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
Fuji Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd, Shizuoka, Japan.
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ther Adv Med Oncol. 2018 Jul 30;10:1758835918786858. doi: 10.1177/1758835918786858. eCollection 2018.
KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the and 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.
A series of and 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.
Preclinical studies showed KW-2450 and lapatinib act synergistically to induce apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed using the MDA-MB-361 xenograft model. KW-2450 showed synergistic 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.
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.
KW-2450是一种口服双胰岛素样生长因子-1受体/胰岛素受体酪氨酸激酶抑制剂。我们研究了KW-2450联合拉帕替尼和来曲唑的临床前活性，并在1例男性和10例绝经后女性晚期/转移性激素受体阳性、人表皮生长因子受体2（HER2）阳性乳腺癌患者中进行了三药联合的I期试验。
开展了一系列关于KW-2450与拉帕替尼及激素药物联合应用的临床前动物研究。进行I期试验以确定KW-2450与拉帕替尼和来曲唑联合给药的安全性、耐受性及推荐的II期剂量（RP2D）。
临床前研究表明，KW-2450和拉帕替尼协同作用可诱导HER2阳性的MDA-MB-361和BT-474乳腺癌细胞系凋亡并抑制其生长。使用MDA-MB-361异种移植模型在体内证实了这种联合效应。KW-2450在雌激素受体（ER）阳性的MCF-7乳腺癌细胞和MCF-7-Ac1芳香化酶转染的MCF-7细胞中与来曲唑和4-羟基他莫昔芬协同抑制生长。在I期研究中，在KW-2450 25 mg/天联合拉帕替尼1500 mg/天和来曲唑2.5 mg/天的剂量水平下，3例患者中有2例出现剂量限制性毒性（DLT，分别为3级皮疹和3级高血糖）。三药联合的RP2D确定为KW-2450 25 mg/天、拉帕替尼1250 mg/天和来曲唑2.5 mg/天，在此剂量水平未出现DLT。
由于预计患者入组困难，拟进行的三药联合RP2D的II期研究未开展，KW-2450的进一步临床开发也已终止。
