背景：子宫内膜癌通常是激素依赖性的，芳香化酶抑制剂在一线化疗（CT）前或化疗后的常规应用阳性患者。Pi3K-Akt-mTOR 信号通路在小鼠体内被解除调控许多肿瘤类型包括子宫内膜癌驱动的肿瘤发生和激素抵抗。Vistusertib（V）是 mTORC1 和 mTORC2 复合物的小分子 ATP 竞争性抑制剂。

Background: Endometrial carcinoma is generally hormone dependent and aromatase inhibitors are used in routine practice before or after 1st line chemotherapy (CT) for HR positive patients. Deregulation of the Pi3K-Akt-mTOR signaling pathway is observed in many tumor types including endometroid carcinoma driven oncogenesis and hormonal resistance. Vistusertib (V) is a small-molecule ATP competitive inhibitor of both mTORC1 and mTORC2 complexes.

方法：对复发性雌激素或孕酮（ER 和/或 PR）阳性的晚期/转移性子宫内膜癌患者进行一次既往化疗（CT），ecog ps 0/1，随机（2:1，根据先前 CT 线分层：0 vs 1）接受静脉注射（125 mg bid/2 天/周，口服）+阿那曲唑（A，1 mg/d，口服）或单独 A。治疗方法是给予直到进展，不能忍受的毒性或病人的意愿退出。安全运行后在第二阶段，采用西蒙的两阶段设计来探索 8 周的进展自由率（PFR-8W）根据中央审查（p1:60%，p0:40%， I 型错误率 5%，功率 80%）。在第二阶段结束时，如果≥24/46 可评估的患者无进展在 A+V 组为 8w 时，该组合将被视为可以进行进一步研究。Recist v1.1 的总有效率（ORR），安全性和无进展生存率（PFS）是关键的次要终点。

Methods: Adult patients (pts) with recurrent oestrogen or progesterone (ER and/or PR) positive advanced/metastatic endometrial carcinoma, one previous line of chemotherapy (CT) allowed, with ECOG PS 0/1, were randomised (2:1, stratification according to prior CT line: 0 vs 1) to receive V (125 mg bid/2 days/week, orally) + Anastrozole (A, 1 mg/d, orally) or A alone. Treatments were given until progression, intolerable toxicity or patient willingness. Following a safety run in phase, a Simon’s 2-stage design was employed to explore the 8-week progression free rate (PFR-8W) according to central review (p1: 60%, p0: 40%, type I error rate of 5%, power of 80%). At the end of Stage II, if ≥24/46 evaluable pts are progression free at 8w in Arm A+V, the combination will be considered of interest for further investigation. Overall response rate (ORR) by RECIST v1.1, safety and progression-free survival (PFS) were key secondary endpoints.

结果：75 例患者中，73 例随机分组和治疗（V+A 组：49；A 组：24；中位年龄：69.5 岁[36.8；87.8]),体重指数≥30 kg/m2:45%）。Ps ecog 为 0（48%），44%的患者未经历过化疗；12%的患者以前接受过激素治疗。在安全试运行结束时，未报告重大安全问题。在西蒙的第二阶段结束时评估 A+V 组 PFR-8W 为 67.3%（33/49[95%CI 单侧：54.7；-]），单纯 A 组为 39.1%（9/23）[95%可信区间：22.2；-[）。中位 PFS 分别为5.2 个月（95%可信区间：3.4-8.9）和 1.9 个月（95%可信区间：1.6-8.9）(A+V Vs A)。1 例完全缓解，联合组有 11 例部分缓解（ORR:24.5%（CI）5%[13.3–38/9%]，单药 A 组仅为 4 例，PR（ORR:17.4%[CI95%: 5-38.8%]).主要不良反应的症状为疲劳、淋巴细胞减少、高血糖和腹泻（10%）与静脉曲张相关的 2 级不良事件。整体生存和转化研究正在进行中。

Results: Out of 75 patients (pts) enrolled, 73 were randomised and treated (Arm V+A: 49; Arm A: 24; median age: 69.5 y [36.8; 87.8]), BMI ≥30 kg/m²: 45%). PS ECOG was 0 (48%) and 44% of randomised pts were chemotherapy naïve; 12% previously received hormonal therapy. At the end of the safety run-in, no major safety concerns were reported. At the end of Simon’ Stage II, centrally assessed PFR-8W was 67.3% (33/49 [95% CI unilateral: 54.7; -]) for A + V arm and 39.1% (9/23 [[95% CI unilateral: 22.2; -[) for arm A. Median PFS was 5.2 months (95% CI: 3.4-8.9) and 1.9 months (95% CI: 1.6-8.9) for A+V and A arms, respectively. One complete response and 11 partial responses (PR) were observed (ORR: 24.5 % (CI 95% [13.3 – 38/9%]) in the combination arm and 4 PR in arm A (ORR: 17.4% [CI 95%: 5-38.8%]). Fatigue, lymphopenia, hyperglycaemia and diarrhoea were the main (≥10%) Grade ≥2 adverse events related to V. Overall survival and translational research are ongoing.

结论：A+V 联合应用具有临床和临床应用价值在毒性可控的情况下，8w PFR 和中位 PFS 有显著改善。PI3K 公司该通路仍然是子宫内膜癌和转化癌新疗法的关键靶点研究必须有助于更好地选择受益于这些靶向治疗的患者。

Conclusions: The A+V combination demonstrated clinically and meaningful improvement in 8w-PFR and median PFS with manageable toxicity. PI3K pathway remains a key target for new therapies in endometrial cancer and translational research must help to better select pts benefiting from these targeted therapies.