Background

IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAF^V600 mutation-positive advanced or metastatic melanoma.

Methods

IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc–IV, BRAF^V600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients.

Findings

Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4–23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63–0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events.

Interpretation

The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAF^V600 mutation-positive advanced melanoma.

Funding

F Hoffmann–La Roche and Genentech.

中文翻译：

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Atezolizumab，vemurafenib和cobimetinib作为不可切除的晚期BRAFV600突变阳性黑色素瘤（IMspire150）的一线治疗：随机，双盲，安慰剂对照的3期临床试验的初步分析。

背景

IMspire150旨在评估BRAF + MEK抑制剂与BRAF ^V600突变阳性晚期或转移性黑色素瘤的一线联合治疗。

方法

IMspire150是一项在20个国家/地区的112个机构进行的一项随机，双盲，安慰剂对照的3期研究。患有无法切除的IIIc–IV期，BRAF ^V600的患者突变阳性的黑色素瘤被随机分配为atezolizumab，vemurafenib和cobimetinib（atezolizumab组）或atezolizumab安慰剂，vemurafenib和cobimetinib（对照组）的1：1至28天周期。在第1周期中，所有患者仅接受vemurafenib和cobimetinib；从第2周期开始添加阿扎佐珠单抗安慰剂。通过乳酸脱氢酶浓度和地理区域对随机分组进行分层。通过相同的静脉安慰剂使阿特珠单抗致盲，通过安慰剂片剂使维拉非尼致盲。主要结果是研究者评估的无进展生存期。该试验（ClinicalTrials.gov，NCT02908672）正在进行中，但不再招募患者。

发现

在2017年1月13日至2018年4月26日之间，对777例患者进行了筛查，并招募了514例患者，并将其随机分配到Atezolizumab组（n = 256）或对照组（n = 258）中。在中位随访期为18·9个月（IQR 10·4–23·8）时，研究者评估的无进展生存期与阿塞珠单抗相比对照组显着延长（15·1比10·6个月；危险比率[HR] 0·78； 95％CI 0·63-0·97； p = 0·025）。Atezolizumab和对照组的常见治疗相关不良事件（> 30％）为：血肌酐磷酸激酶升高（51·3％vs 44·8％），腹泻（42·2％vs 46·6％），皮疹（40 ·两组分别为9％，关节痛（39·1％vs 28·1％），发热（38·7％vs26·0％），丙氨酸转氨酶增加（33·9％vs 22·8％），脂肪酶增加（32·2％vs 27·4％）；Atezolizumab组中有13％的患者和对照组中有16％的患者由于不良事件而停止了所有治疗。

解释

在维拉非尼和cobimetinib的靶向治疗中加入阿扎佐珠单抗是安全和可耐受的，并且可以显着提高BRAF ^V600突变阳性晚期黑色素瘤患者的无进展生存期。

资金

F Hoffmann–La Roche和Genentech。