Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced melanoma with BRAFV600E or BRAFV600K mutations (EBIN): an international, open-label, randomised, controlled, phase 2 study.

We aimed to investigate the use of a targeted-therapy induction regimen before treatment with immune checkpoint inhibitors.

我们旨在研究在使用免疫检查点抑制剂治疗之前，先进行靶向治疗诱导方案的使用。

Methods

This open-label, randomised, controlled, phase 2 trial (EBIN) was conducted at 37 centres in eight European countries.

这项开放标签、随机对照的2期临床试验（EBIN）在欧洲八个国家的37个中心进行。

Eligible patients were 18 years or older and had previously untreated, unresectable, stage III or IV melanoma with BRAFV600E or BRAFV600K mutations and an Eastern Cooperative Oncology Group performance status of 0 or 1.

符合条件的患者年龄在18岁或以上，患有之前未接受治疗、无法手术切除的III期或IV期黑色素瘤，携带BRAFV600E或BRAFV600K突变，并且东部肿瘤协作组（ECOG）表现状态为0或1。

Patients were randomly assigned (1:1) to one of two groups.

患者被随机分配（1:1）到两个组中的一个。

Those in the induction group received targeted therapy (oral encorafenib 450 mg once a day plus oral binimetinib 45 mg twice a day for 12 weeks) followed by immune checkpoint inhibitors (intravenous nivolumab 3 mg/kg plus intravenous ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by intravenous nivolumab 480 mg once every 4 weeks until unacceptable toxicity, disease progression, or 2 years of treatment).

诱导组的患者接受了靶向治疗（口服恩曲替尼450毫克，每天一次，联合口服比美替尼45毫克，每天两次，持续12周），随后接受免疫检查点抑制剂（静脉注射纳武利尤单抗3毫克/公斤，联合静脉注射伊匹木单抗1毫克/公斤，每3周一次，共四剂，随后每4周一次静脉注射纳武利尤单抗480毫克，直到出现不可接受的毒性、疾病进展或治疗满2年）。

Patients in the control group received immune checkpoint inhibitors as above without any induction targeted therapy.

对照组患者接受了上述的免疫检查点抑制剂治疗，但没有进行任何诱导靶向治疗。

Randomisation was conducted using a minimisation technique and was stratified by centre and a variable defined using stage and lactate dehydrogenase activity.

随机分组采用最小化技术，并根据中心以及使用分期和乳酸脱氢酶活性定义的变量进行分层。

The primary outcome was progression-free survivalin the intention-to-treatpopulation.

主要结果是在意向治疗人群中无进展生存期。

Safety was assessed in all patients who initiated the protocol treatment.

所有开始执行方案治疗的患者都进行了安全性评估。

In this Article we report the primary analysis.

在本文中，我们报告了主要分析结果。

The study is registered with ClinicalTrials.gov, NCT03235245, and is ongoing.

该研究已在ClinicalTrials.gov注册，注册号为NCT03235245，并且正在进行中。

Results

Between Nov 12, 2018, and July 11, 2022, 271 patients were randomly assigned: 136 to the induction group and 135 to the control group. 103 (38%) patients were female, 168 (62%) were male, and the median age was 55 years (IQR 43-66).

在2018年11月12日至2022年7月11日期间，共有271名患者被随机分配：136名进入诱导组，135名进入对照组。其中103名（38%）为女性，168名（62%）为男性，中位年龄为55岁（四分位数间距43-66岁）。

The median follow-up time was 21 months (IQR 13-33).

随访的中位时间为21个月（四分位数间距13-33个月）。

There was no evidence of a longer progression-free survivalin the induction group than in the control group (hazard ratio0·87, 90% CI 0·67-1·12; p=0·36).

诱导组与对照组相比，无证据表明无进展生存期更长（风险比0.87，90%置信区间0.67-1.12；p=0.36）。

The median progression-free survivalwas 9 months (95% CI 7-13) in the induction group and 9 months (5-14) in the control group.

诱导组的中位无进展生存期为9个月（95%置信区间7-13），对照组为9个月（5-14）。

Grade 3-5 treatment-related adverse events occurred in 57 (42%) of 136 patients who started treatment in the induction group and in 42 (32%) of 131 patients who started treatment in the control group.

在开始诱导治疗的136名患者中，有57名（42%）发生了3-5级治疗相关不良事件，在开始对照治疗的131名患者中，有42名（32%）发生了3-5级治疗相关不良事件。

The most common grade 3-4 treatment-related adverse eventwas hepatitis (17 [13%] of 136 patients in the induction group and nine [7%] of 131 patients in the control group).

最常见的3-4级治疗相关不良事件是肝炎（诱导组136名患者中有17名（13%），对照组131名患者中有9名（7%））。

Serious treatment-related adverse events occurred in 45 (33%) of 136 patients in the induction group and 33 (25%) of 131 patients in the control group.

在136名诱导组患者中，有45例（33%）发生了严重的治疗相关不良事件，在131名对照组患者中，有33例（25%）发生了严重的治疗相关不良事件。

There were three treatment-related deaths: two from cardiac events (heart failure and arrhythmia) in the induction group and one from meningitis in the control group.

有三例治疗相关死亡：诱导组中两例因心脏事件（心力衰竭和心律失常）死亡，对照组中一例因脑膜炎死亡。

interpretation

The targeted-therapy induction regimen did not improve progression-free survivalcompared with first-line treatment with immune checkpoint inhibitors in unselected patients with advanced melanoma with BRAFV600E or BRAFV600K mutations.

针对携带BRAFV600E或BRAFV600K突变的晚期黑色素瘤患者，靶向治疗诱导方案与一线使用免疫检查点抑制剂治疗相比，并未改善无进展生存期。

funding

Bristol Myers Squibb and Pierre Fabre.

百时美施贵宝和皮埃尔法布尔。