Safety and preliminary activity of neoadjuvant trastuzumab deruxtecan (T-DXd) plus 5-fluorouracil and folinic acid for HER2-positive, resectable esophagogastric adenocarcinoma: Results from the safety run-in cohort of the phase Ib/II UCCL-AIO-STO0124-IKF072 NeoART trial

Introduction: Despite advances in the multimodal treatment of resectable esophagogastric adenocarcinoma (EGA), relapse rates remain high. No human epidermal growth factor receptor 2 (HER2)-targeted treatment is yet established in the perioperative setting. While trastuzumab deruxtecan (T-DXd) has compelling efficacy and is now a well-established drug in the treatment of advanced HER2-positive EGA, safety and efficacy data from the perioperative setting are still lacking. Methods: NeoART is a phase Ib/II platform trial evaluating the safety and efficacy of neoadjuvant T-DXd-containing combination regimens for patients with HER2-positive EGA. We report about the safety, feasibility and preliminary antitumor activity from the safety run-in cohort of the NeoART trial in which patients with locally advanced resectable EGA received three cycles of preoperative T-DXd (5.4mg/kg, Q3W) combined with 5-fluorouracil (5-FU; 2600mg/m2 24 hours, Q2W) and folinic acid (FA; 200mg/m2, Q2W). Results: In the pre-planned safety analysis of the first six patients recruited to NeoART, no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) were reported during neoadjuvant treatment. Relevant treatment-related adverse events (AEs) of grades 1-3 were diarrhea, muscositis, and nausea, but none fulfilled the criteria of DLTs. No relevant hematologic toxicity was observed. Five of six patients underwent curative-intent oncologic resection. In one patient, peritoneal carcinomatosis was detected at the time of surgery and therefore, the tumor was not resected. Two patients experienced grade 3 postoperative complications according to Clavien-Dindo, including one anastomotic leakage which was classified as an SAE. R0 resection was accomplished in four out of five resected patients. Histopathological complete remission (pCR; ypT0 N0) was observed in two patients. Conclusions: Neoadjuvant treatment with T-DXd plus 5-FU/FA was found to be well tolerated and showed preliminary signs of activity during the safety run-in period of the NeoART study.