A New Tyrosine Kinase Inhibitor for Lung Cancer
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Julia Draznin Maltzman
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 9, 2004
Survival in Refractory or Metastatic Lung Cancer
A new orally administered inhibitor of the enzyme Epidermal Growth Factor Receptor (EGFR) tyrosine kinase has been tested in advanced Non Small Cell Lung Cancer (NSCLC ). The drug, called erlotinib or Tarceva, had not yet been approved by the US Food and Drug Administration (FDA) but was granted a fast track status in May 2002 for the treatment of chemotherapy-naive advanced NSCLC. This was later (2004) extended to include second and third line monotherapy for patients who failed standard therapy.
In a recently presented abstract (ASCO 2004), investigators from the National Cancer Institute of Canada showed that erlotinib reduced the risk of death by 29% in patients with relapsed NSCLC. This study was impressive as it is the first to shown an extended survival in patients with recurrent disease. This study was a 731-paitent, double blinded, placebo controlled Phase III trial which compared Tarceva to placebo in the treatment of patients with advanced or metastatic NSCLC. All patients had experienced disease progression following first or second line chemotherapy. Overall survival in the treatment arm was 6.7months versus 4.7 months in the placebo group. This two-month difference was found to be statistically significant with a p value of 0.001. After one year of follow up, 30% of patients taking erlotinib were alive as opposed to 20% of those on placebo.
Mechanism of Action
Tarceva is a small molecule designed to target the human epidermal growth factor receptor 1 (HER1) pathway, which is critical to cell growth in many cancers. HER1, also known as EGFR, is a key component of the HER signaling pathway, which often is involved in the formation and growth of numerous cancers. Tarceva is designed to inhibit the tyrosine kinase activity of the HER1 signaling pathway inside the cell, which blocks tumor cell growth. This is an important pathway for cell growth, differentiation, cell division, metastasis, and cell survival.
Tarceva seems to be a very well tolerated drug. Thus far the only adverse effects noted are a rash, conjunctivitis, and some diarrhea. However, some oncologists contend that the rash seen with Tarceva is actually a surrogate marker for drug activity the worse the rash the more active the drug. This phenomenon was seen with another tyrosine kinase inhibitor currently approved for NSCLC Iressa. The diarrhea is mild and seems to be manageable.
Who May Benefit
Unlike gefitinib (Iressa), all subgroups of patients seem to benefit from erlotinib. This study was unable to differentiate which subset of patients would stand to achieve the greatest benefit from the drug. Some differences in response were noted: women responded better than men, life long non-smokers responded better than current or former smokers, and those with adenocarcinoma better than those with other histologic subtypes of NSCLC. However, all of these observations, with the exception of smoking, did not translate to a survival benefit.
Recent research published in both the New England Journal of Medicine and the journal Nature, from two competing groups at the Harvard Medical Center , showed that an activating mutation in the gene for EGFR appears to determine which patients will respond to the EGFR-inhibitor gefitinib or Iressa. It is unclear what role, if any, does the EGFR mutation play with respect to erlotinib, but it is the subject of current intense investigation. Clinically, a similar patient profile seems to benefit from Iressa as does from Tarceva, but to date, no genetic correlations have been shown.
Studies of Tarceva are ongoing as this drug is still not approved by the FDA for use outside of clinical trials.