Di Cosimo Serena, Sathyanarayanan Sriram, Bendell Johanna C, Cervantes Andrés, Stein Mark N, Braña Irene, Roda Desamparados, Haines Brian B, Zhang Theresa, Winter Christopher G, Jha Sharda, Xu Youyuan, Frazier Jason, Klinghoffer Richard A, Leighton-Swayze Ann, Song Yang, Ebbinghaus Scot, Baselga José
Vall d'Hebron University Hospital, Barcelona, Spain.
Merck & Co., Inc., Whitehouse Station, New Jersey.
Clin Cancer Res. 2015 Jan 1;21(1):49-59. doi: 10.1158/1078-0432.CCR-14-0940. Epub 2014 Oct 15.
Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.
In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.
Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER(+)/high-proliferative breast cancer showed antitumor activity.
Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER(+)/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379).
雷帕霉素哺乳动物靶点（mTOR）抑制可激活代偿性胰岛素样生长因子受体（IGFR）信号传导。我们评估了瑞达法莫司（mTOR抑制剂）和达洛珠单抗（抗IGF1R抗体）联合用药的效果。
探索了体外和体内模型，以及一项I期研究，晚期癌症患者接受瑞达法莫司（10 - 40毫克/天，每天×5/周）和达洛珠单抗（10毫克/千克/周或7.5毫克/千克/每隔一周）治疗。
临床前研究表明，瑞达法莫司和达洛珠单抗联合用药可增强通路抑制作用。在I期研究中，87例患者接受了治疗，联合用药的主要剂量限制性毒性（DLT）主要是mTOR相关的口腔炎和乏力，且瑞达法莫司的剂量低于预期，提示正常组织中的代偿性通路被阻断。报告了6例确诊的部分缓解（3例乳腺癌患者）；23例乳腺癌患者中的10例以及11例雌激素受体阳性（ER(+)）/高增殖性乳腺癌患者中的6例显示出抗肿瘤活性。
我们的研究提供了概念验证，即抑制IGF1R对mTOR抑制的代偿反应是可行的，在经过大量预处理的晚期癌症患者中具有良好的临床活性，尤其是在ER(+)/高增殖性乳腺癌患者中（ClinicalTrials.gov标识符：NCT00730379）。
