PURPOSE The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

中文翻译：

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在 I-SPY 2 试验中，MK-2206 和标准新辅助化疗可改善人类表皮生长因子受体 2 阳性和/或激素受体阴性乳腺癌患者的反应

目的 雷帕霉素的磷脂酰肌醇 3-激酶/Akt/哺乳动物靶点是乳腺癌生存和治疗抵抗的关键途径。我们在高危早期乳腺癌患者中评估了 pan-Akt 抑制剂 MK-2206 与标准疗法的结合。患者和方法 I-SPY 2 是一项多中心、II 期、开放标签、自适应随机新辅助平台试验，可筛选实验疗法并有效识别潜在的预测性生物标志物特征。患者按 2 × 2 × 2 布局按人表皮生长因子受体 2 (HER2)、激素受体 (HR) 和 MammaPrint 状态分类。这 8 种生物标志物亚型中的每一种中的患者都被适应性地随机分配到几种实验疗法中的一种，包括 MK-2206 或对照。针对 10 种生物标志物特征评估治疗，每一种都是这些亚型的组合。主要终点是病理完全缓解（pCR）。如果一种疗法在假设的 III 期试验中具有 85% 的贝叶斯预测成功概率，并针对生物标志物协变量进行调整，则该疗法将具有这些特征中的一个或多个。当前报告中的患者接受了标准紫杉烷和蒽环类新辅助治疗，没有（对照）或口服 MK-2206 135 mg/周。结果 MK-2206 毕业时有 94 名患者和 57 名同时随机分配的对照，分为 3 个毕业特征：HR 阴性/HER2 阳性、HR 阴性和 HER2 阳性。MK-2206 优于对照的各个贝叶斯平均协变量调整 pCR 率和百分比概率分别为 0.48:0.29 (97%)、0.62:0.36 (99%) 和 0.46:0。26 (94%)。在探索性分析中，MK-2206 在其毕业特征中证明了无事件生存率的数值改进。最显着的 3-4 级毒性是皮疹（14% 为斑丘疹，8.6% 为痤疮）。结论 Akt 抑制剂 MK-2206 联合标准新辅助治疗导致 HR 阴性和 HER2 阳性乳腺癌的估计 pCR 率更高。尽管此时 MK-2206 尚未进一步开发，但此类药物仍具有临床意义。结论 Akt 抑制剂 MK-2206 联合标准新辅助治疗导致 HR 阴性和 HER2 阳性乳腺癌的估计 pCR 率更高。尽管此时 MK-2206 尚未进一步开发，但此类药物仍具有临床意义。结论 Akt 抑制剂 MK-2206 联合标准新辅助治疗导致 HR 阴性和 HER2 阳性乳腺癌的估计 pCR 率更高。尽管此时 MK-2206 尚未进一步开发，但此类药物仍具有临床意义。