Background
Phase II single-arm study, N=79, HER2-positive (centrally confirmed) unresectable or metastatic gastric or GEJ cancer with disease progression on or after first-line trastuzumab-containing therapy. Conducted at 24 sites in USA and Europe. DESTINY-Gastric02 evaluated T-DXd in Western patients following the positive DESTINY-Gastric01 results from Japan/Korea.
Interventions and follow up
Regimen: Trastuzumab deruxtecan (T-DXd) 6.4 mg/kg IV q3wk until progression in HER2+ gastric/GEJ cancer post-trastuzumab
Primary endpoint: Confirmed objective response rate (ORR) by independent central review
Follow-up: 10.2 mo (updated analysis)
Primary endpoint: Confirmed objective response rate (ORR) by independent central review
Follow-up: 10.2 mo (updated analysis)
Results
ORR (primary analysis): 38% (30/79; 95% CI 27.3–49.6), including 4% CR + 34% PR
ORR (updated analysis): 42% (33/79; 95% CI 30.8–53.4), including 5% CR + 37% PR
mDOR: ~8 mo (updated)
ORR (updated analysis): 42% (33/79; 95% CI 30.8–53.4), including 5% CR + 37% PR
mDOR: ~8 mo (updated)
Adverse events
Grade ≥3 hematologic/GI: anaemia 14%, decreased neutrophil count 8%, decreased WBC 6%, nausea 8%; drug-related serious AEs in 13%.
ILD/pneumonitis: any grade ~6%, with 2 treatment-related deaths (3%); all-cause death 10 patients (13%).
ILD/pneumonitis: any grade ~6%, with 2 treatment-related deaths (3%); all-cause death 10 patients (13%).
Conclusions
T-DXd demonstrated clinically meaningful activity (ORR 38–42%) in Western HER2-positive gastric/GEJ cancer after prior trastuzumab, consistent with DESTINY-Gastric01 results in Asian patients. ILD-related deaths confirm the need for proactive monitoring.
Key Limitations
Single-arm Phase II without a comparator; response rate without survival context is limited. No head-to-head comparison to standard second-line therapy (ramucirumab + paclitaxel). Small Western cohort (N=79); DESTINY-Gastric01 enrolled only Asian patients. ILD mortality (3%) requires active monitoring and pulmonary toxicity management protocols. Enrollment required post-progression biopsy (HER2 re-testing), adding logistical burden.
Clinical Context
T-DXd is FDA approved for HER2-positive gastric/GEJ cancer after prior trastuzumab, supported by DESTINY-Gastric01 (OS benefit vs chemotherapy in Japan/Korea) and DESTINY-Gastric02 (ORR in USA/Europe). T-DXd is now a preferred second-line option for HER2+ gastric cancer in ESMO guidance. ILD management (grading, hold/discontinuation rules) requires specific institutional protocols.