Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor β by the monoclonal antibody fresolimumab (GC1008)

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2015-04, Vol.64 (4), p.437-446
• Main Authors: Lacouture, Mario E., Morris, John C., Lawrence, Donald P., Tan, Antoinette R., Olencki, Thomas E., Shapiro, Geoffrey I., Dezube, Bruce J., Berzofsky, Jay A., Hsu, Frank J., Guitart, Joan
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - adverse effects; Biomarkers, Tumor - analysis; Cancer Research; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - diagnosis; Carcinoma, Squamous Cell - metabolism; Human papillomavirus; Humans; Immunology; Keratoacanthoma - chemically induced; Keratoacanthoma - diagnosis; Keratoacanthoma - metabolism; Ki-67 Antigen - metabolism; Medicine; Medicine & Public Health; Oncology; Original Article; Skin - drug effects; Skin - immunology; Skin - metabolism; Skin Neoplasms - chemically induced; Skin Neoplasms - diagnosis; Skin Neoplasms - metabolism; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - immunology; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-015-1653-0

Fresolimumab is an antibody capable of neutralizing all human isoforms of transforming growth factor beta (TGFβ) and has demonstrated anticancer activity in investigational studies. Inhibition of TGFβ by fresolimumab can potentially result in the development of cutaneous lesions. The aim of this study was to investigate the clinical, histological, and immunohistochemical characteristics of cutaneous neoplasms associated with fresolimumab. Skin biopsies ( n  = 24) were collected and analyzed from patients ( n  = 5) with treatment-emergent, cutaneous lesions arising during a phase 1 study of multiple doses of fresolimumab in patients ( n  = 29) with melanoma or renal cell carcinoma. Blinded, independent histological review and measurements of Ki-67, p53, and HPV integration were performed. Based on central review, four patients developed lesions with histological characteristics of keratoacanthomas, and of these patients, a single case of well-differentiated squamous cell carcinoma was also found. Expression of Ki-67, no evidence of p53 overexpression, and only focal positivity for human papillomavirus RNA by in situ hybridization in 4/18 cases were consistent with these findings. Following completion of fresolimumab, lesions spontaneously resolved. Therefore, benign, reversible keratoacanthomas were the most common cutaneous neoplasms observed, a finding of importance for adverse event monitoring, patient care, and optimization of therapies targeting TGFβ.