A phase Ib/II trial of neoadjuvant neratinib added to standard therapy in patients with HER2-positive or HR-positive/HER2-negative inflammatory breast cancer (including stage III and IV disease).

Background: Inflammatory breast cancer (IBC) is rare but aggressive, characterized by the rapid onset of diffuse skin erythema, edema, tenderness, induration, and fast metastasis. Both hormone receptor positive (HR+) and human epidermal receptor 2 positive (HER2+) are associated with inferior response after neoadjuvant systemic therapy (NAST) compared to non-IBC. Despite multimodal treatment approaches, the 3-year overall survival rate for stage III IBC remains low at approximately 74%, around 10% lower than the 83% for non-IBC. Objectives: To evaluate whether the addition of neratinib, an irreversible pan-ErbB receptor small molecule tyrosine kinase inhibitor, improves the rate of pathological complete response in both HER2+ and HR+/HER2- IBC in neoadjuvant therapy, and to assess safety and explore biomarkers associated with response. Design: This is a phase I/II (HER2+; cohort 1) and II (HR+/HER2-; cohort II trial conducted at a single center. Methods: Pathological response was assessed using the pathological complete response (pCR) and residual cancer burden (RCB) criteria as the primary efficacy endpoint. Safety and biomarkers were assessed. Results: In cohort 1, dose-limiting toxicities were Grade 2/3 diarrhea. Among the 10 evaluable patients from cohort 1 who underwent surgery, 5 achieved pCR (50%); in the intention-to-treat population of all 14 patients (counting drop-outs as nonresponders), the pCR rate was 36%. In cohort 2, 16 patients were enrolled, and 1 (6%) achieved pCR. Common adverse events (AEs) included Grade 2 alopecia, Grade 2/3 diarrhea, anemia, nausea, and neutropenia. High toxicity led to early closure of accrual. The median event-free survival in cohort 2 was 27.5 months, and was not reached for cohort 1 by data cutoff. Biomarker analysis showed that good responders (pCR + RCB-I) in both cohorts exhibited upregulation of immune-activating pathways, including interferon signaling and cytotoxic T-cell markers. By contrast, poor responders (RCB-II + RCB-III) showed immune-suppressive features, increased angiogenesis, proliferation, and anti-apoptotic gene expression. Conclusion: The addition of neratinib to neoadjuvant therapy showed potential in improving the pCR rate in HER2+ IBC (36% in this study) but not in HR+/HER2- (6%), though high toxicity was a major limiting factor. Further research is needed to optimize the balance between efficacy and safety. Biomarker analysis uncovered interesting new hypothesis-generating data warranting future study in IBC. Trial registration: ClinicalTrials.gov NCT03101748.