Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole

• Published in: Therapeutic advances in medical oncology 2018-01, Vol.10, p.1758835918786858
• Main Authors: Umehara, Hiroshi, Maekawa, Yoshimi, Koizumi, Fumito, Shimizu, Makiko, Ota, Toshio, Fouad, Tamer M., Willey, Jie, Kaito, Hidekuni, Shiraishi, Norihiko, Nakashima, Daisuke, Akinaga, Shiro, Ueno, Naoto T.
• Format: Article
• Language: English
• Subjects: Apoptosis; Aromatase; Breast cancer; Drug dosages; Enzyme inhibitors; Epidermal growth factor; ErbB-2 protein; Growth factors; Hyperglycemia; Insulin; Insulin-like growth factor I; Metastases; Original Research; Post-menopause; Protein-tyrosine kinase receptors; Targeted cancer therapy; Toxicity; Tumor cell lines; Xenografts
• ISSN: 1758-8340; 1758-8359; 1758-8359
• DOI: 10.1177/1758835918786858

Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.