Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic esophageal and gastroesophageal carcinoma with dysphagia: A single arm phase 2 clinical trial, PALEO.

Abstract

TPS4172 Background: Many patients diagnosed with esophageal cancer have dysphagia from their primary tumor and de novo metastatic disease. While multiple therapies are available, there is no accepted standard or sequence of therapies to both relieve dysphagia and control distant disease. Our preceding Phase I clinical trial showed that a 2 week hypofractionated chemoradiotherapy (CRT) protocol (30Gy/10# with concurrent weekly carboplatin and paclitaxel) is well tolerated and provides rapid dysphagia relief. Immune checkpoint inhibition has activity in esophageal and gastroesophageal (GEJ) cancer and concurrent radiotherapy may improve T cell priming through tumor antigen release. In PALEO, patients begin durvalumab concurrent with primary tumor CRT, and receive stereotactic body radiotherapy (SBRT) (24Gy/3#) to a single metastasis to maximize the breadth of tumor antigen exposure. Tissue and blood-based studies are planned to identify biomarkers for response, including immunosequencing to test for post-radiotherapy expansion in T cell receptor diversity. Methods: Eligible patients have biopsy-proven esophageal or GEJ cancer, either squamous cell or adenocarcinoma histology, with oligometastatic (1-5 metastases on FDG-PET scan outside the primary tumor radiotherapy field) or locoregionally advanced disease unsuitable for surgery, dysphagia (Mellow score >0), and ECOG PS 0-2. Key exclusion criteria are prior treatment, tumor HER2 positivity, prior thoracic radiotherapy, tracheo-esophageal fistula, esophageal stent in situ and contraindications to immunotherapy. Patients begin durvalumab 1500mg q4w with CRT to the primary tumour (30Gy/10# with weekly carboplatin AUC2 and paclitaxel 50mg/m2), and continuing to disease progression, unacceptable toxicity or 2 years. SBRT to one metastasis (24Gy/3#) is delivered in week 7. Trial primary endpoint is progression free survival rate at 6 months (PFS6) with the aim to rule out a PFS6 rate of 50% in favor of 67.5%, with 80% power and a one-sided 0.05 significance level. Secondary endpoints include dysphagia relief, nutritional status change (patient weight, removal of enteral feeding tubes, PG-SGA score), quality of life, response rate, toxicity, overall survival and exploratory translational endpoints. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG) for conduct at 8 sites in Australia and New Zealand. 6 of planned 54 patients have been enrolled. ACTRN12619001371189. Clinical trial information: Clinical trial information: ACTRN12619001371189 .