The Churchill Hospital is a teaching hospital in Oxford, England. It is managed by the Oxford University Hospitals NHS Foundation Trust.
TPS4207 Background: An unmet medical need remains in patients (pts) with HER2+ gastric or GEJ cancer. HER2 is a validated target in up to 20% of pts with gastric or GEJ cancer. The KEYNOTE-811 trial demonstrated that adding pembro to trastuzumab and chemo improved progression-free survival (PFS) and overall survival (OS) versus placebo for first-line treatment of pts with HER2+ gastric or GEJ cancer with a PD-L1 combined positive score (CPS) ≥1 (Janjigian Y et al. N Engl J Med. 391;1360:2024). In the DESTINY-Gastric03 trial, first-line combinations involving T-DXd, a HER2-directed antibody-drug conjugate, and fluoropyrimidine (5-FU or capecitabine [CAPE]) ± pembro showed acceptable safety and encouraging efficacy in pts with HER2+ gastric or GEJ cancer, including pts with CPS < 1 (Janjigian Y et al. Ann Oncol . 35;S878:2024). Building on this evidence, the phase 3 DESTINY-Gastric05 trial aims to bring a potentially improved platinum-free treatment approach for all pts with HER2+ gastric or GEJ cancer. Methods: DESTINY-Gastric05 (NCT06731478) is an open-label, randomized, multicenter, phase 3 global trial designed to evaluate the efficacy and safety of T-DXd in combination with 5-FU (or CAPE) + pembro versus standard-of-care chemo with trastuzumab + pembro as first-line treatment in pts with unresectable, locally advanced or metastatic centrally confirmed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization+) gastric or GEJ cancer with a CPS ≥1. Pts must have ≥1 RECIST v1.1 measurable lesion, a left ventricular ejection fraction ≥50%, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Approximately 576 pts will be randomly assigned in a 1:1 ratio to receive: T-DXd 5.4 mg/kg + either 5-FU or CAPE + pembro (arm M1); or trastuzumab + platinum-based chemo (either cisplatin + 5-FU or oxaliplatin + CAPE) + pembro (arm M2). The primary efficacy endpoint is PFS based on blinded independent central review (BICR), and the key secondary endpoint is OS. Other secondary endpoints include overall response rate, duration of response, and time to response per RECIST v1.1 assessed by BICR and investigator. Safety and tolerability will also be assessed. An exploratory cohort (approximately 150 pts) will evaluate the efficacy and safety of T-DXd in combination with 5-FU or CAPE versus trastuzumab plus standard-of-care chemo in pts with PD-L1 CPS < 1. Clinical trial information: NCT06731478 .
Introduction Pleural mesothelioma (PM) is often presaged by benign asbestos-associated pleural inflammation (AAPI), offering a unique window of opportunity for translational research. The PREDICT-Meso International Accelerator Network is leveraging this natural history to perform target identification and develop novel therapies for early-stage or pre-invasive disease. This requires assembly of a unique bioresource of longitudinal human tissue samples spanning the terminal stages of PM evolution, development of preclinical models for drug screening and reliable tools for risk prediction in patients presenting with AAPI.Methods and analysis Mesothelioma Observational study of Risk prediction and Generation of paired benign-meso tissue samples, Including a Nested MRI Substudy (Meso-ORIGINS) is a prospective, multicentre observational study, comprising two arms (A and B), with a nested MRI substudy in arm A. Arm A will recruit 300 AAPI patients and perform 6-monthly surveillance for 2 years. Suspicion of PM evolution will prompt repeat biopsy and banking, delivering a primary objective of ≥38 longitudinal AAPI-PM tissue pairs. This target reflects a projected PM evolution rate of 14% (95% CI 10.5 to 19.2) derived from a prior multicentre feasibility trial. Multiomic risk profiling will be performed in arm A, using blood proteomics, exhaled breath metabolomics and perfusion MRI. Arm B will recruit 300 patients with suspected PM, permitting collection of multiregion pleural biopsies in patients spanning AAPI and PM timepoints for evaluation of anatomical heterogeneity. Where possible, patients in arm B diagnosed with AAPI will be recruited to arm A for 2-year surveillance +/− repeat biopsy in subsequent PM evolution cases. Pleural fluid will be collected in arm B for cell-line generation and diagnostic biomarker evaluation. Exhaled breath will be collected in arm B for diagnostic biomarker evaluation.Ethics and dissemination The study has ethical approval (REC Ref 21/WS/0120). Results will be disseminated via peer-reviewed journals and national/international scientific conferences. Tissues, data and derived omics will be shared via the PREDICT-Meso Research Tissue Bank (REC Ref 21/WS/0011).Trial registration number ISRCTN22929761.
