Pembrolizumab Combined With Neoadjuvant Chemotherapy Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Locally Advanced Oesophageal Squamous Cell Carcinoma: Protocol for a Multicentre, Prospective, Randomized-Controlled, Phase III Clinical Study (Keystone-002)

Abstract

BackgroundTo compare the efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy (neoCT) versus neoadjuvant chemoradiotherapy (neoCRT) followed by surgery for locally advanced resectable oesophageal squamous cell carcinoma (ESCC).MethodsThis study is a multicentre, prospective, randomized-controlled, phase III clinical study. Eligible ESCC (staging: cT1N2M0 or cT2-3N0-2M0 (stage II/III, high-risk lesions in T2N0M0)) patients will be randomly assigned to either the experimental group (pembrolizumab with neoCT, n = 228) or the control group (neoCRT, n = 114) at a ratio of 2:1. Within 4–6 weeks after preoperative therapy, the McKeown procedure will be performed. Patients in the experimental group will also receive pembrolizumab alone as adjuvant therapy after surgery until 1 year or until the radiographically confirmed PD or other condition indicated for premature termination is observed. The primary endpoint is event-free survival (EFS). The secondary endpoints are 1-, 3-, and 5-year overall survival (OS) and disease-free survival (DFS), short-term outcomes, and quality of life.DiscussionThis is the first prospectively randomized controlled trial designed to compare pembrolizumab plus chemotherapy and chemoradiotherapy as neoadjuvant therapy for resectable ESCC. According to our hypothesis, preoperative pembrolizumab combined with chemotherapy will result in a better tumour response and prolong the survival of patients, with acceptable toxicity. This study started in December 2021, and the enrolment time is estimated to be 2 years.Trial RegistrationThis prospective study has been registered at ClinicalTrials.gov (NCT04807673), March 2021.

Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial

“…Due to the short follow-up period, our study has not yet reached the median survival time; however, considering the high pCR rate and the high proportion of patients at the ypT0 stage, we expect that socazolimab plus chemotherapy will promote favorable survival among locally advanced ESCC patients. PD-L1 inhibitor plus chemotherapy may also have several advantages over standard chemoradiotherapy for locally advanced ESCC in neoadjuvant treatment, a potential that may be clarified as the results of several ongoing Phase III trials worldwide-such as KEYSTONE-2, in which pembrolizumab combined with paclitaxel and cisplatin is being evaluated relative to chemoradiotherapy alone-begin to accrue [27].…”

The Molecular Characterization of Genetic Abnormalities in Esophageal Squamous Cell Carcinoma May Foster the Development of Targeted Therapies

“…The phase II KEYSTONE-001 prospective, single-center study investigated pembrolizumab in combination with nC in 43 ESCC patients with stage III, locally advanced tumors and reported a pCRR of 41.4%, with 72.4% of patients achieving a major pathological response [128]. According to the results of this trial, a phase III trial (KEYSTONE-002) was proposed, aiming to compare the efficacy and safety of pembrolizumab combined with nC versus nCRT, followed by surgery for locally advanced ESCCs [129].…”

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.…”