An open-label phase Ib/II study of trastuzumab deruxtecan combined with nivolumab and CAPOX in patients with HER2-low gastroesophageal adenocarcinoma (EPOC2203).

4024 Background: Trastuzumab deruxtecan (T-DXd) is standard of care for previously treated patients with HER2-positive metastatic gastroesophageal adenocarcinoma (mGEA) with exploratory analyses of the DESTINY-Gastric01 trial suggested activity in HER2-low (IHC 1+/2+ ISH-negative) disease and preclinical synergy with anti-PD-1 therapy. Methods: EPOC2203 (jRCT2031230477) is a prospective, multicenter, phase Ib/II study evaluating first-line T-DXd combined with nivolumab and CAPOX in HER2-low mGEA. Patients received T-DXd (5.4 or 4.4 mg/kg, day1) in combination with nivolumab (360mg/body, day1) and CAPOX (capecitabine 750 mg/m² twice daily on days 1–14; oxaliplatin 70 mg/m² on day 1) every 3 weeks. The primary endpoints were DLT rate to determine RP2D in phase Ib and ORR in phase II. Assuming a threshold ORR of 58% and an expected ORR of 80%, 28 patients in the full analysis set (FAS) treated at the RP2D were planned (one-sided α = 0.10; power = 80%). Results: A total of 30 patients were enrolled. The median age was 59 years; 83.3% had HER2 IHC 1+ disease, 63.3% had gastric primary, and 96.7% had PD-L1 CPS ≥1. Two DLTs, both febrile neutropenia, occurred at T-DXd 5.4 mg/kg, while none were observed at 4.4 mg/kg in phase Ib part, which was selected as the RP2D. Among patients in the FAS (n = 28), the investigator-assessed ORR was 89.3% (80% CI, 77.7–96.0; P < 0.001), exceeding the prespecified threshold. At median follow-up of 10.1 months, median PFS was 8.1 months (95% CI, 5.6–not estimable). The 6-month OS was 89.3% (95% CI, 70.4–96.4). Six patients underwent conversion surgery, including three with pathological complete response. Grade ≥3 treatment-emergent adverse events occurred in 46.4% of patients who were treated at the recommended dose (n = 28). The most common grade ≥3 adverse events were neutropenia (25.0%), anemia (14.3%), febrile neutropenia (3.6%), and diarrhea (3.6%). Interstitial lung disease was observed in 3 patients (10.7%), with no grade ≥3 events. No treatment-related deaths were observed. Conclusions: T-DXd (4.4 mg/kg) combined with nivolumab and CAPOX demonstrated encouraging antitumor activity with a manageable safety profile as first-line treatment for HER2-low mGEA, supporting further evaluation. Clinical trial information: jRCT2031230477.