Princess Margaret Cancer Centre, Toronto, ON, Canada.
City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Lancet. 2021 Jan 23;397(10271):281-292. doi: 10.1016/S0140-6736(20)32554-X.
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.
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 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.
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).
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.
US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.
Wee1（WEE1hu）抑制剂adavosertib 和吉西他滨在临床前研究中表现出协同作用和有希望的活性，并在早期临床试验中进行了探索。本研究旨在确定该联合方案在卵巢癌患者中的疗效。
这是一项在美国和加拿大 11 个学术中心进行的双盲、随机、安慰剂对照、2 期临床试验。研究纳入了可测量的复发性铂耐药或铂难治性高级别浆液性卵巢癌患者，纳入标准为：年龄 18 岁或以上，东部肿瘤协作组体能状态 0-2 分，预期寿命超过 3 个月，以及器官和骨髓功能正常。非高级别浆液性组织学类型的卵巢癌患者有资格参加非随机探索性队列。符合条件的高级别浆液性卵巢癌患者，按照 2:1 的比例，采用区组随机化（区组大小为 3 和 6）和不分层，接受静脉注射吉西他滨（第 1、8 和 15 天，剂量为 1000mg/m2）联合口服 adavosertib（第 1、2、8、9、15 和 16 天，剂量为 175mg）或相同的安慰剂，每天一次，28 天为一个周期，直至疾病进展或出现不可接受的毒性。患者和负责每位患者治疗的团队对治疗分组均不知情。主要终点为无进展生存期。安全性和疗效分析人群包括接受至少一剂治疗的所有患者。该试验在 ClinicalTrials.gov 上注册，编号为 NCT02151292，目前已关闭入组。
2014 年 9 月 22 日至 2018 年 5 月 30 日期间，共纳入 124 名女性患者，其中 99 名患有高级别浆液性卵巢癌，随机分为 adavosertib 联合吉西他滨组（65 例[66%]）或安慰剂联合吉西他滨组（34 例[34%]）。另外 25 名非高级别浆液性卵巢癌患者被纳入探索性队列。随机分组后，5 名高级别浆液性卵巢癌患者被发现不符合入组条件（实验组 4 例，对照组 1 例），未接受治疗。所有接受治疗患者（n=119）的中位年龄为 62 岁（IQR 54-67）。adavosertib 联合吉西他滨组的无进展生存期更长（中位 4.6 个月[95%CI 3.6-6.4]，adavosertib 联合吉西他滨组 vs 3.0 个月[1.8-3.8]，安慰剂联合吉西他滨组；风险比 0.55[95%CI 0.35-0.90]；对数秩检验 p=0.015）。最常见的 3 级或更高级别的不良事件为血液学毒性（中性粒细胞减少症，在 adavosertib 联合吉西他滨组的 61 名参与者中为 62%[61/100]，在安慰剂联合吉西他滨组中为 30%[10/33]；血小板减少症，在 adavosertib 联合吉西他滨组的 61 名参与者中为 31%[19/61]，在安慰剂联合吉西他滨组中为 6%[2/33]）。无治疗相关死亡事件；两名患者（高级别浆液性卵巢癌队列各 1 例）在接受研究药物治疗时死亡（实验组因脓毒症死亡，对照组因疾病进展死亡）。
Wee1 抑制剂联合吉西他滨的观察到的临床疗效支持在高级别浆液性卵巢癌中进一步评估 DNA 损伤反应药物，这是一种 TP53 突变的肿瘤类型，具有较高的复制应激。这种治疗方法可能适用于其他具有较高复制应激的肿瘤类型；需要更大的确认性研究。
美国国家癌症研究所癌症治疗评估计划、安大略省癌症研究所、美国国防部、玛格丽特公主癌症基金会和阿斯利康。
