Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study
Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study
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DOI：
10.1016/s1470-2045(20)30464-2
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发表时间：
2020-11-01
期刊：
影响因子：
51.1
通讯作者：
Banerji, Udai
中科院分区：
文献类型：
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作者：
Guo, Christina;Chenard-Poiriet, Maxime;Banerji, Udai
背景CH 5126766（也称为VS-6766，以前命名为R 05126766）是一种新型MEK-pan-RAF抑制剂，已在各种实体瘤中显示出抗肿瘤活性;然而，其最初的开发受到毒性的限制。我们的目的是调查的安全性和毒性的间歇给药方案的CH 5126766，这种药物的抗肿瘤活性的患者与实体瘤和多发性骨髓瘤窝藏RAS-RAF-MEK pathway mutations.Methods我们做了一个单中心，开放标签，1期剂量递增和篮子剂量扩展研究在皇家马斯登国家卫生服务基金会信托（伦敦，英国）。如果患者年龄在18岁或以上，患有常规治疗难治性或不存在常规治疗的癌症，并且如果他们的WHO体力状态评分为0或1，则有资格参加研究。对于剂量递增阶段，合格患者患有组织学或细胞学证实的晚期或不转移性实体瘤。对于篮剂量扩展阶段，合格患者患有晚期或转移性实体瘤或携带RAS-RAF-MEK途径突变的多发性骨髓瘤。在剂量递增阶段，我们评估了三种间歇性口服方案（28天为一个周期）：（1）4.0 mg或3.2 mg CH 5126766，每周3次;（2）4.0 mg CH 5126766，每周2次;和（3）毒性指导的剂量中断时间表，其中以推荐的II期剂量治疗如果患者出现预先规定的毒性反应，则将剂量（4.0 mg CH 5126766，每周两次）递减至3周，然后停药1周（2级或更严重的腹泻、皮疹或肌酐磷酸激酶升高）。在篮子剂量扩展阶段，我们在生物标志物选择的患者中评估了推荐的II期剂量的抗肿瘤活性，该剂量是从剂量递增阶段确定的。主要终点是推荐的II期剂量，在该剂量下，不超过1/6的患者发生治疗相关的剂量限制性毒性，以及每个给药方案的安全性和毒性特征。关键次要终点是剂量扩展阶段的评估者评估的缓解率。接受至少一剂研究药物的患者可评价安全性，接受一个周期研究药物并接受基线疾病评估的患者可评价缓解。该试验在www.example.com注册ClinicalTrials.gov，NCT 02407509。结果在2013年6月5日至2019年1月10日期间，58名合格患者入组研究：29例实体瘤患者被纳入剂量递增队列，29例实体瘤或多发性骨髓瘤患者被纳入篮子剂量扩展队列（12例非小细胞肺癌，5例妇科恶性肿瘤，4例结肠直肠癌，1例黑色素瘤和7例多发性骨髓瘤）。数据截止时的中位随访时间为2.3个月（IQR 1.6-3.5）。剂量限制性毒性包括1例接受4.0 mg CH 5126766每周3次治疗的患者发生的3级双侧视网膜色素上皮脱离，以及接受3.2 mg CH 5126766每周3次治疗的患者发生的3级皮疹（2例患者）和3级肌酐磷酸激酶升高（1例患者）。4.0 mg CH 5126766每周两次（周一和周四或周二和周五）被确定为推荐的II期剂量。最常见的3-4级治疗相关不良事件为皮疹（11例[19%]患者）、肌酐磷酸激酶升高（6例[11%1]）、低白蛋白血症（6例[11%]）和疲乏（4例[7%1]）。5例（9%）患者发生了严重的治疗相关不良事件。无治疗相关死亡。57例患者中有8例（14%）在试验期间因疾病进展死亡。7（27% [95%CI 11.6-47.8]）的26个响应可评估的患者在篮子expansion实现了客观responsibility.Interpretation据我们所知，这是第一个研究表明，RAF-MEK抑制剂的高度间歇性的时间表具有抗肿瘤活性的各种癌症与RAF-RAS-MEK通路突变，这种抑制剂是耐受的。CH 5126766作为单药治疗和联合治疗方案使用需要进一步评价。版权所有（C）2020爱思唯尔有限公司保留所有权利。
Background CH5126766 (also known as VS-6766, and previously named R05126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations.Methods We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or inetastatic solid tumours. For the basket doseexpansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4.0 mg or 3.2 mg CH5126766 three times per week; (2) 4.0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4.0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509.Findings Between June 5,2013, and Jan 10,2019,58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2.3 months (IQR 1.6-3.5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4.0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3.2 mg CH5126766 three times per week. 4.0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%1), hypoalbuminaemia (six [11%]), and fatigue (four [7%1). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11.6-47.8]) of 26 response-evaluable patients in the basket expansion achieved objective responses.Interpretation To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. Copyright (C) 2020 Elsevier Ltd. All rights reserved.