医脉通编译，转载请务必注明出处
2016年6月3-7日，一年一度的美国临床肿瘤学会（American Society of Clinical Oncology，ASCO）年会将在芝加哥举办。6月5日上午的消化系统（结直肠）肿瘤口头报告专场上，一项摘要号为3502的研究，对cobimetinib（cobi）和atezolizumab联合方案治疗结直肠癌的临床活性和安全性进行评估，医脉通整理如下：
Atezolizumab（atezo；MPDL3280A）是一种基因工程抗体，可以抑制PD-L1与其受体PD-1和B7.1结合。Atezo已经证明在多种人类肿瘤类型中存在单药治疗活性。然而，在微卫星稳定（MSS）的CRCs患者中的响应率较其他适应症偏低。在临床前模型中，MEK靶向抑制会导致MHC I对肿瘤细胞作用上调，诱导瘤内T-细胞浸润同时增强抗-PD-L1活性。因而，研究人员开展了一项Ib期研究，观察cobi（MEK抑制剂）和atezo对晚期实体瘤患者的效果。
Cobi每日一次从20mg到60mg逐渐增加（持续21天/7天停止），联合atezo 800mg IV q2w。肿瘤特异性扩张队列，包括KRAS-突变的CRC，同时对实体瘤的连续活检队列通过MTD确定揭示。分别对安全性，耐受性和根据RECIST v1.1证实的ORR进行评估。
截止到2015年10月12日，23例CRC（22例KRAS 突变，1例WT）患者在增量和扩张期间入组。没有观察到剂量限制的毒性，扩张发生在atezo 800mg q2w和cobi 60mg时。在CRC患者中，安全性的中位随访时间是3.78个月（范围，1.1-11.7）。最常见的治疗相关AEs包括腹泻（69.6%），乏力（52.2%），痤疮性皮炎（43.5%），皮疹（34.8%），斑丘疹（26.1%），瘙痒（26.1%）和恶心（26.1%）。治疗相关的G3-4 AEs的发生率是34.8%。在≥2例患者中，仅与治疗相关的G3-4 AE是腹泻（8.7%）。没有G5 AEs报道。ORR为17%（4例PR，5例SD）。3种响应正在进行中（截止到数据采集时间范围，4.0-7.7个月）。3例应答者是错配修复缺陷，1例未知。响应与基线PD-L1表达无关。来自连续活检队列的结果显示增强的PD-L1表达上调，CD8 T细胞浸润，同时MHC I对治疗产生表达，这提供了联合方案的基本原理。
综上所述，在结直肠癌患者中，cobi和atezo联合方案在最大给药剂量时耐受性良好。这些结果表明，MSS CRC患者可以对cobi和atezo联合方案产生应答，并且支持联合方案的继续评估。临床试验信息：NCT01988896。
会议专题》》》2016年ASCO年会专题报道
原文摘要：
Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC).（Abstract 3502）
Authors：Johanna C. Bendell, Tae Won Kim,et al
Session Type：Oral Abstract Session
Background: Atezolizumab (atezo; MPDL3280A) is an engineered antibody that inhibits binding of PD-L1 to its receptors, PD-1 and B7.1. Atezo has demonstrated monotherapy activity in a multitude of human tumor types. However, response rates in microsatellite stable (MSS) CRCs have been lower than in other indications. In preclinical models, targeted inhibition of MEK leads to upregulation of MHC I on tumor cells, induces intratumoral T-cell infiltration and enhances anti-PDL1 activity. We therefore conducted a Phase Ib study combining cobi (MEK inhibitor) and atezo in patients (pts) with advanced solid tumors.
Methods: Cobi was escalated from 20 to 60 mg daily (21 days on/7 days off) and combined with atezo 800 mg IV q2w. Tumor-specific expansion cohorts, including KRAS-mutant CRC, and serial biopsy cohorts in solid tumors were opened upon determination of the MTD. Safety, tolerability and confirmed ORR by RECIST v1.1 were evaluated.
Results: As of October 12, 2015, 23 CRC (22 KRAS mutant, 1 WT) pts were enrolled during escalation and expansion. No dose-limiting toxicities were observed, and expansion occurred at atezo 800 mg q2w and cobi 60 mg. Median follow-up for safety in CRC pts was 3.78 mo (range, 1.1-11.7). The most common treatment-related AEs included diarrhea (69.6%), fatigue (52.2%), dermatitis acneiform (43.5%), rash (34.8%), maculopapular rash (26.1%), pruritus (26.1%) and nausea (26.1%). Incidence of treatment-related G3-4 AEs was 34.8%. The only treatment-related G3-4 AE in ≥ 2 pts was diarrhea (8.7%). No G5 AEs were reported. The ORR was 17% (4 PR, 5 SD). Three responses were ongoing (range, 4.0 to 7.7 mo at time of data cutoff). Three responders were mismatch repair-proficient, and 1 was unknown. Response was not associated with baseline PD-L1 expression. Results from the serial biopsy cohort showed enhanced PD-L1 upregulation, CD8 T-cell infiltration and MHC I expression on treatment, providing mechanistic rationale for the combination.
Conclusions: The combination of cobi and atezo in CRC is well tolerated at the maximum administered doses. These results show that pts with MSS CRC can respond to the combination of cobi and atezo, and provide support for continued evaluation of the combination. Clinical trial information: NCT01988896
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