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

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.

The role of irreversible pan-HER tyrosine kinase inhibitors in the treatment of HER2-Positive metastatic breast cancer

“…In line with the previous findings, the most frequent treatment-related AEs for pyrotinib were diarrhea and hand-foot syndrome. Two trials reported that treatment with neratinib plus capecitabine is useful for HER2-positive breast cancer with brain metastases (Cunningham et al, 2022;Pellerino et al, 2022). The results for PFS, OS, and AEs are similar to data from previous trials.…”

“…The results for PFS, OS, and AEs are similar to data from previous trials. Moreover, treatment with neratinib plus capecitabine significantly improves survival outcomes compared with the use of intrathecal Ara-C or whole-brain radiotherapy (WBRT) (Pellerino et al, 2022). Findings from the NEfERT-T (Awada et al, 2016) trial indicate that although the overall efficacy of neratinib-paclitaxel and trastuzumab-paclitaxel is similar, the neratinib-paclitaxel combination may delay central nervous system (CNS) progression.…”

“…Furthermore, the use of pyrotinib together with radiotherapy can significantly improve the PFS, ORR, and duration of response in patients with HER2-positive breast cancer brain metastases without causing serious AEs (Tian et al, 2022). Pellerino et al (Pellerino et al, 2022) demonstrated that HER2-positive breast cancer patients with leptomeningeal metastases had a 70% probability of receiving a neurological benefit after treatment with neratinib plus capecitabine. Results from the CNS subgroup analysis in NALA (Saura et al, 2020), TBCRC022 (Freedman et al, 2019), and other trials (Hurvitz et al, 2021;Cunningham et al, 2022) also showed that neratinib has an effect on CNS lesions from HER2-positive MBC.…”

Durable responses in patients with HER2+ breast cancer and leptomeningeal metastases treated with trastuzumab deruxtecan

“…Only select anti-HER2 therapies have reported activity in HER2 + LM. In particular, neratinib plus capecitabine showed preliminary activity in LM, with median LM-PFS of 4 months and OS of 10 months 13 . In addition, the use of intrathecal trastuzumab has demonstrated ORR of 19.2%, SD in 50%, with a CBR of 70%, and median-OS of 10.5 months 14 .…”

Novel Therapeutic Approaches in Neoplastic Meningitis

“…Neratinib, a HER2-targeting tyrosine kinase inhibitor combined with capecitabine, demonstrated promising intracranial activity in patients with HER2 overexpressing breast cancer [70]. There are case series of efficacy in leptomeningeal metastases [71]. Preliminary results from a phase II trial evaluating the effectiveness of the combination of tucatinib-trastuzumabcapecitabine in the treatment of NM from HER2+ breast cancer have reported a median OS of 11.9 months in a cohort of 17 patients (NCT03501979) [72].…”