Abstract：
BRAF/MEK targeted therapies and immune checkpoint inhibition have dramatically improved disease control and survival of patients with advanced melanoma. However, most patients do not have durable benefit from either of these therapies. BRAF targeted therapy often has a limited duration of efficacy due to the development of resistance. Pre-clinical data suggest that one possible way to overcome resistance to BRAF/MEK targeted therapy may be the addition of CSF1R inhibition. In this phase I/II study we evaluated the safety and efficacy of LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody in combination with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to discontinuation of the development program for LY3022855 by the sponsor. Between August 2017 and May 2018 five pts were enrolled. Three patients experienced grade 3 events that were deemed possibly related to LY3022855. There were no grade 4 or grade 5 events related to LY3022855. One of the 5 patients had a complete response (CR), whereas the other 4 had progressive disease (PD). Median progression free survival was 3.9 months (90% CI: 1.9-37.2 mos). CSF1R inhibition with LY3022855 in combination with BRAF/MEK inhibition with vemurafenib and cobimetinib was difficult to tolerate in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.
摘要：
BRAF/MEK靶向治疗和免疫检查点抑制已显著改善晚期黑色素瘤患者的疾病控制和存活率。然而,大多数患者都没有从这两种疗法中获得持久的益处.由于耐药性的发展,BRAF靶向治疗通常具有有限的疗效持续时间。临床前数据表明,克服对BRAF/MEK靶向治疗的抗性的一种可能方法可能是添加CSF1R抑制。在这项I/II期研究中，我们评估了抗集落刺激因子-1受体（CSF-1R）单克隆抗体LY3022855与BRAF抑制剂vemurafenib和MEK抑制剂cobimetinib在BRAFV600E/K突变转移性黑色素瘤患者中的安全性和有效性。由于申办方终止了LY3022855的开发计划，该试验提前终止。在2017年8月至2018年5月期间，有5名受试者参加。三名患者经历了被认为可能与LY3022855相关的3级事件。没有与LY3022855相关的4级或5级事件。5例患者中有1例完全缓解（CR），而其他4人患有进行性疾病（PD）。中位无进展生存期为3.9个月(90%CI:1.9-37.2个月)。LY3022855的CSF1R抑制与Vemurafenib和cobimetinib的BRAF/MEK抑制组合在小黑色素瘤群体中难以耐受。在这个小样本患者中观察到一个反应，表明这种组合可能值得进一步探索。
