Herzog Thomas J, Liao John B, Finkelstein Karen, Willmott Lyndsay, Duan Wei, Moroney John W, Buscema Joseph, Campbell-Simms Katie, Yue Yong, Zweizig Susan, Liu Juan, Wang Xiaoyu, Zang Rong-Yu, Yin Rutie, O'Malley David M, Wu Lingying
University of Cincinnati, University of Cincinnati Cancer Center, Cincinnati, OH, USA.
University of Washington, Seattle, WA, USA.
Gynecol Oncol. 2025 Mar;194:145-152. doi: 10.1016/j.ygyno.2025.03.001.
To evaluate the efficacy and safety/tolerability of paclitaxel with and without the AKT inhibitor afuresertib in patients with platinum-resistant ovarian cancer (PROC).
This phase II open-label randomized trial (NCT04374630) enrolled 150 PROC patients to evaluate progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate, and duration of response. Eligible patients received 1-5 prior chemotherapies (≤1 post-PROC therapy). Biomarker analysis assessed PI3K/AKT/PTEN alterations, BRCA1/2-mutations, and phospho-AKT levels. Patients with prior AKT or mTOR inhibitor use were excluded. Randomization was stratified by country and prior use of bevacizumab and platinum-based treatment lines.
In the intent-to-treat population, no statistically significant difference was observed in PFS between afuresertib+paclitaxel (A + P) vs. paclitaxel (Pac) alone (median PFS 4.3mos [95 % CI, 3.58-5.62] vs 4.1mos [95 % CI 2.63-5.36].
0.7 (95 % CI, 0.50-1.10; P = 0.139). No statistically significant difference in median OS was observed either (11.2mos with A + P, 95 % CI, 8.38-13.77) vs. 13.1mos in Pac arm (95 % CI, 7.75-18) and HR = 1.2 (95 % CI, 0.77-1.81). In AKT mutation biomarker+ (IHC > 1) patients, the median PFS of A + P vs. Pac was 5.4mos vs. 2.9mos (HR = 0.4; 95 % CI, 0.12-1.00). Treatment-emergent adverse events (TEAEs) were consistent with AKT inhibitors, with serious TEAEs in 34.3 % (A + P) vs. 25.5 % (Pac), including diarrhea and gastrointestinal perforations.
The addition of afuresertib to paclitaxel did not significantly improve PFS/OS in patients with PROC. However, exploratory biomarker findings suggest potential efficacy in phospho-AKT positive patients, warranting further investigation. The safety/tolerability profile of A + P was consistent with prior AKT-inhibitor studies.
评估在铂耐药卵巢癌（PROC）患者中，使用和不使用AKT抑制剂阿福司替尼的紫杉醇的疗效及安全性/耐受性。
这项II期开放标签随机试验（NCT04374630）纳入了150例PROC患者，以无进展生存期（PFS）作为主要终点进行评估，次要终点包括总生存期（OS）、客观缓解率和缓解持续时间。符合条件的患者之前接受过1 - 5次化疗（PROC治疗后≤1次）。生物标志物分析评估PI3K/AKT/PTEN改变、BRCA1/2突变和磷酸化AKT水平。排除之前使用过AKT或mTOR抑制剂的患者。随机分组按国家以及之前是否使用贝伐单抗和铂类治疗线进行分层。
在意向性治疗人群中，阿福司替尼 + 紫杉醇（A + P）组与单纯紫杉醇（Pac）组的PFS无统计学显著差异（中位PFS 4.3个月[95%CI，3.58 - 5.62] vs 4.1个月[95%CI 2.63 - 5.36]）。PFS风险比（HR）：0.7（95%CI，0.50 - 1.10；P = 0.139）。中位OS也未观察到统计学显著差异（A + P组为（11.2个月，95%CI，8.38 - 13.77），Pac组为13.1个月（95%CI，7.75 - 18），HR = 1.2（95%CI，0.77 - 1.
