DISCUSSION
DFS, NSCLC, toxicity, toxicities, adenocarcinoma of distal esophagus, esophageal and GEJ cancer, adenocarcinoma, PD‐L1
DISEASE, CROSS, ADENOCARCINOMA, NSCLC, DISEASE CHARACTERISTIC
Surgical resection reaction is the only potentially curative intervention for locally advanced adenocarcinoma of esophagus, gastroesophageal junction (GEJ), and stomach. Results from various studies have demonstrated the benefits of perioperative treatment including neoadjuvant and adjuvant chemotherapy or chemoradiation; however, there is lack of universally accepted standard based on several factors: heterogeneity of histopathological and biological disease characteristics, local‐regional versus systemic benefits from chemoradiation, and tolerability and toxicity of systemic cytotoxic chemotherapy regimens.The data of the neoadjuvant chemoradiation in esophageal and GEJ cancer (Cross Trial) showed that the histopathologic type of adenocarcinoma (HR 0.741, 95% CI 0.536–2.024, The perioperative triple agent combination showed evidence of survival benefit from original MAGIC trial of ECF (epirubicin, cisplatin, and 5‐flurourcil) compared with surgery alone (5‐year survival rates, 36% vs. 23%),The significance of pathologic response from the perioperative treatment and its impact on the survival outcome has been established in several studies.This is the first phase II study demonstrating the benefits of the combination of ICI, pembrolizumab, with the cytotoxic chemotherapy regimen, mFOLFOX, at the perioperative setting in patients with locally advanced adenocarcinoma of distal esophagus, GEJ, and stomach.The study population represents the clinical setting with median age of 65 (range 44–86) with more male (30/37) patients. Majority of patients had high degree of locally advanced disease with 25/37 with ≥TThe study met its end points with 21% ypCR (TRS 0, 95% CI: 0.08–0.40) in the primary lesions, and 90% ypRR (TRS ≤2, 95% CI: 0.73–0.98) for patients who underwent curative surgical resection. With the median follow‐up of 36.3 months (12.7–52.2 months), three patients had recurrent/metastatic disease, and one died, the remaining patients (23/26) are all free of disease. The 3 years DFS is 88.5% and 3 years OS is 92.3%. The toxicity data is also encouraging with no unexpected toxicities, and the combination regimen was fairly tolerable in all eligible patients. There were no patients dropping out from the study in either preoperative or postoperative setting because of toxicity. All eligible patients finished planned combination therapy. The mild dose modifications were reported in 32% of patients during the neoadjuvant period; and 42% during the adjuvant period.As a part of the study design, we analyzed the expression of ICI treatment related markers PD‐L1, CD8, and CD20 in the real time before and after preoperative therapy. Several large phase II studies indicated that the PD‐L1 expression level is significant for the anti‐PD‐1/PD‐L1 efficacy at the metastatic setting (12,13). A cohort study with 179 NSCLC quantitative immunofluorescence panels to determine the association of major TILs subpopulations, CD8+, CD4+, CD20+ B cells; PD‐1, LAG3, and TIM‐3T cells with outcomes. The result showed higher density of stromal CD8+ cells was associated the longer survival significantly, and more effect in PD‐L1 cases.There are some limitations for this study and those includes the single arm design and being a single institution trial. In addition, the data analyses were not based on the intention‐to‐treat population (ITT), therefore, the results and data, especially the efficacy should be cautiously interpreted. A large, randomized phase II study with the similar concept and setting, KEYNOTE‐585 (study of the neoadjuvant or adjuvant chemotherapy [cisplatin + 5 FU or capecitabine] ± pembrolizumab in patients with gastric or GEJ adenocarcinoma, NCT03221426), is on‐going, which will likely confirm and validate the results.In conclusion, the pembrolizumab and mFOLFOX combination as perioperative therapy in patients with locally advanced adenocarcinoma of distal esophagus, GEJ, and stomach is effective with very encouraging results including favorable pathologic response and impressive long‐term survival rate. Preoperative ICI + chemotherapy increase immune response and enhances adjuvant treatment benefits and thereafter the overall DFS and OS. Therefore, the preoperative ICI + chemotherapy should be considered as the standard with further confirmation.