Throughout their development over the past years, the EGFR tyrosine kinase inhibitors Iressa (gefitinib) and Tarceva (erlotinib) have been identified as seeming to be particularly helpful in women compared with men. Only Tarceva is commercially available in the US, but Iressa is widely used in other parts of the world, including Asia, where it continues to be avidly used and studied. Both of these drugs have a consistently higher response rate in women, which has led to some different use patterns in women and men. In fact, some US oncologists relegating Tarceva now just to women, despite the fact that it was shown to have a survival benefit in the general population (of women and men). So what’s the fuss about EGFR-based therapies and women?

The differences in response rate were noted in the first reasonably large trials of EGFR inhibitors, which gave Iressa at varying doses to patients predominantly outside of the US (including significant numbers of patients from Asia) in one trial (IDEAL-1 abstract here), and another predominantly from within the US (IDEAL-2 abstract here). In an analysis of multiple variables in these trials, women had a higher response rate in both; the IDEAL-1 trial reported that women were 2.65 times as likely to respond to Iressa as men were, while the IDEAL-2 trial reported that women had a response rate of 19%, compared with 3% for the men on that trial (an approximately 6-fold difference!! Eighteen of their 22 responses on the trial were in women, even though women accounted for less than half of the patients). As described in a prior post, the larger Iressa trial known as ISEL (abstract here), with nearly 1700 previously treated patients randomized 2 to 1 to receive Iressa or placebo, showed no overall survival benefit; women on this trial had a nearly three-fold higher response rate of 14.7%, compared with just 5.1% for men. In the study of Iressa in patients with advanced bronchioloalveolar carcinoma (BAC) that I led (abstract here), women had a median survival more than twice that of men (19 vs. 8 months), and the response rate was nearly twice as high in women as in men, although this was not statistically significant (20% vs 11%):

(click to enlarge)

And then there’s the evidence with Tarceva. The Canadian trial BR.21 (abstract here) that randomized patients 2 to 1 to active drug or placebo showed an overall survival benefit, a response rate of 9% overall, and when broken down by patient sex showed a more than doubling of the male response rate (14.4% vs 6.0%) but NOT a bigger improvement in survival for women than for men:

So, from the figure above, this shows that despite the fact that women were more likely to show tumor shrinkage, the survival benefit for men was just as great in terms of the separation of the curves (a hazard ratio of 0.76 means a 24% improvement in survival from tarceva vs. placebo, compared with 0.80, or a 20% improvement for women – pretty much the same, and definitely not worse for men).

In terms of why there may be differences in clinical activity of EGFR inhibitors, the early presumed answer was that EGFR mutations are considerably more common in women than men. This work is continuing to develop, but an analysis of the EGFR mutations in Taiwanese patients (abstract here) showed no differences in EGFR mutation rates between women and men (about 40% for both), while a molecular analysis of the Canadian BR.21 trial of tarceva (abstract here) also showed no difference in EGFR mutation rates for women vs. men, at 24% for women and 22% for men. On the other hand, a Spanish trial that gave first-line tarceva to patients in whom the investigators found EGFR mutations included a total of 37 patients (abstract here), of whom two-thirds were women, which is definitely skewed compared to general lung cancer population and most clinical trials from Spain. We're still learning more about EGFR mutations, but thus far it doesn't seem that differences in the frequency of EGFR mutations between women and men is the key to the field.

Overall, there are a few themes but some discrepant results. Women have a higher response rate in just about every trial, while in some trials they seem to have a better survival with EGFR inhibitors than men (Iressa in the ISEL trial, and also the BAC trial), but the tarceva trial that we’ve analyzed well shows that men get the same degree of survival benefit despite a lower response rate. Some of the mutation work shows that women and men have the same frequency of EGFR mutation, but others indicate that women do, in fact, have a higher frequency of EGFR mutation. I think this tells us that we are still learning about this, a story that only began a few years ago. For now, my take is that while EGFR inhibitor therapy may be particularly beneficial in women with lung cancer (and especially adenocarcinomas or BAC, and probably never-smokers as well), the benefits don’t seem to be limited enough to restrict EGFR-based treatment to women.