Although EGFR tyrosine kinase inhibitors and chemotherapy agents have been tested in previously treated patients with advanced NSCLC, and tarceva, alimta, and taxotere are all approved by the US FDA in this setting, we haven't had studies directly comparing chemo to targeted therapy. However, we're starting to get the first glimpses of information, including a randomized Phase III trial out of Japan that gave previously treated advanced NSCLC patients either iressa or taxotere.

As I mentioned in prior posts on the topic of second-line therapy, taxotere was the first treatment approved for second-line treatment of NSCLC. Back in 2000, first-line chemo with platinum-based doublets was becoming increasingly established as demonstrating a consistent survival benefit of several months for previously untreated patients with advanced NSCLC, and then a couple of trials came out that demonstrated a modest survival benefit that for second-line taxotere, compared to either supportive care alone or compared to alternative chemotherapy (navelbine or ifosfamide).

Immune-based approaches in lung cancer tend to generate significant buzz among patients and the general public, as well as in the media, but not as much optimism within the oncology world. Much of that is for good reason: while the concept of a minimally toxic, long-lasting anti-cancer approach like a vaccine is very appealing to all of us, oncologists have seen many hyped immune-based therapies deliver far less than their promise. This is for several reasons.

In contrast to the guidelines that exist for treating advanced lung cancer in the first-line setting for 4-6 cycles, there are really just practice patterns and good judgment to guide decisions of how long to treat in the second-line therapy. First, this is a relatively new question. As I previously mentioned when describing the history of treatment for advanced lung cancer, ten years ago there was plenty of debate about whether the benefits of treating NSCLC were sufficient to make this a standard of care.

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.

Yesterday I reviewed a series of studies of the EGFR monoclonal antibody cetixumab, or Erbitux, combined with chemotherapy. Overall, these trials are modestly encouraging, without what I would consider to be a potential antagonistic effect when chemo and EGFR tyrosine kinase inhibitors (TKIs) like Iressa or Tarceva. However, we still don't have studies big enough to establish any role for erbitux. Today, I'll cover the very limited experience of single-agent Erbitux in advanced NSCLC.

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).