小柯机器人

德国汉诺威医学院Ralf Gutzmer团队分析了Atezolizumab+vemurafenib+cobimetinib一线治疗不可切除的BRAF ^V600突变阳性黑色素瘤的效果。该成果发表在2020年6月13日出版的《柳叶刀》上。

IMspire150旨在评估一线联合应用BRAF+MEK抑制剂和免疫检查点治疗BRAF ^V600突变阳性晚期或转移性黑色素瘤的效果。

IMspire150是一项随机、双盲、安慰剂对照的3期临床研究，在20个国家/地区的112个研究所进行。2017年1月13日至2018年4月26日，研究组招募了514例无法切除的IIIc-IV期、BRAF V600突变阳性的黑色素瘤患者，将其按1：1随机分组，其中256例接受atezolizumab+vemurafenib+cobimetinib治疗（Atezolizumab组），258例接受安慰剂+vemurafenib+cobimetinib治疗（对照组），每4周1个疗程。在第1个疗程中，所有患者仅接受vemurafenib+cobimetinib治疗；从第2周期开始添加atezolizumab或安慰剂。

中位随访18.9个月后，atezolizumab组中研究者评估的无进展生存期为18.9个月，显著长于对照组（10.6个月）。Atezolizumab组和对照组的常见治疗相关不良事件发生率超过了30%，其中Atezolizumab组血肌酐磷酸激酶升高、腹泻、皮疹、关节痛、发热、丙氨酸转氨酶增加和脂肪酶增加的发生率分别为51.3%、42.2%、40.9%、39.1%、38.7%、33.9%和32.2%，对照组则分别为44.8%、46.6%、40.9%、28.1%、26.0%、22.8%和27.4%。Atezolizumab组中13%的患者和对照组中16%的患者因不良事件而停止了所有治疗。

总之，Atezolizumab+vemurafenib+cobimetinib治疗BRAF ^V600突变阳性晚期黑色素瘤患者安全耐受，且显著延长了无进展生存期。

附：英文原文

Title: Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial

Author: Ralf Gutzmer, Daniil Stroyakovskiy, Helen Gogas, Caroline Robert, Karl Lewis, Svetlana Protsenko, Rodrigo P Pereira, Thomas Eigentler, Piotr Rutkowski, Lev Demidov, Georgy Moiseevich Manikhas, Yibing Yan, Kuan-Chieh Huang, Anne Uyei, Virginia McNally, Grant A McArthur, Paolo A Ascierto

Issue&Volume: 2020/06/13

Abstract: 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.

DOI: 10.1016/S0140-6736(20)30934-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30934-X/fulltext

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