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2016ESMO世界胃肠肿瘤大会（GI）于6月29日至7月2日在西班牙巴塞罗那召开。ESMO GI涉及胃肠道的各个部分，涵盖了众多常见和不常见肿瘤的筛查、诊断和治疗进展，是胃肠恶性肿瘤领域的世界级盛会。
第18届 ESMO GI大会最新突破性研究（Late Breaking Abstracts）LBA01值得关注。微卫星高度不稳定（Microsatellite instability-high, MSI-H）的结直肠癌突变负荷较高，对PD-L1/PD-1抑制剂治疗反应性好于微卫星稳定（MSS）类型。尽管MEK抑制剂在mCRC中活性不高，但临床前研究发现，MEK抑制剂有促使T细胞（如CD8+）进入肿瘤组织的作用，联合PD-L1/PD-1抑制剂可有持续性的肿瘤退缩。
来自美国、韩国、澳大利亚等国家研究者开展了一项Ⅰ期研究，评估抗PD-L1免疫药物atezolizumab联合MEK抑制剂cobimetinib治疗微卫星不稳定的转移性结直肠癌（mCRC）的潜在疗效。
主要研究内容
该研究为Ⅰb期剂量爬坡和扩张研究，治疗方案为cobi于atezo联合。
◆cobi治疗剂量梯度20、40、60mg/d；21d治疗/7d休息。
◆Atezo固定剂量800mg，两周一次。
◆最后扩张剂量为cobi 60mg+ atezo 800mg。
根据RECIST v1.1标准，评估由研究者评价的联合用药安全性和有效性。截至2016年10月12日，研究共纳入23名经治的mCRC患者，包括22例KRAS突变型和1例KRAS突变型，但没有针对MSI-H状态和PD-L1表达进行选择。
主要结果
在治疗毒性方面：
◆治疗过程中无剂量限制性毒性（DLT）和治疗相关4-5级不良反应事件（AE）发生。
◆治疗相关3级AE见于8名患者（35%）。
◆最常见的AE为皮疹、腹泻和乏力。
在治疗有效性方面：
中位的安全随访时间为3.78个月。
◆所有患者中，4例达到部分缓解（PR），5例达到疾病稳定（SD）。
◆治疗有效持续时间从4.0个月到7.7个月不等，在数据截止时仍有3/4的患者处于有效阶段。
◆研究未发现基线PD-L1表达与联合治疗活性之间存在关系。对治疗有反应的患者中，也没发现MSI-H的情况。
◆局部检测发现，3例达到PR的患者为MSS或低MSI。生物标记物数据显示cobi+ atezo联合后免疫反应增强。
结论
Ⅰb期研究结果显示，当与MEK抑制剂联合使用后，抗PD-L1免疫在MSS mCRC中也有一定的活性。Cobimetinib联合Atezolizumab是一种合理且耐受良好的治疗方案，未来还需要在MSS mCRC中进一步验证。
到目前为止，结直肠癌的免疫治疗仅在微卫星高度不稳定的患者中表现出治疗活性，但这部分群体只占5%。而其他约95%的患者为MSS类型，对PD-1/PD-L1抑制剂几乎不敏感。该研究为那些曾被认为不是免疫治疗受众的结直肠癌患者带来了机会。研究者正在开展一项Ⅲ期临床研究，比较Cobimetinib联合Atezolizumab与标准治疗在难治的转移性结直肠癌患者中的疗效差异。
摘要阅读：
LBA-01
Safetyand efficacy of cobimetinib (cobi) and atezolizumab (atezo) in a Phase 1b studyof metastatic colorectal cancer (mCRC)
Background: Microsatelliteinstability-high (MSI-H) colorectal cancers are associated with high mutationburden and are responsive to PD-L1/PD-1 blockade. However, the majority of mCRCpts are MSS and have lower response rates to PD-L1/PD-1 blockade. Although MEKinhibition has minimal activity in mCRC, preclinical models demonstrateintratumoral T cell accumulation with MEK inhibition and durable tumorregression when combined with anti-PDL1. Therefore, we evaluated thecombination of cobi (MEK inhibitor) and atezo (anti-PDL1) in patients (pts)with mCRC.
Methods: A Phase 1b dose escalationand expansion study treated advanced solid tumor pts with 20, 40, and 60mg cobidaily (21d on / 7d off) in combination with a fixed dose of 800mg atezo IV q2w.The expansion dose was 60mg cobi and 800mg atezo. Safety and preliminaryinvestigator-assessed efficacy by RECIST v1.1 were assessed. As of Oct 12,2015, the study enrolled 23 previously treated mCRC pts, including 22 KRASmtand 1 KRASwt, without selection for MSI-H status or PD-L1 expression.
Results: No DLTs,treatment-related G4, or any G5 AEs were identified. G3 AEs related to studytreatment were reported in 8 pts (35%). The most common AEs of any grade wererash, diarrhea, and fatigue. The median safety follow-up was 3.78 mo (range,1.1-11.7). There were 4 confirmed PRs (17%) and 5 SDs. Duration of responseranged from 4.0 to 7.7 mo and responses were ongoing in 3 of 4 pts at time ofdata cutoff. Baseline PD-L1 expression did not correlate with activity. NoMSI-H pts were identified among the responders. 3 PRs were MSS or MSI-low by localtesting. The MSI status of 1 PR was unknown. Biomarker data suggest enhancedimmune response with the combination.
Conclusions: These early resultsshow that anti-PDL1 immunotherapy can be active in the broader MSS mCRCpopulation when combined with MEK inhibition. Cobi and atezo is a rational andtolerated regimen to investigate further in MSS mCRC. NCT01988896
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文献：Johanna Bendell.et al.Ann Oncol (2016) 27 (suppl 2): ii140
