Pharmacodynamic trial of nimotuzumab in unresectable squamous cell carcinoma of the head and neck: a SENDO Foundation study.
OBJECTIVE
To assess the pharmacodynamic effects of nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody with intermediate affinity for the receptor, in skin and tumor tissues from head and neck cancer patients.


METHODS
Pharmacodynamic study in patients with advanced squamous cell carcinoma of the head and neck, unsuitable for chemoradiotherapy, enrolled in a single-center trial. Patients received 8 weekly infusions of nimotuzumab. The first nimotuzumab infusion was administered 1 week before starting radiation, whereas the remaining doses were administered concomitantly with irradiation. Paired biopsies were taken from skin and primary tumors, before (pretherapy) and 1 week (on single-agent therapy) after first infusion. Immunohistochemistry was conducted to assay the effects of nimotuzumab on total and phosphorylated EGFR, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), p-AKT, and proliferation (Ki-67).


RESULTS
Nimotuzumab was well tolerated and there was no evidence of skin rash. Objective response was achieved in 9 of 10 patients. The pharmacodynamic assays showed inhibition of p-EGFR in both skin and tumor (P = 0.042 in skin and P = 0.034 in tumor). No significant changes in p-ERK1/2, p-AKT, or Ki-67 were detected in skin. In addition, lymphocytic infiltrates, folliculitis, or perifolliculitis were not observed. In tumor samples, there was an upregulation of p-AKT (P = 0.043), a reduction in proliferation index (P = 0.012), and a nonsignificant trend toward a decrease of p-ERK1/2 (P = 0.091).


CONCLUSIONS
The pharmacodynamic data confirmed the ability of nimotuzumab to decrease EGFR phosphorylation. Downstream effects were observed in tumor cells but not in skin, a finding that may help to explain the lack of skin rash in patients treated with nimotuzumab.
Rojo
Federico
F
Cancer Research Program, IMIM-Hospital del Mar, Barcelona, Spain.
Gracias
Elías
E
Villena
Nadia
N
Cruz
Teresa
T
Corominas
Josep Maria
JM
Corradino
Irene
I
Cedeño
Mercedes
M
Campas
Clara
C
Osorio
Marta
M
Iznaga
Normando
N
Bellosillo
Beatriz
B
Rovira
Ana
A
Marsoni
Silvia
S
Gascon
Pere
P
Serrano
Sergio
S
Sessa
Cristiana
C
Crombet
Tania
T
Albanell
Joan
J
D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C501466:nimotuzumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3