Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial
Abstract Background The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse. In gastrointes...
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2025-04-01
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| author | Vincenzo Nasca Francesca Bergamo Luisa Foltran Lorenzo Antonuzzo Katia Bencardino Emanuela Dell’Aquila Salvatore Corallo Andrea Spallanzani Oronzo Brunetti Daniele Spada Stefano Tamberi Chiara Alessandra Cella Antonio Avallone Lorenzo Fornaro Samantha Di Donato Antonia Strippoli Alberto Puccini Emiliano Tamburini Federica Palermo Federica Morano Filippo Pietrantonio Alessandra Raimondi |
| author_facet | Vincenzo Nasca Francesca Bergamo Luisa Foltran Lorenzo Antonuzzo Katia Bencardino Emanuela Dell’Aquila Salvatore Corallo Andrea Spallanzani Oronzo Brunetti Daniele Spada Stefano Tamberi Chiara Alessandra Cella Antonio Avallone Lorenzo Fornaro Samantha Di Donato Antonia Strippoli Alberto Puccini Emiliano Tamburini Federica Palermo Federica Morano Filippo Pietrantonio Alessandra Raimondi |
| author_sort | Vincenzo Nasca |
| collection | DOAJ |
| description | Abstract Background The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse. In gastrointestinal cancers, the presence of circulating tumor DNA (ctDNA) after surgery is associated with a high risk of relapse, and the lack of ctDNA clearance after post-operative treatment is strongly associated with early relapse. Therefore, liquid biopsy may guide the selection of patients with micrometastatic disease after preoperative chemotherapy and surgery for non-cross resistant regimens in the post-operative setting. Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma after failure of at least one prior trastuzumab-based regimen. The DESTINY-Gastric01 and 02 trials showed remarkable activity and efficacy of T-DXd, thus supporting the investigation of this agent in early-stage disease to increase the chance of achieving disease eradication. Finally, the DESTINY-Gastric03 trial showed the safety profile and feasibility, with preliminary promising activity results of the combination of T-DXd with a fluoropyrimidine. Trial design TRINITY is an ongoing multicentre, randomized, open-label, interventional phase II study which will enroll approximately 46 patients with HER2-positive GEA, treated with pre-operative FLOT and radical surgery, and with the persistence of minimal residual disease detected by the Signatera™ assay in a liquid biopsy collected between 2 and 6 weeks after surgery. The trial is designed with an observational phase enrolling patients with HER2-positive GEA eligible for standard treatment with peri-operative FLOT and surgery. Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1–14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1–5) Q3 W for 6 cycles, or to the control arm with standard post-operative FLOT (at the same dose used during the last pre-operative cycle) for 4 cycles. Patients non-eligible for the interventional trial will continue the standard therapy and follow-up in the frame of the observational phase with collection of exploratory longitudinal liquid biopsies. The primary objective is ctDNA clearance at 1 year after randomization. Considering alpha- and beta-errors of 0.10 and 0.20 and hypothesizing a ctDNA clearance of 10% and 35% in the control and experimental arm, respectively, 23 patients per arm are required to prove the superiority of the experimental strategy. Secondary endpoints include disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety. The trial also represents a translational platform, including extensive analysis of circulating, tissue, and immune biomarkers as exploratory endpoints. Enrollment is active and ongoing. Trial registration TRINITY is registered at ClinicalTrials.gov (NCT06253650). |
| format | Article |
| id | doaj-art-0ef7d2d4f8cd4ae099d812f966959891 |
| institution | DOAJ |
| issn | 1471-2407 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj-art-0ef7d2d4f8cd4ae099d812f9669598912025-08-20T03:10:17ZengBMCBMC Cancer1471-24072025-04-0125111110.1186/s12885-025-14063-6Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trialVincenzo Nasca0Francesca Bergamo1Luisa Foltran2Lorenzo Antonuzzo3Katia Bencardino4Emanuela Dell’Aquila5Salvatore Corallo6Andrea Spallanzani7Oronzo Brunetti8Daniele Spada9Stefano Tamberi10Chiara Alessandra Cella11Antonio Avallone12Lorenzo Fornaro13Samantha Di Donato14Antonia Strippoli15Alberto Puccini16Emiliano Tamburini17Federica Palermo18Federica Morano19Filippo Pietrantonio20Alessandra Raimondi21Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriMedical Oncology 1, Veneto Institute of Oncology IOV - IRCCSCentro Riferimento Oncologico (CRO) Aviano, National Cancer Institute IRCCSClinical Oncology Unit, Careggi University HospitalNiguarda Cancer Center, Grande Ospedale Metropolitano NiguardaIRCCS Istituto Nazionale Tumori Regina ElenaSC Oncology, Fondazione IRCCS Policlinico San MatteoDepartment of Oncology and Hematology, University Hospital of ModenaIRCCS Istituto Tumori Giovanni Paolo IIASST CremonaOncology Unit, Ospedale Santa Maria Delle CrociDivision of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Istituto Europeo Di Oncologia IRCCSIstituto Nazionale Dei Tumori Napoli IRCCS PascaleU.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria PisanaNuovo Ospedale S. StefanoComprehensive Cancer Center, Policlinico Universitario Gemelli IRCCSDepartment of Biomedical Sciences, Humanitas UniversityDepartment of Oncology and Palliative Care, Ospedale Cardinale PanicoDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriAbstract Background The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse. In gastrointestinal cancers, the presence of circulating tumor DNA (ctDNA) after surgery is associated with a high risk of relapse, and the lack of ctDNA clearance after post-operative treatment is strongly associated with early relapse. Therefore, liquid biopsy may guide the selection of patients with micrometastatic disease after preoperative chemotherapy and surgery for non-cross resistant regimens in the post-operative setting. Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma after failure of at least one prior trastuzumab-based regimen. The DESTINY-Gastric01 and 02 trials showed remarkable activity and efficacy of T-DXd, thus supporting the investigation of this agent in early-stage disease to increase the chance of achieving disease eradication. Finally, the DESTINY-Gastric03 trial showed the safety profile and feasibility, with preliminary promising activity results of the combination of T-DXd with a fluoropyrimidine. Trial design TRINITY is an ongoing multicentre, randomized, open-label, interventional phase II study which will enroll approximately 46 patients with HER2-positive GEA, treated with pre-operative FLOT and radical surgery, and with the persistence of minimal residual disease detected by the Signatera™ assay in a liquid biopsy collected between 2 and 6 weeks after surgery. The trial is designed with an observational phase enrolling patients with HER2-positive GEA eligible for standard treatment with peri-operative FLOT and surgery. Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1–14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1–5) Q3 W for 6 cycles, or to the control arm with standard post-operative FLOT (at the same dose used during the last pre-operative cycle) for 4 cycles. Patients non-eligible for the interventional trial will continue the standard therapy and follow-up in the frame of the observational phase with collection of exploratory longitudinal liquid biopsies. The primary objective is ctDNA clearance at 1 year after randomization. Considering alpha- and beta-errors of 0.10 and 0.20 and hypothesizing a ctDNA clearance of 10% and 35% in the control and experimental arm, respectively, 23 patients per arm are required to prove the superiority of the experimental strategy. Secondary endpoints include disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety. The trial also represents a translational platform, including extensive analysis of circulating, tissue, and immune biomarkers as exploratory endpoints. Enrollment is active and ongoing. Trial registration TRINITY is registered at ClinicalTrials.gov (NCT06253650).https://doi.org/10.1186/s12885-025-14063-6Gastric cancerEsophageal cancerHER2Liquid biopsyTrastuzumab-deruxtecan |
| spellingShingle | Vincenzo Nasca Francesca Bergamo Luisa Foltran Lorenzo Antonuzzo Katia Bencardino Emanuela Dell’Aquila Salvatore Corallo Andrea Spallanzani Oronzo Brunetti Daniele Spada Stefano Tamberi Chiara Alessandra Cella Antonio Avallone Lorenzo Fornaro Samantha Di Donato Antonia Strippoli Alberto Puccini Emiliano Tamburini Federica Palermo Federica Morano Filippo Pietrantonio Alessandra Raimondi Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial BMC Cancer Gastric cancer Esophageal cancer HER2 Liquid biopsy Trastuzumab-deruxtecan |
| title | Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial |
| title_full | Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial |
| title_fullStr | Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial |
| title_full_unstemmed | Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial |
| title_short | Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial |
| title_sort | adjuvant trastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in her2 positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre operative chemotherapy and radical surgery the multicentre phase ii randomized trinity trial |
| topic | Gastric cancer Esophageal cancer HER2 Liquid biopsy Trastuzumab-deruxtecan |
| url | https://doi.org/10.1186/s12885-025-14063-6 |
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