Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy

Abstract

Purpose Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. Patients and Methods This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. Results Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. Conclusion Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.

Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds

“…The possible mechanisms that underlie the primary resistance of these drugs have been supposed as follows: i) activation of other signaling pathways alternative to EGFR, such as the insulin-like growth factor 1 receptor (IGF-1R) and vascular endothelial growth factor receptor (VEGFR); and ii) deregulation of downstream signaling pathways such as AKT/mTOR (2)(3)(4)(5). Recently, much research has focused on combined treatment with different signaling drugs, representing a novel strategy for cancer therapy (6)(7)(8). Here, mTOR inhibitor emerged as an attractive drug candidate due to the role of the mTOR pathway in the development of lung cancer resistance.…”

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

“…The mTOR inhibitors temsirolimus (Torisel; Pfizer), everolimus (Afinitor; Novartis), and ridaforolimus (Merck & Company, Inc.) have been evaluated in breast cancer, and everolimus was approved by the FDA for postmenopausal women with advanced hormone receptor-positive HER2-negative breast cancer in combination with exemestane after failure of letrozole or anastrozole [90]. Pooled data from two phase I/II studies in HER2-positive MBC patients who progressed on trastuzumab reported an RR of 15% and median PFS of 4.1 months with everolimus plus trastuzumab [91]. Two phase Ib studies of MBC patients with prior trastuzumab therapy showed PFS of 30.1 and 34 weeks with everolimus in combination with trastuzumab/vinorelbine or trastuzumab/paclitaxel, respectively [92,93].…”

Apoptotic and Anti-invasive Effects of Hybrid Liposomes without Drugs against Human Breast Cancer Cells In Vitro

“…The human epidermal growth factor receptor 2 (HER2) is tumour marker of breast cancer, and overexpression of HER2 is found in approximately 30% of patients with breast cancer [1]. Trastuzumab which is monoclonal therapeutic antibody against HER2 is applied to the treatment for patients with breast cancer [2][3][4]. However, the efficacy of Trastuzumab for patients with HER2-negative breast cancer and trastuzumab-resistant HER2-positive breast cancer is limited [4,5].…”

“…Trastuzumab which is monoclonal therapeutic antibody against HER2 is applied to the treatment for patients with breast cancer [2][3][4]. However, the efficacy of Trastuzumab for patients with HER2-negative breast cancer and trastuzumab-resistant HER2-positive breast cancer is limited [4,5]. Therefore, novel nanomedicine against HER2-negative breast cancer is needed.…”