Phase II Trial of Sorafenib in Patients with Chemotherapy Refractory Metastatic Esophageal and Gastroesophageal (GE) Junction Cancer.
OBJECTIVE
Vascular endothelial growth factor receptor (VEGFR2) directed therapies result in a modest survival benefit for patients with advanced esophageal and gastroesophageal (GE) junction cancer. Platelet-derived growth factor receptor (PDGFR) may contribute to escape from VEGFR2 inhibition. We evaluated the efficacy of sorafenib, a broad spectrum tyrosine kinase inhibitor targeting VEGFR2 and PDGFR as well as RET and RAF1, in patients with metastatic chemotherapy refractory esophageal and GE junction cancer.


METHODS
This phase II trial of sorafenib 400 mg twice daily enrolled chemotherapy refractory patients with metastatic esophageal and GE junction cancer with primary endpoint of progression-free survival (PFS) rate at two months. Secondary endpoints included overall survival, objective response rate and toxicity.


RESULTS
Among 34 patients, 8 week Kaplan-Meier estimated PFS was 61% (90%CI 45 to 73%). Median PFS is 3.6 months (95% CI 1.8 to 3.9 months), with median overall survival OS 9.7 months (95% CI 5.9 to 11.6 months). Grade 3 toxicities were uncommon and included hand foot skin reaction, rash, dehydration and fatigue. One patient (3%) with ongoing complete response and remains on trial for over 5 years. Whole exome sequencing of this tumor revealed mutations in many cancer-associated genes including ARID1A, PIK3CA, and TP53, and focal amplifications of HMGA2 and MET.


CONCLUSIONS
Sorafenib therapy results in disease stabilization and encouraging PFS in patients with refractory esophageal and GE junction cancer.


BACKGROUND
ClinicalTrials.gov NCT00917462.
Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States of America.
Yelena Y
YY
Janjigian
Departments of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America.
Efsevia
E
Vakiani
Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States of America.
Geoffrey Y
GY
Ku
Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States of America.
Jessica M
JM
Herrera
Departments of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America.
Laura H
LH
Tang
Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Sloan Kettering Institute, New York, United States of America.
Nancy
N
Bouvier
Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Sloan Kettering Institute, New York, United States of America.
Agnès
A
Viale
Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Sloan Kettering Institute, New York, United States of America; Departments of Bioinformatics, Sloan Kettering Institute, New York, United States of America.
Nicholas D
ND
Socci
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America.
Marinela
M
Capanu
Departments of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America; Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Sloan Kettering Institute, New York, United States of America.
Michael
M
Berger
Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States of America.
David H
DH
Ilson
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004943:Esophagogastric Junction / Q000187:drug effects / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D000077157:Sorafenib; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib