Background
Phase Ib/II open-label international platform trial in HER2-positive, resectable, locally advanced esophagogastric adenocarcinoma (EGA). Designed to evaluate neoadjuvant trastuzumab deruxtecan (T-DXd) combinations, leveraging the superior efficacy of T-DXd over trastuzumab in the metastatic HER2+ EGA setting.
Interventions and follow up
Regimen: Neoadjuvant T-DXd-based combinations with standard chemotherapy backbones, evaluated across sequential platform cohorts each with a safety run-in
Primary endpoint: Pathologic response and surgical feasibility
Median follow up: NR (design/rationale publication)
Primary endpoint: Pathologic response and surgical feasibility
Median follow up: NR (design/rationale publication)
Results
Status: No mature efficacy results reported; this is a design/rationale publication, NR
Rationale: Prior data show neoadjuvant chemotherapy improves pathologic complete response but not yet OS; T-DXd has superior efficacy versus chemotherapy in later-line HER2+ metastatic EGA and high response rates in first-line combinations
Design: Platform structure allows rapid sequential evaluation of multiple T-DXd-chemotherapy combinations
Rationale: Prior data show neoadjuvant chemotherapy improves pathologic complete response but not yet OS; T-DXd has superior efficacy versus chemotherapy in later-line HER2+ metastatic EGA and high response rates in first-line combinations
Design: Platform structure allows rapid sequential evaluation of multiple T-DXd-chemotherapy combinations
Adverse events
Overall: Safety assessment ongoing; each cohort includes a safety run-in to evaluate tolerability, NR
Anticipated monitoring: Interstitial lung disease/pneumonitis and gastrointestinal toxicity are known T-DXd risks requiring close surveillance
Anticipated monitoring: Interstitial lung disease/pneumonitis and gastrointestinal toxicity are known T-DXd risks requiring close surveillance
Conclusions
The NeoART platform trial addresses an unmet need in HER2+ resectable EGA by evaluating the HER2-targeted ADC T-DXd in the neoadjuvant setting, testing whether its superior efficacy over trastuzumab translates into improved perioperative outcomes.
Key Limitations
Design/rationale publication without efficacy outcomes; non-randomized platform structure; interstitial lung disease risk with T-DXd is a key safety concern in a curative-intent perioperative population; results pending.
Clinical Context
Perioperative HER2+ EGA is currently treated with perioperative chemotherapy (FLOT) without routine HER2-targeting; T-DXd is approved for later-line metastatic HER2+ EGA. NeoART explores moving the ADC into the curative-intent setting; no guideline or regulatory change is implied by this design publication.