Background
Phase II, open-label RCT in Japan and South Korea enrolling 187 patients with HER2-positive gastric or GEJ adenocarcinoma that had progressed on at least two prior regimens including trastuzumab. Randomized 2:1 to trastuzumab deruxtecan vs physician's choice chemotherapy. Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate.
Interventions and follow up
Arm A: Trastuzumab deruxtecan 6.4 mg/kg IV Q3W (n=125)
Arm B: Physician's choice of chemotherapy (irinotecan or paclitaxel) (n=62)
Primary endpoint: Objective response
Secondary endpoints: OS, PFS, duration of response, safety
Median follow up: 12.3 mo
Arm B: Physician's choice of chemotherapy (irinotecan or paclitaxel) (n=62)
Primary endpoint: Objective response
Secondary endpoints: OS, PFS, duration of response, safety
Median follow up: 12.3 mo
Results
Objective response: 51% vs 14%, P<.001 (Arm A vs B)
mOS: 12.5 mo vs 8.4 mo, HR 0.59, 95% CI 0.39-0.88, P=.01
mPFS: 5.6 mo vs 3.5 mo, HR 0.47, 95% CI 0.31-0.71
mOS: 12.5 mo vs 8.4 mo, HR 0.59, 95% CI 0.39-0.88, P=.01
mPFS: 5.6 mo vs 3.5 mo, HR 0.47, 95% CI 0.31-0.71
Adverse events
Hematologic (grade ≥3): Neutropenia 51% vs 24%, anemia 38% vs 23%, leukopenia 21% vs 11% (Arm A vs B)
Pulmonary: Interstitial lung disease or pneumonitis in 12 patients on trastuzumab deruxtecan (grade 1-2 in 9, grade 3-4 in 3); 1 drug-related death (pneumonia) vs 0
Pulmonary: Interstitial lung disease or pneumonitis in 12 patients on trastuzumab deruxtecan (grade 1-2 in 9, grade 3-4 in 3); 1 drug-related death (pneumonia) vs 0
Conclusions
Trastuzumab deruxtecan significantly improved objective response and overall survival versus chemotherapy in heavily pretreated HER2-positive gastric/GEJ adenocarcinoma, establishing it as an effective later-line option. Interstitial lung disease requires vigilant monitoring.
Key Limitations
Open-label phase II conducted exclusively in Asian (Japanese/Korean) patients, limiting generalizability. Risk of treatment-related interstitial lung disease, including fatal cases. The global DESTINY-Gastric02 trial subsequently confirmed activity in Western populations.
Clinical Context
FDA approved trastuzumab deruxtecan (Jan 2021) for advanced HER2-positive gastric/GEJ adenocarcinoma after a prior trastuzumab-based regimen. ESMO guidelines recommend trastuzumab deruxtecan as a later-line option for HER2-positive disease. Mandatory ILD monitoring and prompt management of pneumonitis are required.
References
Shitara K et al, NEJM, 2020, PMID 3379420
DESTINY-Gastric02: Van Cutsem E et al, Lancet Oncol, 2023, PMID: 36640793
DESTINY-Gastric02: Van Cutsem E et al, Lancet Oncol, 2023, PMID: 36640793