A phase II study of pembrolizumab plus chemotherapy with short-course radiotherapy as induction treatment for unresectable locally advanced esophageal squamous cell carcinoma: PALADIN trial.

BACKGROUND

Definitive chemoradiotherapy is a standard treatment for unresectable locally advanced esophageal squamous cell carcinoma (LAESCC), but complete response rates remain 15%-25%, and median overall survival (OS) is 13-14 months. More effective strategies are needed.

TRIAL

DESIGN

The PALADIN trial is a nonrandomized, single-arm phase II study evaluating the efficacy and safety of induction pembrolizumab plus chemotherapy with short-course radiotherapy (SCRT) in unresectable LAESCC. Eligible patients have confirmed squamous cell carcinoma with T3br-T4b (Japanese Classification of Esophageal Cancer, 12th edition). Treatment consists of pembrolizumab 200 mg and cisplatin 80 mg/m2 IV day 1, and continuous 5-fluorouracil 800 mg/m2/day on days 1-5 every 3 weeks for four cycles, with SCRT of 25 Gy in five fractions on days 8-12 of cycle 1. After study treatment, patients eligible for R0 resection will undergo subtotal esophagectomy with 2- or 3-field lymph node dissection. The primary endpoint is 2-year OS. Exploratory endpoints include analysis of molecular residual disease using a personalized, tumor-informed circulating tumor DNA assay (SignateraTM, Natera, Inc., Austin, TX) and translational studies. Planned enrollment is 35 patients, assuming a threshold 2-year OS rate of 30% and an expected rate of 50%, with one-sided α of 0.10 and 80% power.