Trial Information

Phase II Trial of Epidermal Growth Factor Ointment for Patients With Erlotinib Related Skin Effects

Erlotinib

Advances in the knowledge of tumor biology and mechanisms of oncogenesis has granted the
singling out of several molecular targets for NSCLC treatment. Among these targets,
epidermal growth factor receptor (EGFR), or HER1, has received particular attention in lung
cancer treatment. EGFR is a transmembrane receptor found primarily on cells of epithelial
origin. Autophosphorylation of its intracellular domain initiates a cascade of events
leading to cell proliferation. EGFR is commonly expressed at a high level in a variety of
solid tumors and it has been implicated in the control of cell survival, proliferation,
metastasis and angiogenesis. The main pharmacological strategies in clinical development for
therapeutic inhibition of EGFR are monoclonal antibodies to antagonize ligand-receptor
binding, and small-molecules to inhibit tyrosine kinase domain activation. The main EGFR
inhibitors are cetuximab, an anti-EGFR monoclonal antibody, and Erlotinib an EGFRtyrosine
kinase inhibitor. The key indications for clinical use are colorectal cancer and head and
neck cancer for cetuximab and NSCLC for Erlotinib. Erlotinib, a quinazolin-4-amine, is a
highly potent, orally available, reversible inhibitor of EGFR tyrosine kinase. Erlotinib, in
a phase III randomized placebo-controlled trial, has been proven to prolong survival (6.7
months versus 4.7 months for Erlotinib and for placebo respectively, p = 0.001) in NSCLC
patients after first or second line chemotherapy. The analysis of quality of life and time
to deterioration of patients reported symptoms showed statistically and clinically
meaningful benefit for patients randomized to Erlotinib. Moreover, Erlotinib resulted active
(response rate of 8.9%) and safe (only 5% of patients discontinued treatment for toxicity).
Following this trial, Erlotinib has been approved by Food and Drug Administration and
Committee for Medicinal Products for Human use in chemotherapy-pretreated advanced NSCLC.
Skin rash is a common side-effect of all HER1/EGFR inhibitors.

EGF ointment

Rash affecting the skin above the waist, is the most common adverse event associated with
Erlotinib, and generally develops within 7-10 days of starting treatment. Skin rash may
spontaneously resolve and reappear and it is reversible following drug discontinuation.
However, when it develops, this chronic side-effect is very distressing for the patient. The
increasing use of EGFR-targeted agents and specifically of Erlotinib in NSCLC treatment, and
simultaneously the lack of clinical trials on this topic, makes rash management and etiology
investigation high priorities.

It has been reported that repeated treatment with EGF increases the epithelial cell
proliferation in a dose dependent manner and accelerates the wound healing process, whereas
a single EGF treatment has no noticeable effect on the wound-healing rate. There have been
many studies aimed at developing a topical formulation with the sustained and stable
pharmacological properties of recombinant human EGF (rhEGF). And the rh-EGF concentration
between 1 and 5 ug/g can be seen as the ideal concentration to achieve the most efficient
results for acute wounds with partial thickness defects.