Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial.
Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial.
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DOI：
10.1016/s0140-6736(21)02175-9
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发表时间：
2022-02-05
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通讯作者：
Gourley C
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作者：
Gershenson DM;Miller A;Brady WE;Paul J;Carty K;Rodgers W;Millan D;Coleman RL;Moore KN;Banerjee S;Connolly K;Secord AA;O'Malley DM;Dorigo O;Gaillard S;Gabra H;Slomovitz B;Hanjani P;Farley J;Churchman M;Ewing A;Hollis RL;Herrington CS;Huang HQ;Wenzel L;Gourley C
卵巢或腹膜的低级别浆液性癌的特征在于MAPK通路畸变和其相对于高级别浆液性癌对化疗的敏感性降低。我们比较了MEK抑制剂曲美替尼与医生选择的治疗复发性低级别浆液性癌患者的标准。这项国际、随机、开放标签、多中心、2/3期试验在美国和英国的84家医院进行。符合条件的患者年龄为18岁或以上，患有复发性低度浆液性癌和可测量的疾病，根据实体瘤疗效评价标准第1.1版的定义，接受过至少一种铂类药物治疗方案，但不是所有五种标准治疗药物，并且接受过不限数量的既往治疗方案。排除了浆液性交界性肿瘤或包含低级别浆液性和高级别浆液性癌的肿瘤患者。符合条件的患者被随机分配（1：1）接受曲美替尼2 mg口服，每日一次（曲美替尼组）或五种标准治疗方案之一（标准治疗组）：在每28天周期的第1、8和15天按体表面积静脉注射紫杉醇80 mg/m2;按体表面积静脉注射聚乙二醇脂质体阿霉素40-50 mg/m2，每4周一次;在每28天周期的第1、8和15天，按体表面积静脉注射托泊替康4 mg/m2;口服来曲唑2.5 mg，每日一次;或口服他莫昔芬20 mg，每日两次。按照地理区域（美国或英国）、既往治疗方案数量（1、2或≥3）、体能状态（0或1）和计划的标准治疗方案对随机化进行分层。主要终点是在意向治疗人群中，接受随机化治疗时，通过基线成像评估的无进展生存期，每8周一次，持续15个月，然后每3个月一次。在接受至少一剂研究治疗的患者中评估安全性。本试验注册于ClinicalTrials.gov，NCT 02101788，正在进行中，但未招募。在2014年2月27日至2018年4月10日期间，260例患者入组并随机分配至曲美替尼组（n=130）或标准治疗组（n=130）。在主要分析中，有217例无进展生存事件（曲美替尼组101例[78%]，标准治疗组116例[89%]）。曲美替尼组的中位无进展生存期为13.0个月（95%CI 9.9 - 15.0），而标准治疗组为7.2个月（5.6 - 9.9）（风险比0.48 [95%CI 0.36 - 0.64]; p<0.0001）。曲美替尼组中最常见的3级或4级不良事件是皮疹（17/128 [13%]）、贫血（16 [13%]）、高血压（15 [12%]）、腹泻（13 [10%]）、恶心（12 [9%]）和疲劳（10 [8%]）。标准治疗组中最常见的3级或4级不良事件为腹痛（22例[17%]）、恶心（14例[11%]）、贫血（12例[10%]）和呕吐（10例[8%]）。未发生给药相关死亡。曲美替尼是复发性低级别浆液性癌患者的一种新的标准治疗选择。NRG肿瘤学，英国癌症研究，靶向卵巢癌和诺华。
Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma. This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40–50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting. Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9–15·0) compared with 7·2 months (5·6–9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36–0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths. Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma. NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis.