durvalumab（抗 PD-L1）联合 trametinib（MEKi）治疗微卫星稳定（MSS）转移性结直肠癌（mCRC）的 II 期研究。

BACKGROUND: Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells. METHODS: Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4. RESULTS: Twenty nine treated pts include 48% females, median age 48 years (range 28-75), and median prior therapies 2 (range 1-5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1-9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively). CONCLUSIONS: T+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials. TRIAL REGISTRATION NUMBER: NCT03428126.

背景：单药免疫检查点阻断对微卫星稳定（MSS）转移性结直肠癌（mCRC）患者无效。本研究旨在通过成功地启动和激活 T 细胞，来探究曲美替尼（T）联合度伐利尤单抗（D）能否改变免疫肿瘤微环境（TME）。

方法：开放标签、单中心、Ⅱ期临床试验，主要终点为难治性 MSS mCRC 患者 T+D 联合治疗的免疫相关缓解率（NCT03428126）。T 起始剂量为 2mg/天，口服，在 D 治疗前 1 周开始使用，D 每 4 周静脉注射 1500mg。采用 Simon 两阶段设计入组 29 例患者，要求在 2 例或更多患者中出现应答才能进入第二阶段。在基线（BL）和治疗早期（第 4 周）采集肿瘤活检。

结果：29 例治疗患者包括 48%的女性，中位年龄为 48 岁（范围 28-75 岁），中位既往治疗线数为 2 线（范围 1-5 线）。无任何等级（G）4 或 5 级治疗相关不良事件（TRAE）。最常见的任何等级 TRAE 是痤疮样皮疹，17%为 G3 级。29 例患者中，1 例有确认的部分缓解（PR），持续 9.3 个月（mo），总缓解率为 3.4%。7 例患者疾病稳定（SD），5 例患者（1 例 PR，4 例 SD）的总癌胚抗原 ng/mL 下降（最佳百分比下降分别为 94%、95%、42%、34%和 22%）。中位无进展生存期为 3.2 个月（范围 1.1-9.3 个月）。3 例同时有肝和肺转移的患者在肺转移中观察到了不一致的反应，但肝转移中无临床获益。BL 和 4 周 OT 肿瘤组织流式细胞术比较显示 T 细胞浸润无变化，但 CD8 T 细胞上 PD-1 和 Tim3 的表达上调。然而，PD-1 和 Tim3 作为单一标志物和共表达标志物的表达在 OT 时观察到比 BL 时增加（p=0.03、p=0.06 和 p=0.06）。

结论：T+D 在难治性 MSS mCRC 患者中表现出可接受的耐受性。研究第一阶段的缓解率未达到进入第二阶段的疗效标准。转移性疾病的特定部位可能会影响新型免疫治疗联合试验的结果。

试验注册编号：NCT03428126。