Efficacy and safety of trastuzumab emtansine in patients with advanced human epidermal growth factor receptor 2-positive extramammary Paget's disease: an investigator-initiated, open-label, single-arm, multicentre, prospective, phase II clinical trial (TEMENOS-2).

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma with no established standard systemic therapy owing to limited clinical evidence. Approximately 40% of metastatic EMPD cases overexpress human epidermal growth factor receptor 2 (HER2), suggesting a potential therapeutic target. However, prospective evidence for HER2-directed antibody-drug conjugates (ADCs) in advanced EMPD is lacking. This study aimed to assess the efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced EMPD. PATIENTS AND METHODS: This investigator-initiated, open-label, single-arm, multicentre, prospective phase II trial enrolled Japanese patients with HER2-positive metastatic EMPD who had not received prior HER2-targeted therapy. Patients received intravenous T-DM1 at 3.6 mg/kg every 3 weeks for up to 2 years. The primary endpoint was objective response rate (ORR) assessed by independent central review. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. RESULTS: Fourteen patients were enrolled and received study treatment between December 2021 and July 2024. The median age was 65 (range: 42-80) years. Thirteen patients had an Eastern Cooperative Oncology Group performance status of 0, and 12 had distant metastases at baseline. The ORR assessed by central review was 92.9% [95% confidence interval (CI) 66.1%-99.8%], with best responses of complete response (n = 2), partial response (n = 11), and progressive disease (n = 1). Median OS was not reached, whereas median PFS was 16.95 months (95% CI 5.75 months-not applicable). Grade 3 adverse events occurred in 6 (42.9%) patients. No grade ≥4 adverse events were observed, and one patient discontinued treatment due to grade 1 interstitial lung disease. CONCLUSIONS: This study provides the first prospective clinical evidence supporting the efficacy and safety of a HER2-directed ADC in HER2-positive advanced EMPD. T-DM1 demonstrated robust antitumour activity with a tolerable safety profile in this predominantly older adult population.