5th Edition of International Neurology Conference 2026

Abstract

Background:
Leptomeningeal metastases (LM) occur in 5–15% of HER2-positive metastatic breast cancer patients and carry a dismal prognosis with median survival of only 4.4 months. Trastuzumab deruxtecan (T-DXd) has demonstrated potent intracranial activity against parenchymal brain metastases, yet its cerebrospinal fluid (CSF) penetration is limited. Intrathecal (IT) trastuzumab, bypassing the blood-CSF barrier, showed positive results in terms of clinical neurologic response. The study was designed to evaluate the efficacy and safety of combining intravenous T-DXd with IT trastuzumab in HER2-positive breast cancer patients with newly-diagnosed LM.

Material and Methods:
This retrospective case series included 6 patients with HER2-positive (IHC 3+ or FISH-amplified) MBC and LM diagnosed by CSF cytology and/or clinical symptoms of LM and LM evidence on magnetic resonance imaging (MRI). LM was newly diagnosed and naïve of treatment. Patients received intravenous T-DXd 5.4 mg/kg every 3 weeks plus IT trastuzumab 150 mg every 3 weeks via Ommaya reservoir or lumbar puncture. Radiological response was assessed using the EORTC/RANO-LM Revised Scorecard. Clinical benefit rate (CBR), objective response rate (ORR), overall survival (OS), and safety were evaluated.

Results:
Median age was 47 years (range 34–62). Patients were heavily pretreated with a median of 4 prior lines (range 3–6). All patients had already received a systemic anti-HER2 therapy (trastuzumab, pertuzumab, trastuzumab emtansinem, pyrotinib), and 4 patients (66.7%) had received at least 2 lines of these treatments. Two had prior whole-brain radiation. All 6 patients (100%) derived clinical benefit (CBR) after 2 cycles of treatment. Three patients (50.0%) achieved partial response (PR) on MRI as best response by RANO-LM criteria, and 3 (50.0%) had stable disease (SD). Median time on therapy was 12.2 months (range 6.2–20.4). Median OS from treatment initiation was 22.6 months (range 7.5–40.2). At data cutoff, 2 patients remained on treatment. No grade ≥3 adverse events attributable to combination therapy were observed. Most common events were fatigue (50.0%), nausea (33.3%)—all grade 1–2. No interstitial lung disease, chemical meningitis, or Ommaya reservoir infections occurred.

Conclusions:
Despite its small scale and some limitations, this retrospective study suggests that the combination of intravenous T-DXd and IT trastuzumab may represent a valuable option for HER2-positive breast cancer patients with LM. This combinational treatment strategy warrants prospective evaluation in dedicated clinical trials.