498TiP - 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 surg

Background

Standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative (op) FLOT, yet around half patients experience relapse. In gastrointestinal cancers, detection of circulating tumor DNA (ctDNA) after surgery and post adjuvant therapy is associated with high risk of relapse. Therefore, liquid biopsy may guide the selection of patients with micrometastatic disease after pre-op therapy and surgery for non-cross resistant post-op regimens. Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced GEA after failure of ≥1 trastuzumab-based regimen. The DESTINY-Gastric01, 02 and 03 trials showed the activity and efficacy of T-DXd alone and the safety of combination with fluoropyrimidine.

Trial design

TRINITY is a multicenter, randomized, open-label phase II study that will enroll ∼46 patients with HER2-positive GEA, treated with pre-op FLOT and surgery, with persistence of minimal residual disease at Signatera^TM liquid biopsy at 2-6 weeks after surgery. The trial includes an observational phase enrolling patients with HER2-positive GEA eligible for standard peri-op FLOT and surgery. Patients will be randomized 1:1 to experimental arm of adjuvant T-DXd (6.4 mg/kg IV) plus capecitabine or 5-Fluorouracil Q3W for 6 cycles or standard post-op FLOT for 4 cycles. Patients non-eligible for the interventional trial continue standard therapy in the observational phase with collection of longitudinal liquid biopsies. The primary endpoint is ctDNA clearance at 1 year after randomization. Setting a- and b-errors at 0.10 and 0.20 and hypothesizing 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 are disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety. The trial also serves as a translational platform, with extensive analysis of circulating and tissue biomarkers.

Clinical trial identification

NCT06253650.

Legal entity responsible for the study

Gruppo Oncologico Nord-Ovest (GONO) Foundation.

Funding

Gruppo Oncologico Nord-Ovest (GONO) Foundation; partially funded by AstraZeneca.

Disclosure

F. Morano: Financial Interests, Personal, Invited Speaker: Servier, Pierre Fabre, Lilly; Financial Interests, Institutional, Research Grant: Incyte. S. Tamberi: Financial Interests, Personal, Advisory Board: Gilead, AstraZeneca. F. Pietrantonio: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, MSD, Bayer, Astellas, Takeda, GSK, Johnson & Johnson, Rottapharm; Financial Interests, Personal, Invited Speaker: Amgen, Merck Serono, BMS, Lilly, Servier, Bayer, Pierre Fabre, AstraZeneca, Astellas, Daiichi Sankyo, Takeda; Financial Interests, Personal, Expert Testimony: Ipsen; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Incyte, Agenus; Financial Interests, Institutional, Invited Speaker: Lilly, Amgen. All other authors have declared no conflicts of interest.