Therapeutic advances in medical oncology · 2025
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).
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Lim Bora, Marx Angela, Kai Megumi, Alexander Angela, Bassett Roland, Ma Wencai, Willey Jie, Sun Huiming, Nasrazadani Azadeh, Mohammad Mohammad M, Zhang Jianhua, Lucci Anthony, Sun Susie X, Stauder Michael C, Whitman Gary J, Le-Petross Huong, Valero Vicente, MDACC Inflammatory Breast Cancer Team, Woodward Wendy A, Layman Rachel M
Аннотация
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.
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.