Most of the discussion with about inhibiting the EGFR axis in lung cancer has focused on the orally available tyrosine kinase inhibitors (TKIs) that work inside the cells. However, another way to inhibit the cells is by giving an IV "monoclonal antibody" which is a protein that attaches to the outside of the cell at the EGFR target and can block activity. A figure of the two approaches is shown here, with the antibody circled in red:

Both standard chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) have been approved in NSCLC, and other anti-EGFR agents like erbitux/cetuximab and vectabix/panitumumab are also commercially available for treating other cancers and are being studied in lung cancer. Iressa was previously approved as a single agent in previously treated patients with advanced NSCLC, and Tarceva is now available but approved also as a single agent therapy. However, some oncologists give EGFR inhibitor therapies in combination with standard chemo.

In my last post, I described the somewhat disappointing results for tarceva compared with chemotherapy in a trial of unselected advanced NSCLC patients with a marginal performance status. However, EGFR tyrosine kinase inhibitors like iressa and tarceva were developed as targeted therapies, so perhaps they might prove to be more effective if used selectively, in a targeted population.

The emergence of targeted therapies provides a goal of treating the cancer more selectively, thereby minimizing side effects, while hopefully achieving results as good as or better than standard chemotherapy. Although this is important in the entire population of cancer patients, this is a particularly welcome benefit in patients who may be reluctant to or not healthy enough to receive standard chemotherapy.

An acne-like rash or dry skin is a very common side effect of the drugs that target the epidermal growth factor receptor, with approximately 3/4 of patients who receive the EGFR tyrosine kinase inhbitor tarceva/erlotinib experiencing skin toxicity. Similar skin toxicities are also seen, but a bit less commonly, with the very similar drug iressa/gefitinib, and also frequently with erbitux/cetuximab, a monoclonal antibody that is less well studied in lung cancer.

I reviewed some of the differences in the biology and clinical behavior of never-smoker lung cancers vs. the much more common lung cancer seen in current or former smokers. The main reason it is worth discussing is that there appear to be important differences in how never-smokers with NSCLC respond to some treatments, particularly EGFR tyrosine inhibitors like Tarceva, or Iressa previously.

As mentioned in prior posts, the anti-angiogenic monoclonal antibody Avastin (bevacizumab) is now approved in first-line treatment of advanced NSCLC in combination with carboplatin/paclitaxel chemotherapy. Among the very interesting questions is whether Avastin should be added with other active drugs for NSCLC. Most of us in the field strongly suspect that the survival benefit from Avastin will also be the case with other types of therapy, but we’re only starting to get the evidence to address this.

Since the earliest clinical trials of EGFR inhibitors in NSCLC, certain clinically defined patient subsets became identified as more likely to show a benefit than others. Such studies suggested that women, patients with adenocarcinomas rather than squamous cell carcinomas, Asian patients, and never-smokers compared with current or former smokers were the patients who would do well with EGFR tyrosine kinase inhibitors like gefitinib (Iressa) or erlotinib (Tarceva).

In a recent post, I described the approval of taxotere as a second-line chemotherapy with a modest but survival benefit for patients previously treated with one line of chemo, usually a platinum-based doublet.

Although we are all frustrated by the relatively slow pace of progress in lung cancer, there are times when we can look back and feel that we have made a real impact. Six years ago there were no treatments that were FDA approved and appeared to benefit patients who had previously been treated with first-line chemo for NSCLC. Now there are several.