Neratinib and Capecitabine for the Treatment of Leptomeningeal Metastases from HER2-Positive Breast Cancer: A Series in the Setting of a Compassionate Program

SIMPLE SUMMARY: Leptomeningeal metastases represent an unmet need due to the lack of effective therapy and poor survival. The tyrosine kinase inhibitor, neratinib, has demonstrated promising activity against brain metastases from HER2-positive breast cancer, as reported by the TBCRC and NALA trials, thus suggesting a potential activity also in leptomeningeal metastases when associated with capecitabine. The aim of the study was to investigate the efficacy and tolerability of neratinib in association with capecitabine in leptomeningeal metastases from heavily-pretreated breast cancer patients who failed multiple lines of treatment. Primary endpoints were 6-month overall survival and intracranial progression-free survival. Secondary endpoints were the responses assessed by whole CNS MRI performed every 8 weeks, neurological improvement, and safety. We obtained a median overall survival of 10 months, an intracranial progression-free survival of 4 months, neurological improvement and stable disease on an MRI lasting 6.5 months in six patients (60%). These preliminary findings suggest a potential activity of this treatment in LM from HER2-positive breast cancer that needs to be further investigated in larger datasets. ABSTRACT: Background: Leptomeningeal metastasis is a neurological complication from HER2-positive breast cancer with a poor prognosis and limited treatment options. This study has evaluated the activity of neratinib in association with capecitabine in 10 patients with LM from HER2-positive BC after the failure of multiple lines of treatment, including trastuzumab-based therapy, within a compassionate program, and a comparison was made with a historical control group of 10 patients. Methods: Patients aged ≥ 18 years with histological diagnosis of primary HER2-positive BC, either amplified or mutated, and newly-diagnosed LM were enrolled. Coexistence of BM that has or has not received radiotherapy, as well as prior chemotherapy, hormone therapy, or monoclonal HER2-targeting antibodies or antibody–drug conjugates, were allowed, with the exclusion of lapatinib. Results: Six-months OS was 60% with a median OS of 10 months (95% CI: 2.00–17.0). Three-month intracranial PFS was 60% with a median intracranial PFS of 4.0 months (95% CI: 2.00–6.0). The neurological benefit was observed in 70% of patients with a median duration of neurological response of 6.5 months. The best radiological response was stable disease in 60% of patients. Conclusions: This small series shows that the combination of neratinib and capecitabine is a safe treatment in LM from heavily pretreated HER2-positive BC with clinical efficacy in some patients and is worth investigating in a larger study.