Phase II study of intrathecal administration of trastuzumab in patients with HER2-positive breast cancer with leptomeningeal metastasis

Abstract

Background Patients with HER2-positive breast cancer (HER2+BC) develop central nervous system metastases twice as often as patients with luminal HER2-negative breast cancer. Leptomeningeal progression results in a drastically altered prognosis with limited therapeutic options. This phase II study was conducted in order to assess the efficacy of intrathecal (IT) trastuzumab in HER2+BC patients with leptomeningeal metastasis (LM), based on a phase I dose-escalation study that had determined the recommended weekly dose of 150 mg for phase II. Methods Eligible patients received weekly administrations of 150 mg of IT trastuzumab. The primary endpoint was clinical neurologic progression-free survival (LM-related-PFS) after 8 weeks. Overall survival (OS), toxicities and quality of life (QoL) were secondary endpoints. Results Among the 19 enrolled patients, 16 (84%) had concomitant brain metastases, 15 of them had received prior radiotherapy to the brain. All patients had received at least one line of systemic anti-HER2 therapy. After 8 weeks, 14 patients (74%) were free of neurological progression. The median LM-related-PFS was 5.9 months and the median OS was 7.9 months. According to the QLQ-C30 and BN20 scales, the global health-related QoL status seemed preserved and no toxicity above grade 3 was observed. Conclusions Conducting studies on patients with LM poses significant challenges and ethical dilemmas inherent to this population. Despite some limits, this phase II study’s findings in terms of clinical neurologic response and quality of life’s control confirms weekly administration of 150 mg of IT trastuzumab as a valuable option for HER+BC patients with LM and support the interest for further investigations.

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2023

“…However, it is not clear whether these results can be reproduced with photon radiotherapy (LoE 2b/ B/AGO+/−). Patients with HER2+ disease may benefit from intrathecal administration of trastuzumab based on recent studies demonstrating improved outcome (LoE 3a/C/AGO+/−) [29,30].…”

Intrathecal Therapy Options for Meningeal Carcinomatosis

“…In the patient cohort of Zagouri et al, 21.7% had previously received methotrexate administered either intravenously or intrathecally [15]. Only 34.5% of patients in the study by Zagouri et al and 32% in the phase II study received no additional therapy for meningeal carcinomatosis during IT trastuzumab therapy [15,17]. In addition to IT trastuzumab, most cases in the study by Zagouri et al and the study by Oberkampf et al received some form of systemic therapy consisting of chemotherapy, endocrine or anti-HER2 targeted therapy as well as radiotherapy of the brain.…”

“…Zu den Nebenwirkungen, die möglicherweise mit der Behandlung zusammenhängen, gehörten: Kopfschmerzen, Krampfanfälle und allergische Reaktionen. Diese sind jeweils in 5% der Fälle aufgetreten [17] [20,23]. Die Validierung des Curie-Score veranschaulichte allerdings die Schwierigkeit der Erstellung eines universell anwendbaren Prognosescores für eine Erkrankung, zu der solch eine geringe Datenmenge existiert [23].…”

“…1 zu entnehmen. [13,17,21,22]. Vier Studien machten keine weitere Angabe zu dem verwendeten Applikationsverfahren [12,15,19,23].…”

Protein Kinase Inhibitors as a New Target for Immune System Modulation and Brain Cancer Management

“…To overcome this limit, a clinical study evaluated the efficacy of intrathecal administration of Trastuzumab in patients with HER2-positive leptomeningeal metastases. The results demonstrated that intrathecal Trastuzumab administration could be a viable option for HER-positive patients [ 48 , 49 ]. A meta-analysis of 12 phases II clinical trials demonstrated the beneficial effect of Lapatinib, a double epidermal growth factor receptor (EGFR) and HER2 inhibitor, in patients with progressive HER2-positive CNS metastases.…”