Trastuzumab deruxtecan in patients with breast cancer with brain metastases: The DE-REAL study.

1032 Background: Almost 30-50% of patients with human epidermal growth factor (HER2)-positive breast cancer (BC) will develop brain metastases (BMs) in their treatment journey. Despite impressive results achieved for extracranial disease, the central nervous system (CNS) compartment remains highly challenging, and local approaches must now be associated with a prompt and adequate systemic intervention. Trastuzumab deruxtecan (T-Dxd) obtained impressive results both in heavily pretreated patients previously received TDM-1 and in the comparative DESTINY BREAST03 phase III trial. However, patients with active CNS involvement were traditionally excluded from clinical trials and BM-related outcomes are not often included among study endpoints. Moreover, a real-world evidence focused on intracranial activity for patients with BMs treated with T-Dxd is still lacking. In an effort to add further information on the clinical activity and safety of T-Dxd in both naïve and previously treated patients with BMs, we performed a sub-analysis of an Italian large retrospective database, the DE-REAL study. Methods: We reviewed a database of 143 patients with HER2-positive BC from 11 Italian Oncological Units, and obtained a total of 39 patients with CNS involvement treated in various lines setting with T-Dxd between April 2021 and October 2022. Results: Overall intracranial response rate (icRR) was 59% (43.5-74.4), with an imPFS of 14.1 months (9.3-18.9). Intracranial disease control rate (icDCR) was 94.9% (87.9-100.0), duration of response (icDoR) was 11.9 months (10.1-13.7), and clinical benefit rate (icCBr) at 6 and 12 months were 69.2% and 59%, respectively. IntracranialOS was not reached, with an overall rate of 76.6% of patients alive at 12 months. When comparing intracranial responders (CR/PR/SD) to non-responders (PD), median PFS was 15.5 months (13.7-17.3) vs 7.9 months (6.4-9.5), p<0.001. Toxicities were in line with what previously reported in larger registered clinical trials. Conclusions: Our real-world analysis indicated a clinically meaningful intracranial activity of T-Dxd in patients with HER2-positive BC and BMs, and supports its use for both patients with treated/stable and untreated/active lesions.