Clinical Cancer Research最新文献

{"title":"Phase 2, Open-Label, Multicenter Study of Nelitolimod in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naive Advanced Melanoma.","authors":"Antoni Ribas,Mohammed M Milhem,Christopher J Hoimes,Asim Amin,Christopher D Lao,Robert M Conry,Jason P Hunt,Gregory A Daniels,Mohammed Almubarak,Montaser Shaheen,Theresa Medina,Minal Barve,Sarwan Bishnoi,Ehtesham Abdi,Michael J Chisamore,Cristiana Guiducci,Jose Gomez-Romo,Albert Candia,Erick Gamelin,Robert L Coffman,Robert S Janssen,Georgina V Long","doi":"10.1158/1078-0432.ccr-25-0987","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0987","url":null,"abstract":"PURPOSENelitolimod (previously SD-101) is a toll-like receptor 9 agonist. We assessed whether intratumoral nelitolimod plus pembrolizumab potentiates antitumor activity in patients with advanced melanoma who had not previously received anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy.PATIENTS AND METHODSPatients with advanced melanoma who were naive to anti-PD-1/PD-L1 therapy received either nelitolimod 2 mg injected into 1-4 lesions or nelitolimod 8 mg injected weekly into a single lesion for 4 weekly doses, then every 3 weeks. Pembrolizumab 200 mg was administered intravenously every 3 weeks.RESULTSForty-five patients received nelitolimod 2-mg and 41 patients received nelitolimod 8-mg per injection. The objective response rate (ORR) was 76% in the 2-mg group and 49% in the 8-mg group. In those with distant metastases, ORRs in both treatment groups were similar to the overall ORRs. In the 2-mg group, treatment responses were similar in those with PD-L1-positive tumors and those with PD-L1-negative tumors. Progression-free survival rate at 18 months (landmark) was 62% in the 2-mg group and 40% in the 8-mg group. Forty-four patients (100%) in the 2-mg group and 37 patients (95%) in the 8-mg group experienced a treatment-related adverse event (TEAE) with either drug; overall, 31 patients (37%) had a grade 3 or 4 TEAE related to either study drug.CONCLUSIONSIn patients with anti-PD-1/PD-L1 treatment-naive advanced melanoma, nelitolimod plus pembrolizumab induced objective responses, including in PD-L1-negative tumors. The treatment combination warrants further study in advanced melanoma.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"47 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701284","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":"Gedatolisib Combined with Palbociclib and Letrozole in Patients with No Prior Systemic Therapy for Hormone Receptor Positive, HER2 Negative Advanced Breast Cancer.","authors":"Robert Wesolowski,Hope S Rugo,Jennifer M Specht,Hyo Han,Peter Kabos,Ulka Vaishampayan,Seth A Wander,Keerthi Gogineni,Alexander Spira,Anne F Schott,Maysa Abu-Khalaf,Sarah C Mutka,Samuel Suzuki,Brian Sullivan,Igor Gorbatchevsky,Rachel M Layman","doi":"10.1158/1078-0432.ccr-25-0992","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0992","url":null,"abstract":"PURPOSENonclinical evidence demonstrating that estrogen receptor (ER), CDK4/6, and PI3K/AKT/mTOR (PAM) pathways cross-promote tumor proliferation in HR+/HER2- breast cancer cell lines led to development of CDK4/6 inhibitors and agents inhibiting single PAM pathway nodes to treat HR+/HER2- advanced breast cancer (ABC). Simultaneous blockade of ER, CDK4/6 and PAM pathways may optimize anti-tumor control in the treatment-naïve ABC setting. Gedatolisib, a pan-PI3K/mTOR inhibitor, was evaluated as first-line therapy, combined with standard-of-care palbociclib and letrozole, for patients with HR+/HER2- ABC.PATIENTS AND METHODSTreatment-naïve patients from a phase 1b study with HR+/HER2- ABC treated with gedatolisib plus palbociclib and letrozole were analyzed. The primary endpoint of the overall study was investigator-assessed objective response. Secondary endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).RESULTSOf 41 patients, all had stage IV disease, 93% measurable disease, 78% visceral metastases, and 22% detectable PIK3CA mutations. The overall response rate (ORR) was 79% in patients with evaluable disease (N=33). Median DOR was 48 months for confirmed responders. Median PFS was 48.4 months and median OS was 77.3 months. ORR and PFS were comparable in patients with and without PIK3CA mutations. Fewer than 10% discontinued treatment due to treatment-related adverse events. The most frequent grade 3/4 adverse events were neutropenia (61%), rash (39%), and oral stomatitis (29%).CONCLUSIONSGedatolisib plus palbociclib and letrozole demonstrated preliminary efficacy in patients with no prior systemic therapy for ABC. These results warrant further evaluation of gedatolisib added to standard-of-care, first-line therapy for HR+/HER2- ABC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"115 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701282","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 immune microenvironment-associated prognostic and mifamurtide-response gene signatures for localized osteosarcoma: a correlative study of the ISG/OS2 trial.","authors":"Emanuela Palmerini,Maria Rosaria Sapienza,Stefano A Pileri,Giorgio Frega,Alberto Righi,Antonina Parafioriti,Alessandro Franchi,Claudio Agostinelli,Simona Righi,Cristina Meazza,Virginia Ferraresi,Sebastian Dorin Asaftei,Luca Coccoli,Angela Tamburini,Marco Gambarotti,Massimo Serra,Davide Maria Donati,Franca Fagioli,Marilena Cesari,Elisa Carretta,Katia Scotlandi,Toni Ibrahim,Maria Antonella Laginestra","doi":"10.1158/1078-0432.ccr-25-0649","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0649","url":null,"abstract":"PURPOSEA risk-adapted treatment strategy, the ISG/OS-2 trial, evaluated the use of mifamurtide in P-glycoprotein (Pgp)-positive localized osteosarcoma patients. The primary objective was the identification of prognostic classifiers based on tumor immune microenvironment (TME) gene profiling in all patients and in those undergoing mifamurtide.EXPERIMENTAL DESIGNRNA from pre-treatment FFPE non-decalcified tissues of 62 patients was analyzed with the PanCancer Immune profiling panel (NanoString Technologies, Seattle, WA, US). Thirty three out of sixty-two (53%) Pgp-positive patients underwent chemotherapy (CT)+mifamurtide, 29/62 (47%) Pgp-negative patients received CT alone. Univariate Cox regression, ROC curve and CIBERSORTx algorithm gene deconvolution analyses were performed.RESULTSA 21-gene signature able to stratify all patients into high-(Hi-R) and low-risk (Lo-R) was identified: 5-year OS for Hi-R 47%; 92% for Lo-R (p = 3e-06). TME of Lo-R vs Hi-R, was significantly enriched in CD8 T-cells, T-regs, and NK activated cells, and diminished in CD4 T- cells. The 21-gene signature was validated in two independent sets: Target-OS TCGA (n=62) and GSE33382 (n=57). For patients treated with CT+mifamurtide 31-mifamurtide related genes able to distinguish Hi-R and Lo-R in terms of OS (p = 1e-09) and EFS (p = 3e-06) were also identified. After multivariate analysis the 21-gene and the 31-gene mifamurtide-related signatures were independently associated with OS (p= 0.00044 and p = 0.000079, respectively).CONCLUSIONSA validated osteosarcoma TME prognostic gene signature has been identified, regardless of mifamurtide treatment. Importantly, a mifamurtide-related signature was also developed. Tumor-immune interactions possibly implicated in disease progression and treatment response were shown.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"114 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701290","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":"First-in-Human Phase 1/2 Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors.","authors":"Omid Hamid,Dana B Cardin,F Stephen Hodi,Patricia LoRusso,Taha Merghoub,Roberta Zappasodi,Rachana Maniyar,John E Janik,Maikel V W van der Velden,Feng Zhou,Zhiwan Dong,Xuejun Chen,James J Harding","doi":"10.1158/1078-0432.ccr-24-4141","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4141","url":null,"abstract":"BACKGROUNDGlucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonism in T cells may potentiate antitumor immunity responses to immune checkpoint blockade therapy. This first-in-human, phase 1/2 dose escalation/expansion study assessed INCAGN01876, a humanized GITR targeting agonistic monoclonal antibody, for advanced solid tumors (NCT02697591).METHODSDose was escalated 0.03 to 20 mg/kg Q2W; flat doses of 400 mg Q4W and 300 mg Q2W were also evaluated. The primary objective was safety/tolerability; secondary objectives were pharmacokinetics and preliminary efficacy; exploratory objectives were immunogenicity, GITR occupancy, and immune biomarker assessment.RESULTSAmong 100 patients enrolled (prior anti-PD-1/PD-L1 therapy, 47%; most common tumors: colorectal [19%]; melanoma [14%]); 2% had one dose-limiting toxicity (grade 4 hypoxia; grade 3 pleurisy). Maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 69% of patients, most frequently fatigue (17%) and pruritus (14%); 10% had grade ≥3 TRAEs, most commonly fatigue (3%); 23% reported immune-related AEs, most frequently generalized pruritus and generalized rash (7% each). Doses ≥5 mg/kg Q2W resulted in full receptor occupancy at trough. INCAGN01876 elicited changes in immune parameters in some patients, including variable peripheral regulatory T-cell (Treg) depletion and cytokine upregulation. Two patients achieved confirmed partial responses; one with appendiceal mucinous carcinoma, and another with melanoma previously treated with pembrolizumab and glembatumumab; 36% of patients had disease control.CONCLUSIONINCAGN01876 was generally well tolerated; fatigue was the most frequent TRAE. INCAGN01876 elicited transient and variable Treg depletion and limited antitumor activity. Future studies will explore combinatorial approaches.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"52 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701291","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":"MYC Point Mutations in Cancer: A Reboot and a Sequel.","authors":"Davide De Luca,Cristina Munafò,Luisa Lorenzi,Francesco Cucco","doi":"10.1158/1078-0432.ccr-25-0940","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0940","url":null,"abstract":"The impact of MYC point mutations on cancer development and progression is poorly explored, particularly compared with other MYC genetic alterations such as translocations and amplifications. MYC point mutations were first observed more than 40 years ago in lymphoid malignancies, and some of these were functionally characterized. In the following decades, only a few studies on MYC point mutations were reported until recently, when analyses of the myriad cancer-related high-throughput sequencing studies brought new life to this research topic and expanded the range of malignancies involved. However, to date, all this information can only be retrieved consulting the specific literature or navigating publicly available databases, and a proper collection and systematic description of these genetic changes is urgently needed. In this review, we run through the steps of the MYC point mutations line of research with a comprehensive illustration of the recurrent variants occurring at the MYC coding, non-coding and regulatory regions in cancer. With this work, we also aim to highlight the current gaps of knowledge to stimulate the research in this field which could ultimately result in the release of its translational potential.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"52 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693275","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":"HBV-Specific TCR-T Cell Therapy Combining mRNA Electroporation and Lentiviral Transduction: Treatment Regime for Recurrent HBV-Related HCC Post-Liver Transplantation.","authors":"Qiang Zhao,Jinbo Huang,Weixin Luo,Haidong Tan,Regina Wan Ju Wong,Zhiying Liu,Meiting Qin,Jiahao Li,Sarene Koh,Lu-En Wai,Tingting Wang,Jia Dan,Zhiyong Guo,Xiaoshun He","doi":"10.1158/1078-0432.ccr-25-1245","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1245","url":null,"abstract":"BACKGROUND & AIMSThis study aimed to preliminarily evaluate the safety, tolerability, and antitumor efficacy of HBV-specific TCR-T cell therapy combining mRNA electroporation and lentiviral transduction in patients with recurrent HBV-HCC post-LT.METHODSIn this pilot study (NCT04677088), two types of autologous HBV-specific TCR-redirected T cells were assessed without prior lymphodepletion: (1) multiple infusions of mRNA-electroporated HBV-TCR-T cells (mRNA-HBV-TCR-T cells) and (2) one to three infusions of lentiviral-transduced HBV-TCR-T cells (lenti-HBV-TCR-T cells). Treatment-related adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE), and anti-tumor efficacy was evaluated using computed tomography (CT) imaging according to RECIST 1.1 criteria. Progression-free survival (PFS) was defined as the time from the start of study treatment until objective tumor progression or death.RESULTSBoth mRNA-electroporated and lentiviral-transduced HBV-specific TCR-T cells demonstrated a favorable safety profile, with only Grade 1 to 2 treatment-related adverse events observed. In the mRNA-HBV-TCR-T cells cohort, the median PFS was 2.32 months (range: 1.87 to 2.77 months). The combination therapy cohort (mRNA-HBV-TCR-T cells + lenti-HBV-TCR-T cells) showed median PFS of 7.34 months (range: 4.47 to 7.60 months). CT imaging indicated effective tumor control in the combination therapy group.CONCLUSIONSThis study preliminarily suggests that the combination of mRNA-HBV-TCR-T cells and lenti-HBV-TCR-T cells could be a safe and potentially effective approach for treating patients following liver transplantation in the context of lifelong immunosuppression drug administration. Further studies are needed to refine treatment strategies and assess long-term safety and efficacy in this special patient population.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"25 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693295","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":"Molecular characterization of NUT carcinoma: a report from the NUT carcinoma registry.","authors":"Justin J Kim, Sara A Walton, Navin R Mahadevan, Jessica Haradon, Francesco Paoloni, Paul K Paik, Jamie E Chaft, Robert Hsu, Sarina A Piha-Paul, Pasi A Jänne, David A Barbie, Lynette M Sholl, Steven G Dubois, Glenn J Hanna, Geoffrey I Shapiro, Christopher A French, Jia Luo","doi":"10.1158/1078-0432.CCR-25-1071","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-1071","url":null,"abstract":"<p><strong>Purpose: </strong>NUT carcinoma (NC) is an underdiagnosed, poorly differentiated squamous cell cancer with a median survival of 6.7 months. Defined by NUTM1 fusions, NC enhances oncogene transcription, including MYC. We investigated the ability of standard next-generation sequencing (NGS) to identify NUTM1 fusions and describe additional molecular features of NC.</p><p><strong>Experimental design: </strong>This study included 116 NC patients whose tumors underwent broad-panel NGS (>80 genes) of DNA, ctDNA, and/or RNA fusion sequencing between 2013-2024. NGS reports and medical records were manually reviewed.</p><p><strong>Results: </strong>Of 116 patients (median age 38, 40.5% female), 84.5% had DNA, 12.1% had ctDNA, and 51.7% had RNA fusion testing. In a subset of 100 patients with DNA/ctDNA testing, 92.9% (n=79/85) had <10 pack-years/never-smoking history, and 58.8% (n=47/80) had a BRD4::NUTM1 fusion. Median TMB was 1.0 mut/Mb (range 0.0-16.0; n=71 known), and 19.7% (n=13/66) had PD-L1 expression ≥1%. DNA, ctDNA, RNA fusion, NUT IHC, and NUTM1 FISH detected NC fusions in 21.6%, 21.4%, 83.9%, 100.0%, and 91.9% of tests, respectively. Co-occurring pathogenic mutations included oncogenes PIK3CA, RET, FGFR3, and tumor suppressors ATM and BRCA1 (n=1 each). Secondary genes altered in >5% of NCs included LRP1B (10.4%), MLL2/KMT2D (8.0%), and FAT1 (5.5%); common pathways with mutated genes were epigenetic (57.0%), cell cycle (26.0%), and DNA repair (24.0%).</p><p><strong>Conclusions: </strong>Standard DNA NGS detects less than a quarter of NUT carcinomas; RNA-based fusion testing, or NUT IHC/NUTM1 FISH, should be routine for suspected NC. NCs are enriched in co-occurring epigenetic, cell cycle, and DNA repair alterations, warranting further evaluation.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697785","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":"Genomic and epigenomic ctDNA profiling in liquid biopsies from heavily pre-treated patients with DNA damage response-deficient tumors.","authors":"Ian M Silverman,Joseph D Schonoft,Benjamin Herzberg,Arielle Yablonovitch,Errin Lagow,Patrick C Fiaux,Pegah Safabakhsh,Sunantha Sethuraman,Danielle Ulanet,Julia Yang,Insil Kim,Paul Basciano,Michael Cecchini,Elizabeth Lee,Stephanie Lheureux,Elisa Fontana,Benedito A Carneiro,Jorge S Reis-Filho,Timothy A Yap,Michael Zinda,Ezra Y Rosen,Victoria Rimkunas","doi":"10.1158/1078-0432.ccr-25-1248","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1248","url":null,"abstract":"PURPOSEThe development of DNA damage response (DDR)-directed therapies is a major area of clinical investigation, yet to date Poly (ADP-ribose) polymerase inhibitors (PARPi) remain the only approved therapy in this space. Major challenges to DDR-targeted therapies in the post-PARPi era are the context dependency of DDR alterations and the presence of pre-existing resistance in this heavily pre-treated population. Blood samples from patients with tumors harboring defects in DDR genes were evaluated the feasibility of liquid biopsy platform for detecting complex genomic events such as BRCA1/2 reversions, HRD signatures, PV allele status, and differentially methylated regions for accurate quantitation of TF.PATIENTS AND METHODSOverall, 173 patients enrolled in two Phase 1/2 clinical trials (TRESR; NCT04497116, ATTACC; NCT04972110) were selected. The pre-treatment circulating tumor DNA (ctDNA) samples were analyzed from these patients, harboring pathogenic variants (PVs) in DDR genes.RESULTSIn a phase I heavily pretreated patient population with DDR defects, ctDNA can detect complex genomic alterations (HRD, biallelic loss, complex reversions) that historically require tumor tissue biopsies. Within the cohort of BRCA-associated tumor types previously treated with PARPi or platinum, HRD reversions were detected in 44% of evaluable patients and included large genomic rearrangements leading to deletion of whole or partial exons which have been underrepresented in the literature due to technological limitations.CONCLUSIONSThis study showcases the genomic complexity of DDR-altered tumors as revealed through baseline ctDNA profiling, an understanding of which is crucial for the future clinical development of novel DDR-directed therapies and combinations.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693289","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":"Durvalumab versus physician's choice chemotherapy in recurrent ovarian clear cell adenocarcinoma (MOCCA/APGOT-OV2/GCGS-OV3): a multicenter, randomized, phase 2 trial.","authors":"Natalie Y L Ngoi,Chel Hun Choi,Junxian Zhu,Diana Lim,Tuan Zea Tan,Haoyang Sun,Valerie Heong,Samuel G W Ow,Wen Yee Chay,Hee Seung Kim,Yi Wan Lim,Siew Eng Lim,Geraldine Goss,Jeffrey C Goh,Jae-Weon Kim,Michael Friedlander,Bee Choo Tai,Kidong Kim,David S P Tan","doi":"10.1158/1078-0432.ccr-25-0201","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0201","url":null,"abstract":"PURPOSEThe optimal treatment of recurrent ovarian clear cell carcinoma (rOCCC) remains unknown. This is the first randomized trial to compare durvalumab with chemotherapy in rOCCC.PATIENTS AND METHODSMOCCA is a randomized, phase 2 trial conducted in Singapore, Korea and Australia. Eligible patients had rOCCC with recurrence after platinum-based chemotherapy, ECOG performance status ≤2 and no prior immune checkpoint blockade. Patients were randomly assigned (2:1) to durvalumab (1500mg every 4 weeks) or chemotherapy. Patients progressing on chemotherapy were allowed to crossover to durvalumab. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rates (ORR), and safety.RESULTS48 eligible women were assigned to durvalumab (N= 31) or chemotherapy (N= 17). Median PFS was 7.6 (95% CI 7.0-16.0) and 14.0 (95% CI 7.0-32.9) weeks with durvalumab or chemotherapy, (HR 1.6, 95% CI 0.8-3.0; P= 0.92). Median OS was 37.9 (95% CI 21.7-143.0) and 40.6 (95% CI 25.0-not reached) weeks, respectively (HR 1.5, 95% CI 0.7-3.3; P= 0.85). The difference in ORR between groups was not statistically significant (durvalumab 9.7% vs PCC 18.8%; difference -9.1%, 95% CI -31.3%-12.9%; P= 0.83). Fewer all-grade (35.5% vs 68.8%) and high-grade (9.7% vs 31.3%) treatment-related adverse events were observed for durvalumab. PD-L1 CPS+ was observed in 28.9% (CPS≥1%) and 10.5% (CPS≥10%) of patients. PIK3CA mutations were associated with time to progression on durvalumab ³12 weeks (RR(-mutated vs -wildtype) 2.83, 95% CI 1.16 to 14.17).CONCLUSIONSDurvalumab was well-tolerated, but did not improve efficacy outcomes compared with chemotherapy in rOCCC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"110 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693274","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":"Oxford Classic-defined EMT risk stratification of High Grade Serous Ovarian cancer for guiding treatment decisions.","authors":"Lena Rai,Antonella Ravaggi,Eliana Bignotti,Robert L Hollis,Dale W Garsed,Ahwan Pandey,Kyriaki Barbara Papalois,Faheemah Patel,Yasmin Kamel,Leticia Campo,Alistair Easton,Joel Nulsen,Breeshey Roskams-Hieter,Mara Artibani,Lili Wang,Nosheen Hussain,Luyao Wang,Nancy Zaarour,Aneesh Aggarwal,Amro Ahmed-Ebbiary,Aws Al-Deka,Michael Churchman,C Simon Herrington,Laura Ardighieri,Federico Ferrari,Christopher Yau,Charlie Gourley,Franco Odicino,Ahmed Ashour Ahmed","doi":"10.1158/1078-0432.ccr-24-4250","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4250","url":null,"abstract":"PURPOSEThe association between epithelial to mesenchymal transition in High Grade Serous Ovarian Cancer (HGSOC) and poor prognosis is known. However, molecularly defining a subset of tumours that reproducibly associates with poor prognosis has been an elusive goal in this disease. A molecular signature that can robustly identify patients with poor prognosis and guide treatment decisions, including surgical strategy and targeted therapies, can improve survival rates.EXPERIMENTAL DESIGNWe carried out RNA sequencing of 139 tumour samples (Brescia cohort), an external validation on 362 and 126 patients from the Scottish and Garsed cohort, respectively; and meta-analysis of 1023 tumours to develop clinically useful risk groups. Identification of therapeutic targets was carried out by transcriptomic analyses of FLOW-sorted tumour epithelial cells from fresh tumours and multiplex IF assessment of tissue sections.RESULTSIn this study we have validated the prognostic strength of the OxC-EMT in three independent patient cohorts- Brescia [HR=3.6 (95% CI=1.59-7.97), p=1.99e-03], Scottish [HR=1.71 (95% CI=1.08-2.70), p=2.23e-02] and Garsed [Kruskal-Wallis p=0.00071]. OxC-based risk-stratification of HGSOC can robustly identify poor risk patients with a 5-year median survival for OxC-EMT-high and OxC-EMT-low risk groups of 13% and 50%, respectively (95%CI: 7.1%-23.5% vs. 36.1%-69.3%) in the Brescia cohort. Further analysis of the risk groups suggests that an alternate surgical strategy and a combination therapy involving EMT targeting drugs and immunomodulators could elicit improved clinical response in poor risk patients.CONCLUSIONSThis study provides a clinically useful risk stratification strategy for HGSOC as well as targeted treatment options for high-risk patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693291","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}