背景：最近关于 EAC 治疗的变革性研究支持将 nivolumab 用于新辅助放化疗(CRT)(Checkmate577)和 pembrolizumab(P)结合化疗治疗未经治疗的转移性疾病后的残留病灶患者(Keynote590)。我们假设术前 P 联合 CRT 可进一步改善局部晚期 EAC 患者的预后。

Background: Recent transformative studies in the treatment of EAC support adjuvant nivolumab for patients with residual disease following neoadjuvant chemoradiotherapy (CRT) (Checkmate 577) and pembrolizumab (P) with chemotherapy in untreated metastatic disease (Keynote 590). We hypothesized that pre-operative P combined with CRT can further improve outcomes in patients with locally advanced EAC.

方法：将符合根治性手术条件的 cT3-4NX 或 T2N1 M0 EAC 或胃食管交界部(GEJ)腺癌患者按 1：1 随机分为两组，分别接受全量紫杉醇(T)/卡铂(C)或 T/C+P 诱导治疗。所有患者均接受 CRT，每周 T/C，放疗 41.4Gy，共 23 次，P 每 3 周一次。切除后，患者接受 P 治疗一年。主要终点是主要病理应答率(MPR)，定义为病理完全应答或接近完全应答(残留癌<10%)，以 80%范围和0.1 的单边显著性水平来检测 30%(历史对照)的 MPR 比例与 47%(术前 P)的替代假设之间的差异。收集组织进行肿瘤免疫微环境(TIME)分析，包括组织整体和单细胞 RNA(ScRNA)表达分析、 DNA 测序和流式细胞术分析。

Methods: Patients with cT3-4Nx or T2N1 M0 EAC or gastroesophageal junction (GEJ) adenocarcinoma eligible for curative surgery were randomized (1:1) to receive either full-dose paclitaxel (T)/ carboplatin (C) or T/C + P induction therapy. All patients then received CRT with weekly T/C, RT 41.4Gy in 23 fractions, and P every 3 weeks. Following resection, patients received P for one year. The primary endpoint is rate of major pathologic response (MPR), defined as pathologic complete response or near complete response ( < 10% residual cancer), with 80% power and 0.1 one-sided significance level to detect the difference between a MPR proportion of 30% (historical control) and an alternative hypothesis of 47% (with preoperative P). Tissue was collected for tumor immune microenvironment (TIME) analysis including bulk and single cell RNA(scRNA) expression analysis, DNA sequencing, and flow cytometry.

结果：入选 40 例患者的中位年龄是 68 岁[38~81 岁]，男 32 例，食管/GEJⅠ型 16 例，GEJⅡ /Ⅲ型 24 例。CRT 耐受性良好，无 P 所致的 3-4 级不良反应。显著的不良反应包括 3-4 级肺炎(13%)、吻合口漏(13%)、感染(35%)。到目前为止，在 31 例可评估的患者中，MPR 率为50.0%(95%CI，32.7%-67.3%)。1 年无病存活率在多药耐药组为 100%，无多药复发组为 31.8%， p=0.002 。食管癌 /GEJ Ⅰ 型癌的 MPR 率明显高于 GEJ Ⅱ / Ⅲ 型癌 (76.9%vs37.5% ，p=0.03)。>100,000 个肿瘤细胞的 scRNA 序列分析显示，EAC/GEJ I 型肿瘤有更高的活化树突状细胞浸润(p=0.12)，而 GEJ 肿瘤有更高的活化 B 细胞浸润(p=0.02)。

Results: From 8/4/17 to 10/26/20, 40 patients were enrolled: median age 68 [38-81], male 32, esophagus/GEJ type I (n = 16), GEJ II/III (n = 24). CRT was well tolerated, with no grade 3-4 adverse events attributed to P. Notable toxicity included grade 3-4 pneumonitis (13%), anastomotic leak (13%), infection (35%). In 31 evaluable patients to date, the MPR rate was 50.0% (95% CI, 32.7%-67.3%). 1-yr disease free survival was 100% for patients with MPR vs. 31.8% without MPR, p = 0.002. Esophageal/GEJ type I cancers had a significantly higher MPR rate when compared with GEJ type II/III (76.9% vs 37.5%, p = 0.03). scRNA seq on > 100,000 tumor cells revealed EAC/GEJ type I had higher infiltration of activated dendritic cells (p = 0.12), whereas GEJ tumors have significantly higher infiltration of activated B cells (p = 0.02).

结论：在 EAC 术前 CRT 中添加 P 是安全的，与历史数据相比与 MPR 率显著升高相关。我们研究发现，与 GEJ II/III 相比，EAC/GEJ I 型肿瘤中 MPR 显著增多，这与基线肿瘤免疫微环境的重要差异有关。

Conclusions: The addition of P to preoperative CRT for EAC is safe and associated with a significantly higher MPR rate compared to historical data. We found MPR to be significantly enriched in EAC/GEJ type I tumors compared with GEJ II/III, associated with important differences in the baseline tumor immune microenvironment.