Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients
Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients
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DOI：
10.1038/s41591-019-0474-7
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发表时间：
2019-06-01
期刊：
影响因子：
82.9
通讯作者：
Hwu, Patrick
中科院分区：
文献类型：
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作者：
Sullivan, Ryan J.;Hamid, Omid;Hwu, Patrick
黑色素瘤治疗在过去十年中取得了进展，靶向程序性死亡1（PD-1）或其配体（PD-L1）和细胞毒性T淋巴细胞相关抗原4的免疫检查点抑制剂以及BRAF（V600）突变患者亚组的BRAF和/或MEK小分子抑制剂的开发和批准（1-9）。BRAF/MEK靶向治疗对肿瘤微环境有影响，支持其与PD-1/PD-L1抑制剂联合使用（10-20）。这项Ib期研究（ClinicalTrials.gov，编号NCT 01656642）评估了atezolizumab（抗PD-L1）与vemurafenib（BRAF抑制剂）或cobimetinib（MEK抑制剂）+ vemurafenib联合治疗BRAF（V600）突变转移性黑色素瘤患者的安全性和抗肿瘤活性。在cobimetinib + vemurafenib的28天导入期后，atezolizumab + cobimetinib + vemurafenib的三联治疗具有显著但可管理的毒性。探索性生物标志物数据显示，cobimetinib + vemurafenib导入期与增殖的CD 4（+）T辅助细胞增加相关，但与仅vemurafenib导入期观察到的T调节细胞增加无关。确认的客观缓解率为71.8%（95%置信区间55.1-85.0）。估计的中位缓解持续时间为17.4个月（95%置信区间10.6-25.3），随访29.9个月后，39.3%的患者持续缓解。第三阶段试验的进一步调查正在进行中。
Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF(V600) mutations(1-9). BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors(10-20). This phase Ib study (ClinicalTrials.gov, number NCT01656642) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAF(V600)-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4(+) T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only runin period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.