Safety and Efficacy Profile of Neratinib: A Systematic Review and Meta-Analysis of 23 Prospective Clinical Trials.

Background: Neratinib is a novel pan-human epidermal growth factor receptor (HER) tyrosine kinase inhibitor that has shown promising activity against several types of malignancies, especially HER2-overexpressing breast cancer.

Objective: The objective of the current study was to provide a comprehensive insight into the efficacy and safety profiles of neratinib-based therapies.

Methods: Comprehensive literature searches of the PubMed, EMBASE, and Web of Science electronic databases were performed for all relevant clinical trials. Adverse events (AEs) of any grade and of grade 3 or higher were summarized and event rates were calculated. For controlled trials, odds ratios (ORs) were calculated to determine the role of neratinib in AEs. A random-effects model was applied if heterogeneity was observed (I ≥ 50%), otherwise a fixed-effects model was used. Kaplan-Meier survival curves were extracted for hazard ratio (HR) calculation, and survival outcomes were measured by progression-free survival (PFS) and overall survival (OS).

Results: Twenty-three studies and 4896 patients were included in the analysis. The most frequently occurring all-grade AEs in neratinib monotherapy were diarrhea (83.9%), nausea (37.9%), and abdominal pain (28.4%). The most common AEs for grades 3 or 4 were diarrhea (25.1%), dyspnea (5.6%), and abnormalities in liver enzyme levels (4.2%). Diarrhea, the most common AE, can be mitigated by prophylactic loperamide. Neratinib demonstrated promising clinical activity as monotherapy in HER2-positive breast cancer; however, in contrast, the effect became much less significant among HER2-mutated breast cancer patients. Notably, neratinib-based combination therapy achieved a higher response rate than neratinib monotherapy.

Conclusions: Neratinib-based therapies led to a higher frequency of some AEs, although these were mostly tolerable. Most studies demonstrated that neratinib provides a benefit in survival outcome. When combined with other anticancer agents, neratinib may hold promise for treating breast cancer with central nervous system metastases.