背景：子宮內膜癌通常是激素依賴性的，芳香化酶抑製劑在一線化療（CT）前或化療後的常規應用陽性患者。Pi3K-Akt-mTOR 信號通路在小鼠體內被解除調控許多腫瘤類型包括子宮內膜癌驅動的腫瘤發生和激素抵抗。Vistusertib（V）是 mTORC1 和 mTORC2 複合物的小分子 ATP 競爭性抑製劑。

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：對複發性雌激素或孕酮（ER 和/或 PR）陽性的晚期/轉移性子宮內膜癌患者進行一次既往化療（CT），ecog ps 0/1，隨機（2:1，根據先前 CT 線分層：0 vs 1）接受靜脈注射（125 mg bid/2 天/周，口服）+阿那曲唑（A，1 mg/d，口服）或單獨 A。治療方法是給予直到進展，不能忍受的毒性或病人的意願退出。安全運行後在第二階段，采用西蒙的兩階段設計來探索 8 周的進展自由率（PFR-8W）根據中央審查（p1:60%，p0:40%， I 型錯誤率 5%，功率 80%）。在第二階段結束時，如果≥24/46 可評估的患者無進展在 A+V 組為 8w 時，該組合將被視為可以進行進一步研究。Recist v1.1 的總有效率（ORR），安全性和無進展生存率（PFS）是關鍵的次要終點。

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.

結果：75 例患者中，73 例隨機分組和治療（V+A 組：49；A 組：24；中位年齡：69.5 歲[36.8；87.8]),體重指數≥30 kg/m2:45%）。Ps ecog 為 0（48%），44%的患者未經曆過化療；12%的患者以前接受過激素治療。在安全試運行結束時，未報告重大安全問題。在西蒙的第二階段結束時評估 A+V 組 PFR-8W 為 67.3%（33/49[95%CI 單側：54.7；-]），單純 A 組為 39.1%（9/23）[95%可信區間：22.2；-[）。中位 PFS 分別為5.2 個月（95%可信區間：3.4-8.9）和 1.9 個月（95%可信區間：1.6-8.9）(A+V Vs A)。1 例完全緩解，聯合組有 11 例部分緩解（ORR:24.5%（CI）5%[13.3–38/9%]，單藥 A 組僅為 4 例，PR（ORR:17.4%[CI95%: 5-38.8%]).主要不良反應的症狀為疲勞、淋巴細胞減少、高血糖和腹瀉（10%）與靜脈曲張相關的 2 級不良事件。整體生存和轉化研究正在進行中。

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.

結論：A+V 聯合應用具有臨床和臨床應用價值在毒性可控的情況下，8w PFR 和中位 PFS 有顯著改善。PI3K 公司該通路仍然是子宮內膜癌和轉化癌新療法的關鍵靶點研究必須有助於更好地選擇受益於這些靶向治療的患者。

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.