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

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.

Conflict of interest statement

Conflict of interest Frank J. Hsu was an employee of Genzyme. Mario E. Lacouture and Joan Guitart were consultants for Genzyme. Jay A. Berzofsky received research support from Genzyme. All other authors do not have any conflict of interest.

Figures

Fig. 1

a Cutaneous neoplasms following fresolimumab treatment. Patient 007 was a 65-year-old woman with MM who received fresolimumab at 1 mg/kg ×4 doses followed by extended treatment at 3 and 15 mg/kg ×4 who achieved a PR. An asymptomatic, self-limited, papular rash developed after three doses of fresolimumab 1 mg/kg. At 3 mg/kg, a papular rash with a few keratosis pilaris-like papules developed, which on biopsy revealed an enlarged hair follicle with irregular keratinization and lichenoid keratosis. Between courses, rashes improved and tumor continued to regress. At 15 mg/kg, lesions with features of keratoacanthomas developed on her face, chest, and arms. These lesions completely regressed over a period of months following completion of therapy. b Characteristic appearance of a keratoacanthoma. Lesions were characterized by skin-colored, domeshaped papules or nodules with a crateriform center and keratin plug

Fig. 2

Histology of keratoacanthoma arising in a patient treated with fresolimumab. Hematoxylin- and eosin-stained skin biopsy section demonstrates a central keratinous plug present within an acanthotic epidermis with few atypical keratinocytes. A sparse inflammatory dermal infiltrate underlies this lesion