Hudis Clifford, Swanton Charles, Janjigian Yelena Y, Lee Ray, Sutherland Stephanie, Lehman Robert, Chandarlapaty Sarat, Hamilton Nicola, Gajria Devika, Knowles James, Shah Jigna, Shannon Keith, Tetteh Ernestina, Sullivan Daniel M, Moreno Carolina, Yan Li, Han Hyo Sook
Breast Cancer Res. 2013 Nov 19;15(6):R110. doi: 10.1186/bcr3577.
Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling.
Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.
A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.
Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation.
ClinicalTrials.gov; identifier: NCT00963547.
曲妥珠单抗对人表皮生长因子受体2（HER2）过表达的乳腺癌和胃癌有效。然而，患者可能通过磷脂酰肌醇3激酶（PI3K）/AKT途径的下游信号传导产生耐药性。开展这项1期试验是为了确定研究性AKT抑制剂MK-2206的安全性和耐受性，为未来研究联合曲妥珠单抗是否能抑制代偿性信号传导做准备。
纳入HER2阳性且治疗难治的乳腺癌和胃食管癌患者。治疗方案包括标准剂量的静脉注射曲妥珠单抗，以及采用隔日（45毫克和60毫克隔日一次）或每周一次（135毫克和200毫克每周一次）给药方案递增剂量的口服MK-2206。
共纳入34例HER2阳性疾病患者；31例接受了研究药物治疗。MK-2206与曲妥珠单抗联合使用时，隔日给药方案的最大耐受剂量（MTD）为60毫克，每周一次给药方案为135毫克，不过由于试验提前终止，未确定真正的MTD。最常见的治疗中出现的毒性反应包括疲劳、高血糖和皮疹，与既往经验一致；报告了1例与治疗无关的死亡病例。1例转移性乳腺癌患者出现完全缓解，1例患者达到部分缓解，5例患者疾病稳定至少4个月，尽管此前接受多种基于曲妥珠单抗和拉帕替尼的治疗均出现进展。结果还表明曲妥珠单抗不影响MK-2206的药代动力学。
结果表明AKT抑制剂MK-2206可与曲妥珠单抗安全联合使用，并具有临床活性，支持进一步研究。
ClinicalTrials.gov；标识符：NCT00963547。
