Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
EMD Serono Research and Development Institute, Inc., Billerica, MA, USA.
J Hematol Oncol. 2021 Aug 18;14(1):127. doi: 10.1186/s13045-021-01132-z.
The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies.
M2698 was administered as monotherapy (escalation, 15-380 mg daily; food effect cohort, 240-320 mg daily) and combined with trastuzumab or tamoxifen.
Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively.
M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.
PI3K/AKT/mTOR（PAM）通路是肿瘤治疗耐药的关键调节因子。我们研究了 M2698，一种口服 p70S6K/AKT 双重抑制剂，用于标准治疗失败的晚期癌症患者。
M2698 作为单药治疗（递增，15-380mg/天；食物效应队列，240-320mg/天）和与曲妥珠单抗或他莫昔芬联合使用。
共有 101 名患者接受治疗（M2698，n=62；M2698/曲妥珠单抗，n=13；M2698/他莫昔芬，n=26）。患者主要为年龄<65 岁，女性，表现状态 1，且预处理程度较重。外周血单核细胞和肿瘤组织中 pS6 水平呈剂量和浓度依赖性抑制。M2698 耐受性良好；最常见的治疗相关不良事件为胃肠道、异常梦境和疲劳（严重，归因于 M2698：单药治疗，8.1%；M2698/曲妥珠单抗，7.7%；M2698/他莫昔芬，11.5%的患者）。M2698 的推荐 2 期剂量为 240mg QD（单药治疗）、160mg QD（M2698/曲妥珠单抗）和 160mg QD/240mg 间歇方案（M2698/他莫昔芬）。在单药治疗组中，12 周时 27.4%的患者疾病稳定；未观察到客观缓解。PAM 通路改变患者（KRAS、EGFR、AKT2）和无混杂标志物患者的中位无进展生存期（PFS）分别为 1.4 个月和 2.8 个月。两名乳腺癌患者（M2698/曲妥珠单抗，n=1；M2698/他莫昔芬，n=1）有部分缓解；他们的 PFS 分别为 31 个月和 2.7 个月。
M2698 耐受性良好。与曲妥珠单抗或他莫昔芬联合使用，M2698 显示出对多种标准治疗耐药的晚期乳腺癌患者的抗肿瘤活性，表明它可以克服治疗耐药性。试验注册 ClinicalTrials.gov，NCT01971515。于 2013 年 10 月 23 日注册。
