Biomarker-Stratified Phase II Trial of Trastuzumab Rezetecan in Advanced Salivary Gland Carcinoma Across Cohorts With High and Low Human Epidermal Growth Factor Receptor 2 Expression.

PURPOSE: Systemic treatment options for advanced salivary gland carcinoma (SGC) are limited, and prospective data for human epidermal growth factor receptor 2 (HER2)-directed therapy remain sparse, particularly in HER2-low disease. We evaluated trastuzumab rezetecan (SHR-A1811), a HER2-directed antibody-drug conjugate, in prospectively defined HER2-high and HER2-low cohorts. PATIENTS AND METHODS: In this phase II trial, patients with unresectable locally advanced or recurrent/metastatic SGC were enrolled in separate HER2-high (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) and HER2-low (IHC 1+ or IHC 2+/ISH-) cohorts. Each cohort was independently evaluated using Simon's optimal two-stage design. SHR-A1811 was administered intravenously once every 3 weeks at a recommended starting dose of 4.8 mg/kg. The primary end point was confirmed objective response rate (ORR) per RECIST version 1.1. RESULTS: Forty-six patients were enrolled and treated, including 24 in the HER2-high cohort and 22 in the HER2-low cohort. The median follow-up was 21.9 months (95% CI, 16.9 to 26.9) and 11.3 months (95% CI, 6.9 to 15.7), respectively. The confirmed ORR was 91.7% (95% CI, 73.0 to 99.0), including four complete responses, in the HER2-high cohort and 45.5% (95% CI, 24.4 to 67.8) in the HER2-low cohort. Median progression-free survival (PFS) and overall survival (OS) were not reached in the HER2-high cohort. In the HER2-low cohort, the median PFS was 12.7 months and the median OS was 21.3 months. Grade 3 or higher treatment-related adverse events occurred in 41.3% of patients, most commonly neutrophil count decreased (32.6%). Interstitial lung disease occurred in 6.5% of patients, all grade 1. No treatment-related deaths occurred. CONCLUSION: SHR-A1811 showed high antitumor activity in HER2-high SGC and promising activity in HER2-low SGC, with a manageable safety profile.