加拿大多伦多玛格丽特公主癌症中心Amit M Oza团队研究了adavosertib联合吉西他滨治疗铂耐药或铂难治复发性卵巢癌患者的疗效。2021年1月23日，该研究发表在《柳叶刀》杂志上。

Wee1（WEE1hu）抑制剂adavosertib和吉西他滨在早期临床试验中显示出临床前协同作用和有希望的抗癌活性。

为了确定这种联合疗法对卵巢癌患者的疗效，研究组在美国和加拿大的11个学术中心进行了一项双盲、随机、安慰剂对照的临床2期试验，招募具有可评估的复发性铂耐药或铂难治性高级别浆液性卵巢癌的女性，这些女性的年龄在18岁及以上，在东方肿瘤合作组表现状态为0-2，预期寿命超过3个月，并且器官和骨髓功能正常。

非高级别浆液组织学卵巢癌女性有资格参加非随机探索性队列研究。高级别浆液性卵巢癌的合格参与者按2：1随机分配，在静脉注射吉西他滨的基础上，分别接受口服adavosertib，或安慰剂治疗，28天为一周期，直到疾病进展或出现不可接受的毒性。主要终点为无进展生存。

2014年9月22日至2018年5月30日，研究组共招募了124名女性，其中99名患有高级别浆液性卵巢癌，65名被分配至adavosertib+吉西他滨组（实验组），34名被分配至安慰剂+吉西他滨组（对照组）。25名患有非高级别浆液性卵巢癌的妇女被纳入探索性队列研究。随机分组后，研究组发现有5例高级别浆液性卵巢癌患者不合格，其中实验组4例，对照组1例，最终未接受治疗。

119例接受治疗的患者中位年龄为62岁。实验组的中位无进展生存期为4.6个月，显著长于对照组（3.0个月），风险比为0.55。最常见的3级及以上不良事件是血液学反应，其中实验组中有62%发生中性粒细胞减少，高于对照组（30%）；实验组中有31%发生血小板减少，高于对照组（6%）。无治疗相关死亡；有两名患者（高级别浆液性卵巢癌队列中每组一名）在服用研究药物期间死亡（实验组死于败血症，对照组死于疾病进展）。

该研究中Wee1抑制剂联合吉西他滨的临床疗效，支持了使用DNA损伤反应药物治疗高级别浆液性卵巢癌（一种tp53突变的高复制应激型肿瘤）的预估。

附：英文原文

Title: Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial

Author: Stephanie Lheureux, Mihaela C Cristea, Jeffrey P Bruce, Swati Garg, Michael Cabanero, Gina Mantia-Smaldone, Alexander B Olawaiye, Susan L Ellard, Johanne I Weberpals, Andrea E Wahner Hendrickson, Gini F Fleming, Stephen Welch, Neesha C Dhani, Tracy Stockley, Prisni Rath, Katherine Karakasis, Gemma N Jones, Suzanne Jenkins, Jaime Rodriguez-Canales, Michael Tracy, Qian Tan, Valerie Bowering, Smitha Udagani, Lisa Wang, Charles A Kunos, Eric Chen, Trevor J Pugh, Amit M Oza

Issue&Volume: 2021/01/23

Abstract:

Background

The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer.

Methods

In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m 2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual.

Findings

Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54–67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6–6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8–3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35–0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group).

Interpretation

The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required.

DOI: 10.1016/S0140-6736(20)32554-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32554-X/fulltext