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

Mario E. Lacouture*, John C. Morris, Donald P. Lawrence, Antoinette R. Tan, Thomas E. Olencki, Geoffrey I. Shapiro, Bruce J. Dezube, Jay A. Berzofsky, Frank J. Hsu, Joan Guitart

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)437-446
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume64
Issue number4
DOIs
StatePublished - Mar 22 2015

Keywords

  • Fresolimumab
  • GC1008
  • Keratoacanthoma
  • Squamous cell cancer
  • Transforming growth factor β

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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