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EGFR Molecular Markers and the Impact of Gene Mutations
We’ve been talking about the potentially relevant molecular markers for EGFR, and the importance of EGFR as a cancer target (see prior post), without really describing what these markers are. There are three main aspects of EGFR biology that have been studied for their potential predictive value in consideration of EGFR inhibitor therapy, whether the oral tyrosine kinase inhibitors like tarceva (erlotinib) or iressa (gefitinib), or the monoclonal antibodies against EGFR such as erbitux (cetuximab). What are these markers?
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What is EGFR and Why Do We Target It?
The topic of what is EGFR is one that really deserves to have been covered here from the beginning, but somehow I skipped to the drugs and what they do in cancer patients. It’s time to take a step back and discuss EGFR and why it’s been an important target in cancer.
EGFR stands for Epidermal Growth Factor Receptor, and it can be targeted from the outside of the cell by intravenous monoclonal antibodies against the target protein (also known as a ligand) binding portion of the cell, or from the inside of the cell by oral small molecule inhibitors against the part of the receptor called the tyrosine kinase domain that activates the intracellular machinery:
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Inhibiting the mTOR Pathway as an Anti-Cancer Strategy
There’s a class of drugs that are being studied in fighting cancer, known as mTOR inhibitors. mTOR stands for mammalian target of rapamycin, which is an immunosuppressant drug that also has anti-fungal activity, but which was also found to have anti-proliferative activity (keeping cells from growing and dividing), which suggesed that it could have useful anti-cancer activities. The entire class of drugs that block the rapamycin target are now the subject of study in fighting cancer, and one called temsirolimus has been approved against kidney cancer. The target is shown in this figure that illustrates that mTOR is downstream as part of a path that starts with growth factor receptors we’ve met before, such as the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor (IGF-1R):
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New Treatment Being Developed for EGFR Inhibitor Skin Rash
The leading side effect of EGFR inhibitors, both the oral tyrosine kinase inhibitors (such as tarceva (erlotinib)) and the IV monoclonal antibodies (such as erbitux (cetuximab)), is rash, dryness, and other skin side effects. While a rash sounds modest to many people compared to many of the leading problems with chemo, many of the members here can attest that while an EGFR rash can range be as mild as a pimple or two, it can also be itchy, painful, and be as severe as a skin rash covering large amounts of the body, sometimes with open lesions. And for some patients, the skin side effects can require dose reductions or even lead patients to discontinue their EGFR inhibitor, even if it might help against their lung cancer.
As described in a press release last week, Hana Biosciences, based in South San Francisco, has initiated a study of topical menadione, a precursor to forms of vitamin K that also activates EGFR. This topical medication is being studied in the setting of both a prophylactic treatment and as a treatment for skin side effects that emerge on treatment. This research is being led by Dr. Mario Lacouture at Northwestern, who I’d consider to be the leading expert in EGFR rash treatment right now.
There have been several posts and forum threads on managing the rash, but it’s very encouraging to see that not only is more attention being paid to this problem, there are actually trials being run, even with new agents, that are trying to reduce a side effect that can significantly worsen the quality of life for patients on EGFR inhibitors, sometimes even keeping them from getting the drug, or perhaps a dose that could be managed chronically if the rash was controlled more effectively.
EGFR Inhibitor Combination Tested in Advanced NSCLC
As I’ve described in various posts about targeting the epidermal growth factor receptor (EGFR), one of the main signals that is important in many lung cancers, there are agents like gefitinib (iressa) and erlotinib (tarceva) that target the internal switch that triggers activity inside the cell, and there are agents like cetuximab (erbitux) that work on the external front end receptor to block activity:
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I must admit that I’ve always been curious whether combining these two appoaches, giving an oral EGFR tyrosine kinase inhibitor (TKI) with a weekly IV EGFR monoclonal antibody would potentially provide a synergistic inhibition and impressive activity. For the first time, Ramalingam and colleagues have published their limited experience of combining iressa and erbitux in a small trial of patients with advanced NSCLC (abstract here). Unfortunately, the results don’t look particularly impressive.
My friend Dr. Ramalingam has just recently moved from Pittsburgh to head the lung cancer program at Emory University in Atlanta, but while at the University of Pittsburgh he and colleagues there conducted this study to assess the safety and get a sense of the activity of a combination of iressa with erbitux. Iressa, the first EGFR TKI approved for NSCLC, was studied at the previously approved standard dose of 250 mg daily (subsequently found to not be significantly superior to placebo in a large trial of previously treated patients with advanced NSCLC and taken off the market). Erbitux was given at increasing doses, starting at a rather low dose and escalating to a point of maximum safe/tolerable dose for the combination. For these “phase I” trials of safety, small numbers of patients are usually enrolled. This study included 13 patients who had received at least one prior chemo regimen for advanced NSCLC.
Although the numbers were small, there were no responses seen, and only 4 patients (31%) even showed stable disease. Progression was pretty quick, and 3 patients developed severe declines in blood magnesium levels, which is a known side effect of erbitux, but this was a high rate.
The investigators also tried to do some molecular studies from the subset of 10 patients who had some tissue to work with. They didn’t find any EGFR mutations that would be expected to be associated with robust EGFR TKI responses. They also did not detect any RAS mutations that are generally recognized as being very unlikely to show a response on EGFR TKIs.
There are many reasons why this little study is far from the definitive word on the subect. Iressa at the dose tested is not as effective as tarceva, so perhaps the results would have been more favorable with tarceva. Perhaps these results just happen to be particularly disappointing in a small number of patients who happened to not benefit, but a larger study would have shown better results that represent reality better. Or maybe this combination isn’t particularly useful in a general population but could be very impressive in a more selected population, based on EGFR mutations or never-smoker status. I’ve also wondered whether adding erbitux to tarceva in a patient who has now become resistant to tarceva after a prior good response would restore activity. But we don’t have any evidence on any of these questions.
For now, I think all we can say is that a combination of EGFR TKI and monoclonal antibody doesn’t lead to blockbuster activity in NSCLC. But expect to see a lot more trials of targeted agents in coming years.
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