麻省医院癌症研究中心Ryan J. Sullivan团队取得一项新突破。他们研究了阿替唑单抗联合考比替尼和维莫非尼治疗BRAF突变黑色素瘤患者。该成果于2019年发表于国际一流学术期刊《Nature Medicine》杂志上。

BRAF/MEK靶向治疗对支持与PD-1/PD-L1抑制剂结合的肿瘤微环境有影响。本阶段Ib研究（ClinicalTrials.gov，编号NCT01656642）评估了联合阿特珠单抗（抗-PD-L1）和维罗非尼（BRAF抑制剂）或考比替尼（MEK抑制剂）+维莫非尼治疗BRAFV600突变转移性黑色素瘤的安全性和抗肿瘤活性。联合应用阿特珠单抗+考比替尼+维罗非尼的三联疗法，在与考比替尼+维罗非尼的28天导入期后，具有重大但可控的毒性。探索性生物标记数据表明，考比替尼+维罗非尼的导入与CD4⁺T辅助细胞的增殖有关，但与T调节细胞的增加无关，正如维罗非尼仅导入期所观察到的。确定的客观缓解率为71.8%（95%置信区间55.1-85.0）。随访29.9个月后，39.3%的患者的平均缓解时间估计为17.4个月（95%置信区间10.6-25.3）。正在进行第三阶段试验的进一步调查。

据介绍，黑色素瘤治疗在过去十年中取得了进展，包括针对程序性死亡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，以及针对BRAFV600突变患者的BRAF和/或MEK的小分子抑制剂的治疗方法。

附：英文原文

Title: Atezolizumab plus cobimetinib and vemurafenib in BRAF -mutated melanoma patients

Author: Ryan J. Sullivan, Omid Hamid, Rene Gonzalez, Jeffrey R. Infante, Manish R. Patel, F. Stephen Hodi, Karl D. Lewis, Hussein A. Tawbi, Genevive Hernandez, Matthew J. Wongchenko, YiMeng Chang, Louise Roberts, Marcus Ballinger, Yibing Yan, Edward Cha, Patrick Hwu

Issue&Volume: Volume 25 Issue 6，June 2019

Abstract: 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 BRAFV600 mutations. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors. 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 BRAFV600-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 run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1–85.0). The estimated median duration of response was 17.4months (95% confidence interval 10.6–25.3) with ongoing response in 39.3% of patients after 29.9months of follow-up. Further investigation in a phase III trial is underway.

DOI: 10.1038/s41591-019-0474-7

Source: https://www.nature.com/articles/s41591-019-0474-7