Milton Seiler1, Isabelle Ray-Coquard2, Bohuslav Melichar3, Denise A Yardley4, Rui X Wang5, Pierre F Dodion6, Mark A Lee7. 1. Hematology and Oncology Specialists, LLC, New Orleans, LA. Electronic address: milton.seiler@touro.com. 2. Département d'oncologie médicale adulte, Lyon, France. 3. Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. 4. Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN. 5. Biostatistics and Research Decision Sciences, Asia Pacific MSD R&D (China) Co. Ltd., Beijing, China. 6. ARIAD Pharmaceuticals, Inc., Cambridge, MA. 7. Merck & Co., Inc., Whitehouse Station, NJ.
Abstract
BACKGROUND: Although trastuzumab-containing therapies prolong survival in patients with metastatic breast cancer (MBC), most tumors develop trastuzumab resistance, potentially mediated by aberrant phosphatidylinositide 3-kinase (PI3K)/AKT signaling. Ridaforolimus (a mammalian target of rapamycin [mTOR] inhibitor) may overcome trastuzumab resistance by inhibiting PI3K signaling. METHODS: A single-arm, phase IIb trial was conducted to evaluate the efficacy and safety of ridaforolimus-trastuzumab in human epidermal growth factor receptor 2-positive (HER2(+)) trastuzumab-refractory MBC (NCT00736970). Ridaforolimus was administered orally (40 mg daily) for 5 d/wk plus weekly trastuzumab. The primary end point was objective response (OR). RESULTS: Thirty-four patients were enrolled (91% had received 1 or 2 previous trastuzumab-based therapies, whereas 9% had received 3 previous therapies). The most common reasons for discontinuation were disease progression (62%) and adverse events (AEs; 24%). Three patients died; 1 because of bowel perforation, which was possibly ridaforolimus related. Partial response was observed in 5 patients (15%). Median duration of response was 19.1 weeks (range, 15.9-80.1 weeks). Fourteen patients (41%) achieved stable disease (SD); 7 patients (21%) maintained SD for ≥ 24 weeks. The clinical benefit response (CBR) rate was 34.3%. Median progression-free survival (PFS) and overall survival (OS) were 5.4 months (range, 0-20.3 months; 95% confidence interval [CI], 2.0-7.4) and 17.7 months (range, 0-25.9 months; 95% CI, 8.8-20.8), respectively. PFS rate at 6 months was 37%. The most common treatment-related AEs were stomatitis (59%), diarrhea (27%), and rash (27%). CONCLUSION: Ridaforolimus-trastuzumab was well tolerated and demonstrated antitumor activity in trastuzumab-resistant HER2(+) MBC.
BACKGROUND: Although trastuzumab-containing therapies prolong survival in patients with metastatic breast cancer (MBC), most tumors develop trastuzumab resistance, potentially mediated by aberrant phosphatidylinositide 3-kinase (PI3K)/AKT signaling. Ridaforolimus (a mammalian target of rapamycin [mTOR] inhibitor) may overcome trastuzumab resistance by inhibiting PI3K signaling. METHODS: A single-arm, phase IIb trial was conducted to evaluate the efficacy and safety of ridaforolimus-trastuzumab in humanepidermal growth factor receptor 2-positive (HER2(+)) trastuzumab-refractory MBC (NCT00736970). Ridaforolimus was administered orally (40 mg daily) for 5 d/wk plus weekly trastuzumab. The primary end point was objective response (OR). RESULTS: Thirty-four patients were enrolled (91% had received 1 or 2 previous trastuzumab-based therapies, whereas 9% had received 3 previous therapies). The most common reasons for discontinuation were disease progression (62%) and adverse events (AEs; 24%). Three patients died; 1 because of bowel perforation, which was possibly ridaforolimus related. Partial response was observed in 5 patients (15%). Median duration of response was 19.1 weeks (range, 15.9-80.1 weeks). Fourteen patients (41%) achieved stable disease (SD); 7 patients (21%) maintained SD for ≥ 24 weeks. The clinical benefit response (CBR) rate was 34.3%. Median progression-free survival (PFS) and overall survival (OS) were 5.4 months (range, 0-20.3 months; 95% confidence interval [CI], 2.0-7.4) and 17.7 months (range, 0-25.9 months; 95% CI, 8.8-20.8), respectively. PFS rate at 6 months was 37%. The most common treatment-related AEs were stomatitis (59%), diarrhea (27%), and rash (27%). CONCLUSION:Ridaforolimus-trastuzumab was well tolerated and demonstrated antitumor activity in trastuzumab-resistant HER2(+) MBC.
Authors: Linda S Steelman; Alberto M Martelli; Lucio Cocco; Massimo Libra; Ferdinando Nicoletti; Stephen L Abrams; James A McCubrey Journal: Br J Clin Pharmacol Date: 2016-05-10 Impact factor: 4.335
Authors: Hye Sook Chon; Sokbom Kang; Jae K Lee; Sachin M Apte; Mian M Shahzad; Irene Williams-Elson; Robert M Wenham Journal: BMC Cancer Date: 2017-06-08 Impact factor: 4.430