As I described in a post describing the general principles of SCLC, it is typically responsive to treatment initially, but upon recurrence it is much less likely to respond.

As introduced in the last post, ZD6474, or Zactima, is a pill that blocks tumor blood supply and at higher doses (in the 300 mg per day range) also blocks EGFR. This mutli-targeted therapy has shown some intriguing activity when combined with chemo, and today I'll focus on the research that gave it as a single agent and where it has led us in terms of current trials.

In prior posts I've described the idea of combining targeted agents like Tarceva and Avastin, but there are also some single agents that inhibit multiple targets within cancer cells. I've described sorafenib/nexavar in a prior post. Today I'll focus on another multi-targeted agent, known previously as ZD6474, and with a marketing name of Zactima. Similar to the combination of avastin and tarceva, this single oral drug is anti-angiogenic and also blocks EGFR. Although less well studied, it also blocks a protein called RET and can inhibit cell proliferation that way.

The oral EGFR inhibitors Iressa and Tarceva both have activity in advanced NSCLC, with proven responses in a minority of patients and improvements in cancer-related symptoms as well.

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.

Prophylactic cranial irradiation, or PCI, for SCLC, usually limited disease (LD-SCLC), remains a controversial issue, although this is generally recommended for patients with LD-SCLC who have a complete response to treatment (no evidence of disease). However, the idea of radiating the brain of someone who has no evidence of cancer there and may never get it is something that many patients and also some oncologists (radiation oncologists and medical oncologists) may not embrace.

While SCLC accounts for only about 13% of lung cancer, and only approximately one third of patients with SCLC have limited disease SCLC (LD-SCLC), this remains a high stakes area with the potential for being cured, so it needs to be treated as optimally as possible. I'm going to give a brief history and highlight some of the current principles of what has developed as the current standard of care.