Background
Phase III RCT enrolling 203 HER2-positive patients (of 603 assessed) with newly diagnosed T1N1–2 or T2–3N0–2 esophageal adenocarcinoma, testing addition of trastuzumab to neoadjuvant chemoradiotherapy.
Interventions and follow up
Arm A: trastuzumab + chemoradiotherapy then surgery (trastuzumab 4 mg/kg week 1, then 2 mg/kg weekly ×5 during CRT, 6 mg/kg presurgery, then 6 mg/kg q3wk ×13 starting 21–56 days post-op)
Arm B: chemoradiotherapy then surgery (paclitaxel 50 mg/m2 + carboplatin AUC 2 weekly ×6 with RT 50.4 Gy/28 fr)
Primary endpoint: disease-free survival (DFS)
Arm B: chemoradiotherapy then surgery (paclitaxel 50 mg/m2 + carboplatin AUC 2 weekly ×6 with RT 50.4 Gy/28 fr)
Primary endpoint: disease-free survival (DFS)
Results
mDFS: 19.6 vs 14.2 months, arm A vs B; HR 0.99, 95% CI 0.71–1.39; log-rank P=.97
Overall survival: no significant difference between arms
pCR: similar between arms
Overall survival: no significant difference between arms
pCR: similar between arms
Adverse events
Grade 3 treatment-related: 43% vs 54% (arm A vs B), most commonly hematologic then gastrointestinal
Grade 4 events: 21% vs 22%; no excess cardiac toxicity with trastuzumab
Grade 4 events: 21% vs 22%; no excess cardiac toxicity with trastuzumab
Conclusions
Adding trastuzumab to neoadjuvant chemoradiotherapy did not improve disease-free survival in HER2-overexpressing esophageal adenocarcinoma; outcomes were similar with or without trastuzumab.
Key Limitations
Slow accrual and modest HER2-positive sample size limited power. Only single-agent HER2 blockade (no dual blockade) was tested, and the chemoradiation backbone may have masked any trastuzumab benefit.
Clinical Context
Negative result; trastuzumab is not added to neoadjuvant chemoradiotherapy for localized esophageal adenocarcinoma. HER2-targeted therapy remains established only in the metastatic setting (ToGA, KEYNOTE-811) per ASCO/ESMO. The CROSS regimen remains standard neoadjuvant chemoradiotherapy.