Department of Dermato Cancerology, Nantes University, Nantes, France.
Department of Medicine, Hematology/Oncology, Jonsson Comprehensive Cancer Center, The University of California, Los Angeles, Los Angeles, USA.
Ann Oncol. 2017 May 1;28(5):1137-1144. doi: 10.1093/annonc/mdx040.
In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study.
Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations.
Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation.
These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care.
CLINICALTRIALS.GOV: NCT01689519.
在 coBRIM 三期试验中，与维莫非尼（BRAF 抑制剂）相比，添加 cobimetinib（一种 MEK 抑制剂）可显著改善晚期 BRAF 突变黑色素瘤患者的无进展生存期[风险比（HR），0.58；P<0.0001]和总生存期（HR，0.70；P=0.005）。在此，我们报告了 coBRIM 研究中关键不良事件（AE）的发生率、病程和管理情况。
患者以 1:1 的比例随机接受维莫非尼（960mg 每天两次）联合 cobimetinib（60mg 每天一次，21 天用药/7 天停药）或安慰剂治疗。除了标准的安全性评估外，患者还定期进行眼科、心脏和皮肤科检查。
共招募 495 例患者进入该研究，493 例患者接受了治疗，构成了安全性人群（cobimetinib 联合维莫非尼 247 例，维莫非尼 246 例）。截至数据截止日期（2015 年 9 月 30 日），中位随访时间为 18.5 个月。几乎所有患者均发生 AE。接受 cobimetinib 联合维莫非尼治疗的患者中，≥3 级 AE 的发生率高于单独接受维莫非尼治疗的患者（75%比 61%）。大多数 AE，包括≥3 级 AE，发生在首个治疗周期内。首个周期（28 天）后，随着时间的推移，常见 AE（皮疹、腹泻、光敏性、肌酸磷酸激酶升高、浆液性视网膜病变、发热和肝实验室异常）的发生率显著降低。大多数 AE 通过支持性护理措施、研究治疗的剂量调整，偶尔还需要永久停药来保守治疗。
这些数据表明，cobimetinib 联合维莫非尼治疗引起的大多数 AE 通常发生在治疗早期，为轻度或中度，通过患者监测、剂量调整和支持性护理即可控制。
临床试验.gov：NCT01689519。
