Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy

Awada, Ahmad; Dirix, Luc; Manso, Luis; Xu, Binghe; Luu, T; Dièras, Véronique; Hershman, Dawn L.; Agrapart, V.; Ananthakrishnan, Revathi; Starosławska, Elżbieta

doi:10.1093/annonc/mds284

Cited by 105 publications

(59 citation statements)

References 42 publications

(43 reference statements)

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“…Neratinib is an irreversible inhibitor of EGFR and HER2. Phase II data in patients with HER2-positive metastatic breast cancer have been encouraging with respect to single-agent activity, as well as activity in combination with chemotherapy (63)(64)(65). A prospective, phase II study evaluating neratinib monotherapy enrolling patients with progressing breast cancer brain metastases has recently completed accrual (NCT01494662) and plans are ongoing to further study the effects of neratinib in the brain when given in conjunction with capecitabine (R. Freedman, Dana-Farber Cancer Institute; personal communication).…”

Section: Her2-directed Agentsmentioning

confidence: 99%

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

Lin

Amiri‐Kordestani

Palmieri

et al. 2013

Clinical Cancer Research

236

208

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Despite major therapeutic advances in the management of patients with breast cancer, central nervous system (CNS) metastases remain an intractable problem, particularly in patients with metastatic HER2-positive and triple-negative breast cancer. As systemic therapies to treat extracranial disease improve, some patients are surviving longer, and the frequency of CNS involvement seems to be increasing. Furthermore, in the early-stage setting, the CNS remains a potential sanctuary site for relapse. This review highlights advances in the development of biologically relevant preclinical models, including the development of brain-tropic cell lines for testing of agents to prevent and treat brain metastases, and summarizes our current understanding of the biology of CNS relapse. From a clinical perspective, a variety of therapeutic approaches are discussed, including methods to improve drug delivery, novel cytotoxic agents, and targeted therapies. Challenges in current trial design and endpoints are reviewed. Finally, we discuss promising new directions, including novel trial designs, correlative imaging techniques, and enhanced translational opportunities. Clin Cancer Res; 19(23); 6404-18. Ó2013 AACR. Disclosure of Potential Conflicts of InterestN.U. Lin has received commercial research grants from GlaxoSmithKline, Genentech, Array, and Novartis. N.U. Liu is a consultant/advisory board member for Novartis, GlaxoSmithKline, to-BBB, and Genentech. P.S. Steeg has received commercial research grants from GlaxoSmithKline and Sanofi. No potential conflicts of interest were disclosed by the other authors. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose. Learning Objective(s)Upon completion of this activity, the participant should have a better understanding of brain metastases in different subtypes of breast cancer, the development of preclinical models, and the novel systemic strategies for breast cancer brain metastasis.

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Section: Her2-directed Agentsmentioning

confidence: 99%

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

Lin

Amiri‐Kordestani

Palmieri

et al. 2013

Clinical Cancer Research

236

208

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“…Neratinib has also been found to be a safe and efficacious treatment in HER2 amplified breast cancers when given in combination with cytotoxic agents including paclitaxel and vinorelbine. [19], [20]. Given the overall tolerability of the drug, its specificity, and potent signaling inhibition properties, neratinib was evaluated further in clinical trials to determine its potential efficacy.…”

Section: Discussionmentioning

confidence: 99%

Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo

Schwab

English

Black

et al. 2015

Gynecologic Oncology

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Objective-Carcinosarcoma is a deadly gynecologic malignancy with few effective treatment options. The study of new therapies is difficult because of its rarity. The objective of this study was to determine the efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma.Methods-The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Data regarding IC 50 , cell cycle distribution, and cell signaling changes were assessed by flow cytometry. The efficacy of neratinib was determined in treating mice harboring HER2 amplified carcinosarcoma xenografts.Results-Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC 50 : 0.014μM±0.004 vs. 0.164μM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Neratinib inhibited tumor growth (p=0.012) and prolonged survival in mice harboring HER2 amplified carcinosarcoma xenografts (p=0.0039).Conclusions-Neratinib inhibits HER2 amplified carcinosarcoma proliferation, signaling, cell cycle progression and tumor growth in vitro. Neratinib inhibits HER2/neu amplified xenograft growth and improves overall survival. Clinical trials are warranted.

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“…In a phase II study, neratinib showed a median PFS of 22.3 and 39.6 weeks in 136 HER2-positive MBC patients with or without prior trastuzumab, respectively [52]. In another phase II MBC study with neratinib/vinorelbine, RRs were 41% (no prior lapatinib) and 8% (prior lapatinib) [53]. In a phase I/II trial of neratinib/paclitaxel, the RR among patients with HER2-positive MBC was 71% in those who had received up to one prior non-lapatinib-containing chemotherapy regimen and 77% in those pretreated with two or three chemotherapy regimens, which may have included lapatinib [54].…”

Section: Lapatinibmentioning

confidence: 99%

Human Epidermal Growth Factor Receptor Family-Targeted Therapies in the Treatment of HER2-Overexpressing Breast Cancer

2014

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Purpose. Chemotherapy has been tested extensively in conjunction with standard therapy in the treatment of head and neck cancer, primarily in the form of neoadjuvant chemotherapy, but few trials have shown a survival benefit. Although a few studies have suggested that adjuvant chemotherapy given after standard treatment may improve survival, to date these trials have been troubled by various problems in design and dosing. The purpose of our trial was to determine the feasibility of giving moderately intensive chemotherapy exclusively after standard therapy, and to determine whether survival appeared to be improved as measured against historical data. Methods. We used adjuvant chemotherapy in two groups of patients with squamous cell carcinoma of the head and neck: group A consisted of 46 patients with newly diagnosed stage III and IV disease, and group B consisted of 46 patients with relapsed disease having been treated with salvage surgery. In all patients, the intended adjuvant chemotherapy consisted of two cycles of combination cisplatin, bleomycin, and infusional 5‐fluorouracil (5‐FU) given three weeks apart, followed by four cycles of bolus methotrexate, 5‐FU, and bleomycin given every two weeks. Results. In group A, the two‐year survival was 72%. In group B, the two‐year survival was 58%. Conclusion. Compared to the vast majority of similarly staged patients with head and neck cancer reported in the literature, the survival of our group seemed considerably better, suggesting that a definitive randomized study testing this schedule of adjuvant chemotherapy is warranted.

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Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy

Cited by 105 publications

References 42 publications

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo

Human Epidermal Growth Factor Receptor Family-Targeted Therapies in the Treatment of HER2-Overexpressing Breast Cancer

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