It has been noted for many years that Asian women appear to be particularly predisposed to lung cancer despite a low frequency of smoking. Many of the series from resected NSCLC series have never-smoker rates of 30-50%, with the majority of these never-smokers as women. As we've struggled to understand and explain risks, hormonal differences between men and women have emerged as a possibility, as has genetic differences.

Several trials have recently opened up for never-smokers with any lung adenocarcinoma or those with BAC (or adeno/BAC mix, invasive adenocarcinoma with BAC features) with any smoking status. Both of these groups have only recently gained recognition as likely being a distinct clinical entity with a different natural history (clinical behavior outside of treatment) and pattern of responsiveness to treatments that is different from other types of lung cancer.

The study I was just discussing, the French trial of Iressa at 250 mg daily for advanced BAC (abstract here), provided interesting clinical information, especially when viewed in the context of previous work on EGFR inhibitors in BAC.

As I've described in a prior post, one of the most consistent findings in the work with the EGFR inhibitors Iressa (gefitinib) and Tarceva (erlotinib) is that never-smokers are far more likely to demonstrate a response and survival benefit than patients who do smoke or did smoke. Here, for instance, is the set of survival curves separated by smoking status for the large randomized trial of tarceva vs.

Most of the focus on predicting response to EGFR inhibitors has been on identifing molecular markers that are associated with major response to this kind of treatment. But we know that there is a group of patients who get no benefit from these expensive drugs, and in these patients, EGFR inhibitors would just lead to side effects and keep them from a potentially more effective therapy for them.

Iressa was approved by the US FDA in May of 2003 as a third-line therapy, and for the next 18 months it was the only EGFR inhibitor on the market.

I haven’t really covered the history or issues of directly comparing the two oral inhibitors of the epidermal growth factor receptor, or EGFR, which are Iressa (gefitinib) and Tarceva (erlotinib). This is really because over the last few years, gefitinib has had disappointing results in some important trials and is no longer readily used or available, while the remarkably similar drug Tarceva has been approved by the US FDA and is a standard treatment for patients with advanced NSCLC that has previously been treated with chemotherapy.

My good friend Heather Wakelee, along with her colleagues at Stanford, just published an important study in the Journal of Clinical Oncology on the incidence of lung cancer among never-smokers, essentially the first and most comprehensive work defining the magnitude of the problem.

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.

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.