Neratinib Combo Effective in HER2+ Breast Cancer Brain Metastases

Despite expanded targeted treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, nearly half of patients with metastatic disease develop central nervous system (CNS) metastases, which are a source of major morbidity and mortality for the majority of patients. Evidence-supported therapies for these patients are limited, and treatment of CNS progression remains challenging. However, the pan-HER-targeted TKI neratinib, which inhibits signaling through erbB1, HER2, and erb4, demonstrated activity in patients with progressive HER2-positive brain metastases in one of the cohorts of a multicenter phase II Translational Breast Cancer Research Consortium (TBCRC) 022 study. The combination of neratinib and capecitabine in patients with progressive HER2-positive brain metastases was evaluated in two other cohorts of the study, in lapatinib-naïve patients (cohort 3A) and those who had previously received lapatinib (cohort 3B).

A total of 49 patients were enrolled in the lapatinib-naïve (n = 37) and prior lapatinib (n = 12) cohorts, though the latter cohort was closed due to slow accrual. The majority of patients (92%) had progressed on a prior CNS-directed therapy. The composite CNS objective response rate (ORR) following treatment with neratinib plus capecitabine was impressive, 49% in lapatinib-naïve patients and 33% in those who had previously received lapatinib. Endocrine receptor (ER) expression status did not significantly impact outcomes. The median progression-free survival (PFS) was 5.5 months in the lapatinib-naïve cohort and 3.1 months in the prior lapatinib cohort. Median overall survival (OS) was 13.3 months and 15.1 months in lapatinib-naïve patients and in those who had prior treatment with lapatinib, respectively.

The most common treatment-related adverse events (AE) were diarrhea, nausea, vomiting, and fatigue. While all patients received diarrheal prophylaxis while on study, 33% of patients experienced grade 2 diarrhea and 29% experienced grade 3 diarrhea. Neratinib dose reductions were required in 33% of patients to manage AEs.

The investigators concluded that combination of neratinib and capecitabine is active in patients with HER2-positive brain metastases and represents a potential treatment option for these patients. Toxicity remains a concern and new strategies to reduce treatment-associated diarrhea are needed. Results from the ongoing randomized NALA trial, which compares neratinib plus capacitabine to lapatinib plus capecitabine in patients with HER2-positive breast cancer who have progressed on multiple prior lines of HER-2 targeted therapy, are expected to further clarify the role of neratinib in treating patients with progressive brain metastases.

In the accompanying editorial, Sara Hurvitz, MD (University of California, Los Angeles), highlighted that, despite AEs that require careful management, the efficacy results of neratinib plus capecitabine are among most promising seen to date for HER2-positive breast cancer brain metastases, showing activity even in patients with leptomeningeal metastases, which have a particularly poor prognosis. However, she noted that the decision to use neratinb plus capecitabine in place of standard first-line or second-line systemic treatment is not yet supported by phase III evidence.

J Clin Oncol. 2019 March 12. [Epub ahead of print.]
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