Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

Saura, Cristina; García-Sáenz, José Á.; Xu, Binghe; Harb, Wael A.; Moroose, Rebecca; Pluard, Timothy; Cortés, Javier; Kiger, Corinne; Germa, Caroline; Wang, Kongming; Martín, Miguel; Baselga, José; Kim, Sung‐Bae

doi:10.1200/jco.2014.56.3809

Cited by 119 publications

(73 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Considerably higher overall response rates were observed when neratinib was combined with chemotherapeutic agents, notably paclitaxel (73%) [64] and capecitabine (63%) [70] (Table 3), findings that have prompted larger randomized trials of these combinations. The results from the first of these studies -NEfERT-T -have recently been reported [69] (Table 3).…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 94%

“…Early phase II trials indicated that single-agent neratinib has efficacy in trastuzumab-pretreated patients [61,66], and subsequent trials showed that this effect could be enhanced through combination with either chemotherapeutic agents (i.e. capecitabine, vinorelbine) [63,70] or temsirolimus [73]. NALA -an active phase III trial -is comparing neratinib in combination with capecitabine with standard third-line therapy, lapatinib plus capecitabine, in patients who have progressed after two or more HER2-directed regimens for metastatic disease.…”

Section: Expert Opinionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Kourié

Chaix

Gombos

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

show abstract

Section: Pharmacokinetics and Metabolismmentioning

confidence: 94%

Section: Expert Opinionmentioning

confidence: 99%

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Kourié

Chaix

Gombos

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

show abstract

“…Patients with trastuzumab pretreated HER2-positive metastatic breast cancer receiving neratinib plus capecitabine had an overall response rate of 64 % for those with no prior lapatinib therapy and 57 % for those previously treated with labtinib [54]. A recent news release from Puma Biotechnology, currently developing neratinib, states a positive effect in a randomized phase III trial of using neratinib in extended adjuvant therapy after adjuvant therapy with trastuzumab (http://www.pumabiotechnology.…”

Section: Discussionmentioning

confidence: 95%

In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib

Chakraborty

Zerillo

DiGiovanna

2015

Breast Cancer Res Treat

View full text Add to dashboard Cite

The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile.

show abstract

“…HKI-272 is an irreversible, small molecule, tyrosine kinase inhibitor of HER1, HER2, and HER4 that is orally bioavailable (129). This trial has approximately 105 participants across 3 arms.…”

Section: Effects Of Egfr- and Her2-targeted Therapies On Breast Camentioning

confidence: 99%

EGFR and HER2 signaling in breast cancer brain metastasis

et al. 2016

View full text Add to dashboard Cite

Breast cancer occurs in approximately 1 in 8 women and 1 in 37 women with breast cancer succumbed to the disease. Over the past decades, new diagnostic tools and treatments have substantially improved the prognosis of women with local diseases. However, women with metastatic disease still have a dismal prognosis without effective treatments. Among different molecular subtypes of breast cancer, the HER2-enriched and basal-like subtypes typically have higher rates of metastasis to the brain. Basal-like metastatic breast tumors frequently express EGFR. Consequently, HER2- and EGFR-targeted therapies are being used in the clinic and/or evaluated in clinical trials for treating breast cancer patients with brain metastases. In this review, we will first provide an overview of the HER2 and EGFR signaling pathways. The roles that EGFR and HER2 play in breast cancer metastasis to the brain will then be discussed. Finally, we will summarize the preclinical and clinical effects of EGFR- and HER2-targeted therapies on breast cancer metastasis.

show abstract

Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

Abstract: Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.

Cited by 119 publications

References 28 publications

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib

EGFR and HER2 signaling in breast cancer brain metastasis

Contact Info

Product

Resources

About