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.

中文翻译：

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M2698（一种 p70S6K/AKT 双抑制剂）在晚期癌症患者中的 1 期研究

PI3K/AKT/mTOR (PAM) 通路是肿瘤治疗抵抗的关键调节因子。我们在标准治疗失败的晚期癌症患者中研究了 M2698，一种口服 p70S6K/AKT 双重抑制剂。M2698 作为单一疗法给药（逐步增加，每天 15-380 毫克；食物效应队列，每天 240-320 毫克）并与曲妥珠单抗或他莫昔芬联合使用。总体而言，101 名患者接受了治疗（M2698，n = 62；M2698/曲妥珠单抗，n = 13；M2698/他莫昔芬，n = 26）。患者主要年龄 < 65 岁，为女性，体能状态为 1 且接受过大量预处理。外周血单个核细胞和肿瘤组织中 pS6 水平存在剂量和浓度依赖性抑制。M2698 耐受性良好；最常见的治疗出现的不良事件是胃肠道、梦境异常和疲劳（严重，归因于 M2698：单一疗法，8.1%；M2698/曲妥珠单抗，7.7%；M2698/他莫昔芬，11.5% 的患者）。推荐的 M2698 2 期剂量为 240 mg QD（单一疗法）、160 mg QD（M2698/曲妥珠单抗）和 160 mg QD/240 mg 间歇方案（M2698/他莫昔芬）。在单药治疗队列中，27.4% 的患者在 12 周时病情稳定；没有注意到客观反应。伴有和不伴有混杂标志物（KRAS、EGFR、AKT2）的 PAM 通路改变患者的中位无进展生存期 (PFS) 持续时间分别为 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）部分缓解；他们的 PFS 持续时间分别为 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合用，M2698 在对多种标准疗法耐药的晚期乳腺癌患者中表现出抗肿瘤活性，表明它可以克服治疗耐药性。试验注册 ClinicalTrials.gov，NCT01971515。2013 年 10 月 23 日注册。