背景：最近關於 EAC 治療的變革性研究支持將 nivolumab 用於新輔助放化療(CRT)(Checkmate577)和 pembrolizumab(P)結合化療治療未經治療的轉移性疾病後的殘留病灶患者(Keynote590)。我們假設術前 P 聯合 CRT 可進一步改善局部晚期 EAC 患者的預後。
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：將符合根治性手術條件的 cT3-4NX 或 T2N1 M0 EAC 或胃食管交界部(GEJ)腺癌患者按 1：1 隨機分為兩組，分別接受全量紫杉醇(T)/卡鉑(C)或 T/C+P 誘導治療。所有患者均接受 CRT，每周 T/C，放療 41.4Gy，共 23 次，P 每 3 周一次。切除後，患者接受 P 治療一年。主要終點是主要病理應答率(MPR)，定義為病理完全應答或接近完全應答(殘留癌<10%)，以 80%範圍和0.1 的單邊顯著性水平來檢測 30%(曆史對照)的 MPR 比例與 47%(術前 P)的替代假設之間的差異。收集組織進行腫瘤免疫微環境(TIME)分析，包括組織整體和單細胞 RNA(ScRNA)表達分析、 DNA 測序和流式細胞術分析。
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.
結果：入選 40 例患者的中位年齡是 68 歲[38~81 歲]，男 32 例，食管/GEJⅠ型 16 例，GEJⅡ /Ⅲ型 24 例。CRT 耐受性良好，無 P 所致的 3-4 級不良反應。顯著的不良反應包括 3-4 級肺炎(13%)、吻合口漏(13%)、感染(35%)。到目前為止，在 31 例可評估的患者中，MPR 率為50.0%(95%CI，32.7%-67.3%)。1 年無病存活率在多藥耐藥組為 100%，無多藥複發組為 31.8%， p=0.002 。食管癌 /GEJ Ⅰ 型癌的 MPR 率明顯高於 GEJ Ⅱ / Ⅲ 型癌 (76.9%vs37.5% ，p=0.03)。>100,000 個腫瘤細胞的 scRNA 序列分析顯示，EAC/GEJ I 型腫瘤有更高的活化樹突狀細胞浸潤(p=0.12)，而 GEJ 腫瘤有更高的活化 B 細胞浸潤(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).
結論：在 EAC 術前 CRT 中添加 P 是安全的，與曆史數據相比與 MPR 率顯著升高相關。我們研究發現，與 GEJ II/III 相比，EAC/GEJ I 型腫瘤中 MPR 顯著增多，這與基線腫瘤免疫微環境的重要差異有關。
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.
