Safety and Preliminary Activity of Neoadjuvant Trastuzumab Deruxtecan 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 (5.4 mg/kg, Q3W) combined with 5-fluorouracil (5-FU; 2,600 mg/m2 24 h, Q2W) and folinic acid (FA; 200 mg/m2, Q2W).

RESULTS

In the preplanned safety analysis of the first 6 patients recruited to NeoART, no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) were reported during neoadjuvant treatment. Relevant treatment-related adverse events of grades 1-3 were diarrhea, mucositis, 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; therefore, the tumor was not resected. Two patients experienced grade 3 postoperative complications according to Clavien-Dindo classification, 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.