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Trastuzumab deruxtecan is an antibody–drug conjugate with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic ...

Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. The PFS of 14 months compares well with the 15-month PFS reported in the subset of patients with stable brain metastases at baseline in the DESTINY-Breast03 trial 17 and is probably the longest PFS ever observed in a prospective trial evaluating systemic therapy in patients with active brain metastases to date. trastuzumab emtansine (T-SM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7–10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res. 82, Abstract GS3-01 (2022). In the DESTINY-Breast03 study, trastuzumab deruxtecan yielded an objective intracranial response rate of 63.9% in patients with stable brain metastases at baseline 17. In the subset of patients with measurable brain metastases without previous local radiotherapy, the response rate with single-agent T-DM1 was 49.3% 31. In a population of 15 patients with newly diagnosed or progressive brain metastases, trastuzumab deruxtecan yielded responses by RANO-BM criteria in 11 of 15 patients, for a response rate by central review of 73.3% in the ITT population. The study was specifically designed to evaluate efficacy and safety of trastuzumab deruxtecan in a population of HER2-positive breast cancer patients with active brain metastases (that is, newly diagnosed brain metastases or brain metastases progressing after previous local therapy) and more broadly as proof of principle for the intracranial activity of ADCs. In the subset of patients with measurable brain metastases, the triple combination yielded a response rate of 47.3% compared with 20% in the control arm. Serum neuron-specific enolase (sNSE) and serum S100 (sS100) levels were assessed in a total of 37 blood samples drawn at cycles 1 and 4 and end of treatment (EOT) in all patients of the ITT population ( Methods). Matched samples were available from 11 patients. Between 30 July 2020 and 23 July 2021, a total of 15 planned patients (14 women, 1 man) had received at least one cycle of trastuzumab deruxtecan; 60% had brain metastases progressing after previous local therapy and 60% had received previous T-DM1. The median time from the last local intervention to study inclusion in patients with previous local therapy was 13 months (range 5–65 months). The median age on inclusion was 69 years (30–76 years), Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 60% of patients and 40% had neurological symptoms at baseline. A dose reduction by one step was recorded in five patients (33.3%) and two dose reductions were required in four patients (26.7%). Reasons for dose reduction were fatigue (four patients), diarrhea (three patients), neutropenia (one patient) and patient’s wish (one patient), respectively. Two patients (13.3%) had a complete intracranial response, nine (60%) had a partial intracranial response and three (20%) had stable disease as the best intracranial response, with a best overall intracranial response rate of 73.3% (95% confidential interval 48.1–89.1%), thus meeting the predefined primary outcome.