Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Breast and Gynecologic Research Program, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee, USA.
Cancer. 2023 Jun 15;129(12):1919-1929. doi: 10.1002/cncr.34733. Epub 2023 Mar 27.
In this first-in-human phase 1b study (ClinicalTrials.gov identifier NCT02761694) of advanced solid tumors with PIK3CA/AKT/PTEN mutations, the authors investigated the safety and efficacy of the pan-AKT inhibitor vevorisertib (MK-4440; ARQ 751) as monotherapy or with paclitaxel or fulvestrant.
Patients with histologically confirmed, advanced or recurrent, PIK3CA/AKT/PTEN-mutated solid tumors, measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status ≤1 received vevorisertib (dose range, 5-100 mg) alone or with paclitaxel 80 mg/m or fulvestrant 500 mg. The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1.
Of 78 patients enrolled, 58 received vevorisertib monotherapy, 10 received vevorisertib plus paclitaxel, and nine received vevorisertib plus fulvestrant. Dose-limiting toxicity occurred in three patients (vevorisertib monotherapy, n = 2 [grade 3 pruritic and maculopapular rashes]; vevorisertib plus paclitaxel, n = 1 [grade 1 asthenia]). Across doses, treatment-related AEs occurred in 46 patients (79%) with vevorisertib monotherapy, in 10 patients (100%) with vevorisertib plus paclitaxel, and in nine patients (100%) with vevorisertib plus fulvestrant; and grade 3 treatment-related AEs occurred in 13 (22%), 7 (70%), and 3 (33%) patients, respectively. No grade 4/5 treatment-related AEs occurred. Maximum vevorisertib concentrations were reached 1-4 hours after dosing; the elimination half-life ranged from 8.8 to 19.3 hours. The objective response rate was 5% with vevorisertib monotherapy (three partial responses), 20% with vevorisertib plus paclitaxel (two partial responses), and 0% with vevorisertib plus fulvestrant.
Vevorisertib alone or with paclitaxel or fulvestrant had a manageable safety profile, and vevorisertib alone or with paclitaxel had minimal to modest antitumor activity in this patient population with PIK3CA/AKT/PTEN-mutated advanced solid tumors.
ClinicalTrials.gov, NCT02761694.
在这项针对具有 PIK3CA/AKT/PTEN 突变的晚期实体瘤的首次人体 1b 期研究（ClinicalTrials.gov 标识符 NCT02761694）中，作者研究了泛 AKT 抑制剂 vevorisertib（MK-4440；ARQ 751）作为单药或与紫杉醇或氟维司群联合治疗的安全性和疗效。
经组织学证实的晚期或复发性 PIK3CA/AKT/PTEN 突变的晚期或复发性固体肿瘤患者，根据实体瘤反应评估标准 1.1 可测量疾病，东部合作肿瘤学组表现状态≤1，接受 vevorisertib（剂量范围 5-100mg）单药或联合紫杉醇 80mg/m 或氟维司群 500mg。主要终点是安全性和耐受性。次要终点包括药代动力学和根据实体瘤反应评估标准 1.1 的客观缓解率。
78 例患者入组，58 例接受 vevorisertib 单药治疗，10 例接受 vevorisertib 联合紫杉醇治疗，9 例接受 vevorisertib 联合氟维司群治疗。3 例患者（vevorisertib 单药治疗，n=2[3 级瘙痒和斑丘疹性皮疹]；vevorisertib 联合紫杉醇治疗，n=1[1 级乏力]）发生剂量限制毒性。在 vevorisertib 单药治疗的 46 例（79%）、vvevorisertib 联合紫杉醇治疗的 10 例（100%）和 vevorisertib 联合氟维司群治疗的 9 例（100%）患者中发生了与治疗相关的不良事件；3 级治疗相关不良事件分别发生在 13 例（22%）、7 例（70%）和 3 例（33%）患者中。未发生 4/5 级治疗相关不良事件。最大 vevorisertib 浓度在给药后 1-4 小时达到；消除半衰期范围为 8.8 至 19.3 小时。在 vevorisertib 单药治疗组中，客观缓解率为 5%（3 例部分缓解），在 vevorisertib 联合紫杉醇组中为 20%（2 例部分缓解），在 vevorisertib 联合氟维司群组中为 0%。
Vevorisertib 单药或联合紫杉醇或氟维司群具有可管理的安全性特征，在具有 PIK3CA/AKT/PTEN 突变的晚期实体瘤患者中，Vevorisertib 单药或联合紫杉醇具有最小至适度的抗肿瘤活性。
ClinicalTrials.gov，NCT02761694。
