Background
Phase II single-arm trial. N=57 patients with locally advanced and/or recurrent or metastatic HER2-positive salivary duct carcinoma (SDC), HER2 overexpression defined as IHC 3+ or IHC 2+/FISH amplified. Enrolled at a single Japanese institution (International University of Health and Welfare Mita Hospital), 2011–2018. No prior HER2-targeted therapy allowed. SDC is a rare, aggressive malignancy with poor prognosis; ~50% of cases are HER2-positive. First prospective phase II trial of dual HER2-targeted therapy in SDC.
Interventions and follow up
Arm A: Trastuzumab 8 mg/kg loading → 6 mg/kg q3wk + docetaxel 70 mg/m² q3wk until PD or unacceptable toxicity
Primary endpoint: Overall response rate (ORR)
mFollow up: Not stated (ongoing accrual)
Primary endpoint: Overall response rate (ORR)
mFollow up: Not stated (ongoing accrual)
Results
ORR: 70.2% (95% CI 56.6–81.6%)
Clinical benefit rate (CR+PR+SD ≥6 months): 84.2% (95% CI 72.1–92.5%)
mPFS: 8.9 months (95% CI 7.8–9.9 months)
mOS: 39.7 months (95% CI not reached)
Clinical benefit rate (CR+PR+SD ≥6 months): 84.2% (95% CI 72.1–92.5%)
mPFS: 8.9 months (95% CI 7.8–9.9 months)
mOS: 39.7 months (95% CI not reached)
Adverse events
Main adverse events: Grade 4 decreased neutrophil count: 60% of patients. Anemia grade 3–4: 91% any grade, 14% grade 3 febrile neutropenia. No grade ≥2 cardiac events or LVEF decline <50%. Docetaxel-driven hematologic toxicity predominant.
Conclusions
Trastuzumab + docetaxel achieved an ORR of 70.2% and clinical benefit rate of 84.2% with a median OS of 39.7 months in HER2-positive SDC, representing the best outcomes reported for systemic therapy in advanced SDC at the time. This trial established HER2-targeted therapy as the preferred first-line approach for HER2+ SDC.
Key Limitations
Key Limitations: Single-center, single-arm study without a comparator — no direct evidence of superiority over chemotherapy alone. Small sample size (N=57) and single Japanese institution limit generalizability. No assessment of pertuzumab, T-DM1, or T-DXd (trastuzumab deruxtecan), which have subsequently shown activity and may supersede this regimen. Subsequent data with T-DXd (DS-8201) show impressive ORRs even after trastuzumab failure. HER2-testing standardization across SDC (vs breast/gastric cancer criteria) remains an open issue.
Clinical Context
Takahashi 2019 established trastuzumab + docetaxel as the preferred first-line regimen for HER2+ SDC, and it remains the most commonly used regimen globally. NCCN lists HER2-directed therapy as the preferred systemic treatment for HER2-amplified/overexpressed salivary gland carcinoma. Subsequent data with T-DXd (trastuzumab deruxtecan) show ORR ~50% post-trastuzumab failure, and T-DXd is increasingly used as second-line. Molecular profiling (NTRK, HRAS, BRAF) is recommended for HER2-negative or refractory SDC to identify targetable alterations.
References
References: Takahashi H et al, JCO 2019 (primary)