + metformin in HPV+ HNSCC.","authors":"Pablo Llerena,Hani Samarah,Kathryn Nunes,Zhao Lin,Kelly Bridgham,Sruti Tekumalla,Amiti Jain,Larry Harshyne,Sanket K Shukla,Ioannis Vathiotis,Madalina Tuluc,Stacey Gargano,John R Eisenbrey,Scott Keith,David M Cognetti,Voichita C Bar-Ad,Adam J Luginbuhl,Rita Axelrod,Rajanikanth Vadigepalli,Hushan Yang,Diana Whitaker-Menezes,Megan Roche,My G Mahoney,Athanassios Argiris,Charalambos Solomides,Jennifer M Johnson,Mouadh Barbirou,Amanda Miller,Andrew P South,Ramkrishna Mitra,Alban J Linnenbach,Ubaldo Martinez-Outschoorn,Joseph M Curry","doi":"10.1158/1078-0432.ccr-25-1098","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1098","url":null,"abstract":"BACKGROUNDImmune checkpoint inhibitors (ICI) have demonstrated clinical benefit in head and neck squamous cell carcinoma (HNSCC); however, single-agent efficacy is limited, leaving significant unmet needs. Metformin may synergize with ICI, offering promise to improve response rates. We leveraged multi-omic data from a randomized, presurgical neoadjuvant trial (NCT03618654) evaluating a single infusion of the anti-programmed death ligand 1 (PD-L1) ICI, durvalumab, with or without daily, standard dose metformin in previously untreated, non-diabetic patients with HNSCC to understand predictors of response and the effect of combination therapy.METHODSClinical, pathological, and correlative data were analyzed to investigate response and resistance mechanisms. We present an in-depth multi-omic analysis of primary tumor specimens to study treatment response/resistance in HPV+ HNSCC.RESULTSBaseline samples revealed that myofibroblastic cancer-associated fibroblast (MYCAF) and extracellular matrix (ECM) signatures were enriched in durvalumab plus metformin (DM) nonresponders which were localized to the leading tumor edge on spatial transcriptomics. In contrast, baseline responder samples were enriched for the Langerhans-like dendritic cell (DC) state and interferon (IFN) signatures. Treatment increased intratumoral CD8+ T cell and IFN signatures and peripheral blood CCL2 levels. Responders demonstrated macrophage and dendritic cell enrichment and antigen processing and presentation upregulation. Enrichment of cell cycle-related gene sets, specifically the MYC targets V1 Hallmark gene set, correlated with nonresponse.CONCLUSIONEarly response and resistance dynamics for DM in HPV+ HNSCC reveal baseline ECM-MYCAF as predictive of nonresponse. In contrast, responders were distinguished by baseline enrichment in the Langerhans-like DC cell state and post-treatment antigen-presenting gene sets.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032059","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":"Effect of CVA21, an Oncolytic Virus, in combination with Pembrolizumab on immunogenicity and the tumour microenvironment in advanced NSCLC: a phase I/II trial.","authors":"Adithya Balasubramanian,Claire Marceaux,Sehrish Kanwal,Ilariya Tarasova,Daniel Batey,Clare Senko,Khashayar Asadi,Kenta Yokote,Jodie Palmer,Michael Christie,Ashray Gunjur,Surein Arulananda,Sagun Parakh,David Adams,Belinda Phipson,Sean Grimmond,Jonathan Cebon,Marie-Liesse Asselin-Labat,Thomas John","doi":"10.1158/1078-0432.ccr-25-1449","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1449","url":null,"abstract":"PURPOSEAcquired or de novo resistance to immune checkpoint inhibitors occurs in the majority of advanced non-small cell lung cancers (NSCLC). There is an unmet need to improve outcomes for patients with this condition. Oncolytic viruses represent an attractive treatment approach due to their dual activity in inducing tumor cell lysis directly and potentially augmenting anti-tumor immunity. Here, we present the safety, efficacy and translational findings from a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab in patients with advanced pre-treated NSCLC.PATIENTS AND METHODSWe performed paired biopsies pre- and post-treatment in 10 patients who received intravenous CVA21 and pembrolizumab, 8 of whom had prior treatment with immune checkpoint inhibitor (ICI) therapy. Whole genome sequencing and spatial proteomics were performed to comprehensively characterise the response to CVA21.RESULTSCombination CVA21/pembrolizumab (anti PD-1) therapy was well tolerated with no serious treatment-related adverse events. Partial responses were seen in two patients with prior acquired anti-PD-1 resistance and disease stabilisation in 6 patients, giving a clinical benefit rate of 80%. High baseline tumor mutational burden and PD-L1 expression were observed in patients with better response to treatment. Interestingly, an increase in antigen presentation and CD8+ T cell infiltration was observed on treatment compared with baseline in patients with better progression-free survival.CONCLUSIONSThis study demonstrates the potential of CVA21 to modulate the immunogenicity of tumor cells and remodelling the tumor microenvironment, providing novel insights for patient selection for trials involving novel immunotherapeutic approaches.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032055","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":"Immunocompetent murine models recapitulate the heterogeneous tumor immune microenvironment of human liposarcoma.","authors":"Amanda M Shafer, Emma Kenna, Lexi-Ann F Golden, Ahmed M Elhossiny, Kyle D Perry, Jodi Wilkowski, Wei Yan, Brynn Kaczkofsky, Jake McGue, Scott C Bresler, Adam H Courtney, Jessie M Dalman, Craig J Galbán, Wei Jiang, Carlos E Espinoza, Rashmi Chugh, Matthew K Iyer, Timothy L Frankel, Marina Pasca di Magliano, Andrzej A Dlugosz, Christina V Angeles","doi":"10.1158/1078-0432.CCR-25-1628","DOIUrl":"10.1158/1078-0432.CCR-25-1628","url":null,"abstract":"<p><strong>Purpose: </strong>Liposarcoma (LPS) is the most common soft tissue sarcoma. Well-differentiated LPS (WDLPS) can progress to dedifferentiated LPS (DDLPS), a more aggressive form with higher metastatic potential and poor response to existing therapies. Progress in understanding and treating LPS has been limited. To address this, we sought to develop an immunocompetent genetically engineered mouse model of LPS.</p><p><strong>Experimental design: </strong>We developed an autochthonous, immunocompetent LPS mouse model (ACPP) by using targeted Cre-mediated deletion of Trp53 and Pten in adipocytes to mimic the signaling alterations observed in human LPS. We characterized the histology, transcriptional features, and tumor microenvironment of this model. Additionally, we established syngeneic cell lines derived from ACPP DDLPS tumors and evaluated them for tumor formation, growth dynamics, and immune composition after implantation.</p><p><strong>Results: </strong>ACPP mice develop WDLPS, DDLPS, and mixed tumors, mirroring human disease. Both murine and human DDLPS tumors share key transcriptional features and exhibit heterogeneous T cell infiltration. Syngeneic DDLPS cell lines reliably form tumors in vivo, with each line demonstrating distinct growth kinetics, aggressiveness, and immune profiles.</p><p><strong>Conclusions: </strong>The ACPP model provides a novel and clinically relevant platform to study LPS in an immunocompetent setting. Along the with ACPP-derived cell lines, these models not only provide essential tools to understand the complex immunobiology of LPS but also can be used to elucidate the underlying molecular mechanisms driving LPS generation and progression and significantly accelerate the pace of preclinical studies aimed at uncovering more effective new therapies for patients with this aggressive malignancy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032829","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":"Tarlatamab exposure-efficacy and exposure-safety relationships to inform dose selection in patients with small cell lung cancer (SCLC).","authors":"Po-Wei Chen,Mukul Minocha,Stephanie Kong,Tony Jiang,Erik S Anderson,Amanda Parkers,Pablo Martinez,Brett E Houk,Chih-Wei Lin","doi":"10.1158/1078-0432.ccr-25-2134","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2134","url":null,"abstract":"PURPOSETarlatamab is a first-in-class, half-life extended bispecific T-cell engager (BiTE®) immunotherapy targeting delta-like ligand 3 (DLL3) currently approved for the treatment of adult patients with small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Here we report tarlatamab exposure-response relationships to inform dose selection in patients with SCLC.EXPERIMENTAL DESIGNPharmacokinetic data were correlated with therapeutic effect [exposure-response (ER) analyses] for efficacy and safety measures using pooled data from DeLLphi-300 and DeLLphi-301 studies. Efficacy measures included objective response rate, disease control rate, best change from baseline in tumor size, progression-free survival, and overall survival. Safety events included treatment-emergent adverse events [TEAEs], treatment-related adverse events [TRAEs], and TEAEs of interest including cytokine release syndrome [CRS], neutropenia, and neurologic toxicity including immune effector cell-associated neurotoxicity syndrome [ICANS]). Effects of patient specific factors were also assessed. Doses ranging from 0.003 mg to 100 mg Q2W and 200 mg Q3W were explored.RESULTSSignificant positive ER relationships were established for all evaluated efficacy measures. Near maximal efficacy was reached at exposures associated with the clinical regimen of 10 mg Q2W. No relationships with exposure were identified for the following grade ³ 3 events: TEAEs, TRAEs, CRS, and neurologic toxicity including ICANS. A shallow trend was observed for higher percentage of patients experiencing grade ³ 3 neutropenia with higher exposures.CONCLUSIONSThis analysis supports 10 mg Q2W regimen and that no dose adjustment is necessary based on age, race, bodyweight, immunogenicity, number of prior therapies or disease burden.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031908","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":"Drug targets in prostate cancer: an appetite for KLK2-mediated destruction.","authors":"Steven Blinka,Evan Y Yu","doi":"10.1158/1078-0432.ccr-25-2546","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2546","url":null,"abstract":"Human Kallikrein 2 (KLK2) is a prostate cancer tissue specific protein that is regulated by androgen receptor (AR) signaling. KLK2 was not previously recognized as a therapeutic target as it is secreted. It has now been demonstrated that KLK2 is expressed on the cell surface and targetable by various methodologies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025448","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":"CD27 agonist antibodies mediate clinical responses through intratumoral stimulation in B-cell malignancies: multicenter RiVa trial","authors":"Lara E. Buermann, Louise Stanton, Matthew J.J. Rose-Zerili, Kerensa Thorne, Adam Coleman, Anna H. Turaj, Josh Caddy, Christopher Wignall, Nicole Keyworth, Zoe Konn, Pamela McKay, Wendy Osborne, Kim Linton, Patrick Medd, Robert Lown, Andrew J. Davies, Peter W.M. Johnson, Aymen Al-Shamkhani, Mark S. Cragg, Graham P. Collins, Tibor Keler, Michael Yellin, Andrew J. Gentles, Gareth Griffiths, Sean H. Lim","doi":"10.1158/1078-0432.ccr-25-2029","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2029","url":null,"abstract":"Purpose: Varlilumab is a CD27 agonist antibody, delivering a T-cell costimulation. Preclinical studies show agonistic CD27 antibodies can activate intratumoral T-cells to release chemokines and cytokines to augment macrophage-dependent tumor killing induced by CD20 antibodies, i.e. rituximab, in B-cell lymphoma. This clinical trial evaluated the safety and efficacy of rituximab and varlilumab in patients with previously treated B-cell non-Hodgkin lymphoma (B-NHL). Patient and Methods: This multicenter phase IIa trial recruited patients with relapsed or refractory CD20+ B-NHL. Patients were randomized to Arm A or B. All received rituximab on Day 1 of Cycles1-6, and varlilumab on Day 2 (Arm A) or Day 8 (Arm B) of Cycle 1, and Day 2 of Cycles 3 and 5. Tumor biopsies were collecting pre-treatment and on-treatment (after varlilumab in Arm A and before varlilumab in Arm B). The primary objective was to assess safety and anti-tumor activity. Results: Twenty-seven participants were evaluable, with modest overall response and disease control rates of 15.4% (4/27) and 38.8% (8/27), respectively. Intratumoral bulk RNA sequencing analysis demonstrated that adding varlilumab to rituximab enhanced CD4+ T-cell infiltration and increased T- and innate-cell signatures; inflamed tumor signatures were observed pre-treatment in responders. Single-cell analysis further showed that higher levels of CD27-expressing T and NK cells, along with activated γδ T-cell signatures, were associated with response, whereas CD27-expressing B cells correlated with non-response. Conclusions: Rituximab and varlilumab show modest activity. However, CD27 agonist antibodies may elicit meaningful anti-tumor responses when tumors express sufficient intratumoral targets and exhibit existing immune priming.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"35 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017613","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":"Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas","authors":"Emelie Gezelius, Natasha Rekhtman, Marina K. Baine, Charles M. Rudin, Alexander Drilon, Alissa J. Cooper","doi":"10.1158/1078-0432.ccr-25-2090","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2090","url":null,"abstract":"Seizure-related homolog protein 6 (SEZ6) is a cell surface type 1 transmembrane protein involved in neuronal development, expression of which in adult tissues is almost exclusively limited to the central nervous system. Aberrant expression of SEZ6 has been associated with neurodevelopmental and psychiatric disorders including epilepsy, schizophrenia, and Alzheimer’s disease. More recently, SEZ6 overexpression has been detected in small cell lung cancer (SCLC) and other high-grade neuroendocrine malignancies, although our understanding of the function of SEZ6 as a driver of cancer is limited. A lineage-defining transcription factor of SCLC, ASCL1, has been implicated as a regulator of SEZ6 expression. SEZ6 has emerged as a novel target for antibody-drug conjugate (ADC) therapy, and early studies have shown promising antitumor activity, demonstrating the potential for SEZ6 to be targeted by drugs with alternate mechanisms of action. Here, we review the current knowledge of the biology of SEZ6 and its implications in malignancy, summarize the preclinical and clinical findings of SEZ6 targeted ADCs, and discuss future directions to further elucidate the role of SEZ6 in SCLC and other neuroendocrine neoplasms.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"39 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002895","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":"FDA Approval Summary: Vorasidenib for IDH-mutant Grade 2 Astrocytoma or Oligodendroglioma following surgery","authors":"Michael I. Barbato, Amy K. Barone, Stephanie L. Aungst, Claudia P. Miller, Suryatheja Ananthula, Youwei Bi, Yuching Yang, Xiaoxue Li, Ye Xiong, Jianghong Fan, Sarah E. Dorff, Hong Zhao, Hua Zhou, Shan Pradhan, Barbara Scepura, Arup K. Sinha, Maritsa Stephenson, Vishal Bhatnagar, Haleh Saber, Nam Atiqur. Rahman, Shenghui Tang, Richard Pazdur, Paul G. Kluetz, Erin Larkins, Nicole Drezner","doi":"10.1158/1078-0432.ccr-25-1333","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1333","url":null,"abstract":"On August 6, 2024, the U.S. Food and Drug Administration (FDA) granted traditional approval to vorasidenib (VORANIGO, Servier Pharmaceuticals, LLC) for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or 2 (IDH1 or IDH2) mutation following surgery including biopsy, sub-total resection, or gross total resection. The approval was based on data from a randomized, multicenter, double-blind trial of vorasidenib compared to placebo. The primary objective was to demonstrate the efficacy of vorasidenib based on radiographic progression-free survival (PFS) per blinded independent central review (BICR) according to the modified Response Assessment for Neuro-oncology for Low-Grade Gliomas (RANO-LGG) criteria. PFS was assessed in 331 patients, and the hazard ratio (HR) was 0.39 (95% CI: 0.27, 0.56; p-value &amp;lt;0.0001). The most common (≥15%) adverse reactions included fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizure. PFS was considered an appropriate endpoint for this disease considering the long natural history and the randomized design allowed for interpretation of the treatment effect in this rare malignancy. This was the first FDA approval of a targeted therapy for IDH-mutant, Grade 2 gliomas.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"27 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002897","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}