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.