Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage III) esophageal squamous cell carcinoma: a study protocol for a prospective, single-arm, single-center, open-label, phase-II trial (Keystone-001)

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most refractory malignant tumors. Esophageal cancer (EC) is a malignant tumor with a high incidence worldwide, and over 50% of EC cases occur in China. Under the National Comprehensive Cancer Network (NCCN) guidelines, concurrent chemoradiotherapy is the only standard neoadjuvant treatment for locally advanced ESCC. In the first-line treatment of advanced ESCC, the efficacy of immune checkpoint inhibitors (ICIs) combined with systemic chemotherapy is significantly better than that of chemotherapy alone. Paclitaxel and cisplatin (TP), as one of the neoadjuvant chemotherapy regimens for locally advanced ESCC, have been widely used in China in recent years. ICIs combined with TP as neoadjuvant therapy seems promising. Methods:This is an open-label, single-arm, single-center, phase-II trial. Locally advanced resectable (stage III) ESCC patients who have not undergone previous systemic treatments will be enrolled in this study. All the subjects will intravenously receive 3 cycles of pembrolizumab (200 mg) on day 1, paclitaxel (135 mg/m 2 ) on day 2, and cisplatin (20 mg/m 2 ) on days 2-4, every 3 weeks. After an efficacy evaluation, the subjects will undergo Da Vinci robot-assisted radical resection. If the postoperative pathologic results do not reveal a complete response, pembrolizumab will be administrated for at least 6 cycles as an adjuvant therapy with the same usage as before. The primary endpoints are the major pathological response and safety. The ^ ORCID: 0000-0002-2211-5496.

Pembrolizumab combined with paclitaxel and platinum as induction therapy for locally advanced esophageal squamous cell carcinoma: a retrospective, single-center, three-arm study

“…Combination therapy with PD-1 inhibitors results in high rates of surgical conversion; however, further research needs to be conducted to determine the benefits (if any) of PD-1 inhibitors or chemotherapy. According to this study and several previously reported small-sample phase-II prospective studies ( 9 , 16 ), the MPR rate was approximately 60–70% and the pCR rate was approximately 40–50%, which means that 40–50% of the patients did not benefit from treatment with PD-1 inhibitors. The selection of immunotherapy-sensitive populations is a difficult problem in clinical settings.…”

“…In addition, given the recent clinical benefits of paclitaxel in head and neck squamous cell carcinoma and ESCC populations, it has been conjectured that paclitaxel sensitizes tumor cells to T cells, disturbs immunosuppressive mechanisms, and has a strong synergistic effect with PD-1/PD-L1 inhibitors. Thus, in 2 prospective, single-arm, phase-II clinical trials, TD-NICE ( 15 ) and KEYSTONE-001 ( 9 ), researchers used PD-1 inhibitors in combination with paclitaxel and platinum in patients with resectable locally advanced ESCC. The results showed that the R0 resection rates were 97.2% and 100%, the MPR rates were 72% and 72.4%, and the pCR rates were 50% and 41.1%, respectively.…”

“…Pembrolizumab is a humanized monoclonal immunoglobulin G4 antibody that targets against PD-1 and is a PD-1 inhibitor. The KEYSTONE-001 study showed that the use of pembrolizumab in combination with chemotherapy as neoadjuvant therapy for resectable ESCC had a high major pathological response (MPR) rate, pathological complete response (pCR) rate, and R0 resection rate, and acceptable tolerability ( 9 ). In the KEYNOTE-590 study, pembrolizumab plus chemotherapy significantly improved overall survival (OS) and the objective response rate (ORR) compared to chemotherapy alone as a first-line treatment for patients with locally advanced and metastatic ESCC ( 10 ).…”

Evaluation of Clinical and Safety Outcomes of Neoadjuvant Immunotherapy Combined With Chemotherapy for Patients With Resectable Esophageal Cancer

“…Following the footprint of the KEYNOTE-590 trial, numerous clinical trials of immunotherapy-based neoadjuvant treatment for esophageal cancer were registered. 14 , 15 Most of the trials are still ongoing, and only part of their data have been released at academic conferences. However, no systematic review of the outcomes of current neoadjuvant immunotherapy trials for locally advanced ESCC or EAC has been performed.…”

Immune checkpoint inhibitors in esophageal cancer: Clinical development and perspectives

“… 58 Phase II Keystone-001 trial (NCT0438917) and Phase III Keystone-002 trial (NCT04807673) are currently ongoing in China which evaluate the efficacy and safety of pembrolizumab plus chemotherapy (cisplatin plus paclitaxel) over CRT in neoadjuvant setting. 59 , 60 The Phase I PALACE-1 trial, which evaluated the safety of pembrolizumab in combination with neoadjuvant CRT (carboplatin plus paclitaxel with RT), showed high pCR rate of 55.6% and manageable safety, 61 and subsequent Phase II PALACE-2 trial (NCT04435197) is underway. 62 However, the pCR rate of same regimen was poor at 23.1% in the Phase II study (NCT02844075) which conducted in Korea.…”