Durable responses to trastuzumab deruxtecan in patients with leptomeningeal metastases from breast cancer with variable HER2 expression.

Objective: Emerging data suggest that trastuzumab deruxtecan (T-DXd) is an active treatment for brain metastases from HER2 + breast cancer. We aimed to characterize the activity of T-DXd in the treatment of leptomeningeal metastases (LM) from a range of HER2-altered cancers.

Methods: We reviewed neuro-oncology clinic records between July 2020 and December 2023 to identify patients who received T-DXd to treat LM.

Results: Of 18 patients identified, 6 had HER2 + breast cancer, 8 had HER2-low/negative breast cancer, 2 had HER2 + gastroesophageal cancer, and 2 had HER2-mutant non-small cell lung cancer (NSCLC). 10/18 (56%) patients had cytologically confirmed LM by CSF cytology or circulating tumor cell (CTC) capture. A partial response (PR) on MRI using the EORTC/RANO-LM Revised-Scorecard occurred in 4/6 (67%) patients with HER2 + breast LM, 2/8 (25%) patients with HER2-low/negative breast cancer, and 0/4 (0%) patients with HER2 + gastroesophageal cancer or HER2-mutant NSCLC. Median overall survival after initiating T-DXd was 5.8 months. Survival after initiating T-DXd was numerically longer for HER2 + breast cancer patients compared with HER2-low/negative breast and HER2-altered non-breast cancer patients (13.9 months vs. 5.2 months and 4.6 months, respectively). Landmark analysis showed that patients with radiologic LM response to T-DXd by 2.5 months had longer survival than non-responders (14.2 months vs. 2.6 months, HR 0.18, 95% CI 0.05-0.63, p < 0.05), and landmark analyses at 3.5 and 4.5 months after starting T-DXd showed a similar but nonsignificant trend.

Conclusions: T-DXd induces LM responses in a subset of patients, and such responses may be associated with prolongation of survival. Prospective trials are needed to clarify the role of T-DXd in treating LM and which patients are most likely to benefit.