A prospective phase 2 single-arm study to evaluate the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy in patients with locally advanced esophageal squamous cell carcinoma (Keypoint-1).

Abstract

4088 Background: Esophageal squamous cell carcinoma (ESCC) is the most prevalent esophageal cancer type worldwide with poor prognosis and limited treatment options. Combination immunotherapy and chemotherapy improved the outcomes in patients (pts) with metastatic esophageal cancer. However, the benefit of neoadjuvant immuno-chemotherapy in pts with locally advanced ESCC is unknown. We evaluated the efficacy and safety of neoadjuvant treatment with pembrolizumab plus chemotherapy in pts with locally advanced ESCC. Methods: Eligible pts who were aged 18-80 years with untreated, locally advanced ESCC were enrolled in this single-arm, phase 2 trial at Peking Union Medical College Hospital (China) from July 2020 to April 2022. Pts received neoadjuvant treatment with docetaxel 75 mg/m2, carboplatin area under the curve (AUC) 4-5 (or cisplatin 75 mg/m2), and pembrolizumab 200 mg via IV every 3 weeks. Within 4-8 weeks of completion of neoadjuvant treatment, pts underwent surgery. The primary endpoint was pathological complete response (pCR) rate. The secondary endpoints were treatment-related adverse events and R0 resection rate. The study is registered at ClinicalTrials.gov (NCT05302011). Results: Thirty pts were enrolled (Table). As of December 1, 2023, median follow-up time was 27.9 months. Twenty-eight pts received 4 cycles and 2 received 3 cycles of the neoadjuvant treatment. Six pts did not proceed with surgery because of disease progression (3/6) and personal choice (3/6). Twenty-four pts (24/30, 80%) underwent minimally invasive esophagectomy (MIE). The R0 resection rate was 100%. Perioperative complications were manageable, including anastomotic leakage (2/24, 8.3%) and nerve injury (1/24, 4.2%). Of these 24 pts, 7 (29.2%) achieved pCR and 5 (20.8%) were CAP1 (near complete response, College of American Pathologists protocol). The median disease-free survival (DFS) was 30.6 months. Median overall survival data is not yet available. Grade 3/4 treatment-related adverse events include leukopenia (10, 33.3%), alopecia (3, 10.0%), and pneumonitis (1, 3.3%). One patient died of Stevens-Johnson syndrome. We are conducting molecular and immunological correlative studies to explore potential biomarkers related to the treatment. Conclusions: Neoadjuvant treatment with combination pembrolizumab and chemotherapy demonstrated encouraging anti-tumor activities, good surgical outcomes and a manageable safety profile in pts with locally advanced ESCC, supporting further evaluation in a prospective randomized phase 3 trial. Clinical trial information: NCT05302011 . [Table: see text]