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.

Abstract

TPS471 Background: Definitive chemoradiotherapy is one of the standard treatments for unresectable locally advanced esophageal squamous cell carcinoma (ESCC). However, the complete response (CR) rate remains low at 15–25%, and median overall survival (OS) is only 13–14 months, highlighting the need for more effective strategies. According to the NCCN guidelines, chemotherapy is considered for patients with unresectable locally advanced ESCC involving the trachea, great vessels, vertebral body, or heart. Recent randomized phase III trials have demonstrated that anti-PD-1 antibodies in combination with chemotherapy represent a promising treatment option in this population. Based on these findings, we are conducting a phase II study to evaluate pembrolizumab plus chemotherapy with short-course radiotherapy (SCRT) as induction treatment for unresectable locally advanced ESCC. Methods: The PALADIN trial is a single-center, single-arm phase II study designed to assess the efficacy and safety of induction pembrolizumab plus chemotherapy with SCRT in patients with unresectable locally advanced ESCC. Key eligibility criteria include unresectable locally advanced ESCC; age ≥18; ECOG PS 0–1; histologically confirmed squamous cell carcinoma, adenosquamous carcinoma, or basaloid squamous cell carcinoma; T3br, T4a, or T4b (Japanese Classification of Esophageal Cancer, 12th edition) without distant metastasis; and no prior treatment for esophageal cancer. Patients receive pembrolizumab 200 mg IV on day 1, cisplatin 80 mg/m² IV on day 1, and 5-fluorouracil 800 mg/m²/day by continuous infusion on days 1–5 every 3 weeks for 4 cycles, with SCRT of 25 Gy in 5 fractions administered on days 8–12 of cycle 1. After completion of study treatment, patients deemed eligible for R0 resection based on re-evaluation with CT and endoscopy will undergo subtotal esophagectomy with 2- or 3-field lymph node dissection. The primary endpoint is the 2-year OS rate. Secondary endpoints include R0 resection rate, pathological CR rate, major pathological response rate, progression-free survival, distant metastasis-free survival, recurrence patterns, and safety. Exploratory endpoints include analysis of minimal residual disease using circulating-tumor DNA and other translational studies. The planned sample size is 35 patients, based on a threshold 2-year OS rate of 30% and an expected rate of 50%, with a one-sided α of 0.10 and 80% power. Patient enrollment began in July 2025. Clinical trial information: 1031250183 .