The safety and efficacy of neoadjuvant PD-1 inhibitor with chemotherapy for locally advanced esophageal squamous cell carcinoma

Abstract

Background: Neoadjuvant therapy followed by esophagectomy has been recognized as an effective treatment for locally advanced esophageal cancer, though still has a dismal prognosis. Antibodies against programmed death 1 (PD-1) protein improve survival in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) compared with chemotherapy in second-line therapy. However, neoadjuvant PD-1 inhibitor combined with chemotherapy has not been tested in locally advanced ESCC.We conducted this study to evaluate the efficacy and safety of pd-1 inhibitor in neoadjuvant chemotherapy.Methods: In this study, we administered 28 adults with untreated, surgically resectable locally advanced ESCC. PD-1 inhibitor with chemotherapy [albumin paclitaxel 100 mg/m 2 on days 1 and 8 + carboplatin with an area under the curve (AUC) of 5 on day 1] were administered every 3 weeks intravenously, and surgery was performed approximately 3-5 weeks after the second dose. The primary purpose of the study was to evaluate the feasibility and safety of this regimen.Results: In all, 28 locally advanced ESCC patients were enrolled, 27 patients received surgery, 9 (33.3%) patients' postoperative pathological specimens suggested pCR, and 11 (40.7%) patients' primary tumor suggested complete response. Neoadjuvant PD-1 inhibitor with chemotherapy had an acceptable side-effect profile, 26 patients' tumors were completely resected (96.3% were R0). According to the RESIST v.1.1, the response in all 27 patients was evaluated by a computed tomography (CT) scan before surgery, showing 12 patients with complete response (CR), 12 with partial response (PR), and 3 with stable disease (SD). For surgical procedures, 15 (55.6%) patients underwent minimal invasive surgery, 4 (14.8%) underwent right transthoracic open esophagectomy, and 8 (29.6%) underwent hybrid approaches. Conclusions:The novel treatment of PD-1 inhibitor with chemotherapy in the neoadjuvant setting for locally advanced ESCC produced satisfactory outcomes: an unprecedentedly high pCR rate for neoadjuvant chemotherapy, a high R0 resection rate, and a low-toxicity profile were achieved. The long-term efficiency of this novel treatment and the validity of the present findings should be confirmed with longer follow-up and prospective comparative trials.

Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma

“…Another study recently presented at ESMO congress 2020 employed a similar regimen comprising nab-paclitaxel/S1 plus toripalimab for preoperative treatment of a similar population, but their pCR rate (16.67%) was much lower than ours, which could possibly be explained by the fact that their cohort received only two courses of treatment before surgery while our entire cohort was subjected to 3 cycles of treatment (24). In another study conducted by Shen et al, the pCR elicited by neoadjuvant PD-1 plus chemotherapy was 33%, which was exactly the same as ours (25). Actually, our study does differ from theirs.…”

Neoadjuvant camrelizumab plus chemotherapy in treating locally advanced esophageal squamous cell carcinoma patients: a pilot study

“…Regarding pathological response, previous studies exhibited that an R0 resection rate was 96.3% and a pCR rate was 33.3% in patients with locally advanced ESCC receiving neoadjuvant nivolumab and pembrolizumab plus chemotherapy [ 9 ]. Likewise, in another study, pCR rate was 34.21%; meanwhile, R0 resection rate was 92.11% in locally advanced ESCC patients receiving neoadjuvant camrelizumab and pembrolizumab plus chemotherapy [ 25 ].…”

“…PD-1 inhibitor, as a novel developed immune therapy, blocks the PD-1/PD-L1 linkage and has been widely applied in numerous carcinomas [ 12 , 14 ]. In addition, in locally advanced ESCC, nivolumab and pembrolizumab combination with chemotherapy was recently used for neoadjuvant therapy, which exhibited an acceptable therapeutic response, progression-free survival (PFS), and overall survival (OS) [ 9 ]. Camrelizumab, a domestic product developed in China, is a novel IgG4-kappa anti-PD-1 inhibitor that has been used for treatment of a variety of malignancies, such as refractory classical Hodgkin’s lymphoma and gastric or gastroesophageal junction adenocarcinoma [ 15 , 16 ].…”

Neoadjuvant sintilimab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: a single-arm, single-center, phase 2 trial (ESONICT-1)

“…Although immunotherapy has showed promising results in advanced ESCC, however, the efficacy and safety of combination of PD-1 or PD-L1 with chemotherapy for locally ESCC. Recently, a retrospective analysis showed that neoadjuvant immunochemotherapy (nICT) for locally advanced ESCC has promising outcomes including: a high pathological complete response (pCR) rate (9/27, 33.3%), high microscopically margin-negative (R0) resection rate (26/27, 96.3%), and a low-toxicity profile (2/28, 7.1%, ≥ grade 3) (14). Based on the above compelling rationale, the role of PD-1 or PD-L1 inhibitors combined with chemotherapy in neoadjuvant treatment for locally advanced ESCC has gained much attention (e.g., NCT04654403, NCT04506138, NCT03946969, NCT04177797, NCT04280822).…”