Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland.
Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy.
Lancet Oncol. 2018 Oct;19(10):1315-1327. doi: 10.1016/S1470-2045(18)30497-2. Epub 2018 Sep 12.
Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival.
COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF or BRAF mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.
Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.
The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF-mutant melanoma.
Array BioPharma, Novartis.
在 COLUMBUS 试验中，与vemurafenib 相比，encorafenib 加 binimetinib 和 encorafenib 单药治疗改善了 BRAF 突变型黑色素瘤患者的无进展生存期。在此，我们报告了总生存期这一次要终点的结果。
COLUMBUS 是一项在 28 个国家的 162 家医院进行的两部分、随机、开放标签、3 期研究。符合条件的患者年龄至少为 18 岁，组织学证实为局部晚期、不可切除或转移性皮肤黑色素瘤，或未知原发性黑色素瘤，BRAF 或 BRAF 突变，东部肿瘤协作组（ECOG）体能状态为 0 或 1，并且是初治患者或在一线免疫治疗后进展。在研究的第一部分，患者通过交互式响应技术以 1:1:1 的比例随机分配接受口服 encorafenib 450 mg 每日一次加口服 binimetinib 45 mg 每日两次（encorafenib 加 binimetinib 组）、口服 encorafenib 300 mg 每日一次（encorafenib 组）或口服 vemurafenib 960 mg 每日两次（vemurafenib 组）。随机分组按美国癌症联合委员会分期、ECOG 体能状态和 BRAF 突变状态分层。试验的主要终点，即 encorafenib 加 binimetinib 与 vemurafenib 相比的无进展生存期，之前已经报道过。在此，我们呈现了预先指定的中期总生存期分析。疗效分析采用意向治疗。安全性分析纳入了至少接受一剂研究药物的患者。研究的第二部分是应美国食品和药物管理局的要求启动的，目的是通过比较 encorafenib 300 mg 每日一次加 binimetinib 45 mg 每日两次与 encorafenib 300 mg 每日一次单药治疗，更好地了解 binimetinib 对联合治疗的贡献。第二部分的结果将单独公布。这项试验正在进行中，在 ClinicalTrials.gov 注册，编号为 NCT01909453，在 EudraCT 注册，编号为 2013-001176-38。
2013 年 12 月 30 日至 2015 年 4 月 10 日，在 1345 名筛查患者中，577 名被随机分配接受 encorafenib 加 binimetinib（n=192）、encorafenib（n=194）或 vemurafenib（n=191）治疗。总生存期的中位随访时间为 36.8 个月（95%CI 35.9-37.5）。encorafenib 加 binimetinib 组的中位总生存期为 33.6 个月（95%CI 24.4-39.2），而 vemurafenib 组为 16.9 个月（14.0-24.5）（风险比 0.61 [95%CI 0.47-0.79]；双侧 p<0.0001）。第一次报告后，最常见的 3 级或 4 级不良事件没有实质性变化；与 encorafenib 加 binimetinib 治疗相关的发生率超过 5%的不良事件为γ-谷氨酰转移酶升高（192 例患者中 18 例[9%]）、血肌酸磷酸激酶升高（14 例[7%]）和高血压（12 例[6%]）；与 encorafenib 单药治疗相关的不良事件为掌跖红细胞发育不良综合征（192 例患者中 26 例[14%]）、肌痛（19 例[10%]）和关节痛（18 例[9%]）；与 vemurafenib 相关的最常见的 3 级或 4 级不良事件是关节痛（186 例患者中 11 例[6%]）。组合治疗组中 1 例死亡被研究者认为可能与治疗有关。
与 vemurafenib 相比，encorafenib 加 binimetinib 联合治疗在无进展生存期和总生存期方面均显示出良好的疗效，改善了 BRAF 突变型黑色素瘤患者的预后，且具有良好的耐受性。这些数据表明，encorafenib 加 binimetinib 联合治疗可能成为 BRAF 突变型黑色素瘤患者的重要治疗选择。
Array BioPharma，诺华。
