Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report

Abstract

Metastatic breast cancer demonstrates HER2/neu amplification approximately 15% of the time. However, HER2 mutations, which often stimulate tumor growth, occur in only 3% to 5% of patients, and are seen more frequently in metastatic versus primary tumors. They are more frequent in lobular carcinoma, including triple-negative lobular cancer. Many of these variants are resistant to trastuzumab and lapatinib. However, neratinib can be efficacious, and recent data suggest that antibody–drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan may also be helpful. Laboratory and clinical data raise the possibility that simultaneous treatment with ADCs plus neratinib may be even more efficacious. Tucatinib, which has demonstrated significant activity in the central nervous system, has also been shown in vitro to be active against a number of these HER2 variants. This report describes a patient with metastatic estrogen receptor–positive, HER2-nonamplified breast cancer with an activating HER2 mutation whose tumor became resistant to neratinib as well as capecitabine, but whose subsequent leptomeningeal disease had a dramatically successful response to tucatinib plus capecitabine. As the frequency of HER2 mutations increases during the evolution of metastatic breast cancer, it is important to obtain genomic evaluation on these tumors with either repeat tissue or liquid biopsy as they progress over time.

Long-term response to sequential anti-HER2 therapies including trastuzumab-deruxtecan in a patient with HER2-positive metastatic breast cancer with leptomeningeal metastases: a case report and review of the literature

“…Yan et al. published the case of a patient resistant to neratinib and capecitabine that demonstrated a significant response of LM to tucatinib ( 112 ). In the TBCR049 trial, tucatinib was detectable in CSF within 2 hours after drug administration, with concentrations ranging from 0.57 to 25 ng/mL and CSF-to-plasma ratios of 0.83 ( 68 ).…”

Novel approaches to treatment of leptomeningeal metastases

“…(1) HER2þ: There are multiple CNS active regimens in this space [3,[45][46][47][48][49][50]. Tucatinib, trastuzumab and capecitabine combination therapy showed median OS at 11.9 months (95% CI: 4.1, NR) […”

Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases

“…Tucatinib, a third-generation reversible and highly selective HER2 inhibitor, gained FDA approval in April 2020 after its use was associated with improvements in both CNS-PFS (9.9 vs 4.2 months) and OS (18.1 vs 12.0 months), when used in combination with trastuzumab and capecitabine in those with stable or active brain metastases [ 35 , 127 ]. While this study excluded patients with LM, a subsequent case report suggested leptomeningeal disease control lasting 10 months with whole brain radiotherapy (WBRT) followed by combination tucatinib and capecitabine in a patient with HER2-activating variant breast cancer [ 128 ]. To appropriately investigate this question, a phase II study is currently underway investigating combination tucatinib, trastuzumab, and capecitabine in patients with HER2+ breast cancer and LM (NCT03501979), with encouraging preliminary results supportive of durable leptomeningeal activity [ 129 ].…”