NE Oncology Issue - November 2007

Epidermal Growth Factort Receptor Inhibitors Come of Age

Dr. Goss' perspective:

An epidermal growth factor receptor inhibitor shows noninferiority to docetaxel for second-line treatment of locally advanced or metastatic non-small cell lung cancer: INTEREST

Like previous trials such as BR.21, the INTEREST study confirms that EGFR TKIs are effective in NSCLC. Perhaps the most surprising result in the INTEREST study is that the biomarkers did not predict response or survival. In the ISEL study, a positive association was seen between EGFR FISH-positive status and the survival benefit of gefitinib compared to placebo. By extrapolation, it was expected that FISH-positive patients would have a higher response rate and better survival in the gefitinib arm than the docetaxel arm. Surprisingly this was not the case! We await the further delineation of the role of EGFR protein expression, FISH, and mutational status in selected populations, which are being studied in trials such as TITAN, comparing erlotinib to docetaxel or pemetrexed in patients who have been stratified according to their EGFR-FISH status. However, based on the preliminary data from the INTEREST study, it would appear that EGFR FISH status correlates with sensitivity to treatment regardless of whether an EGFR TKI or chemotherapy is delivered. Moreover, the BR.21 and ISEL studies demonstrate that clinical parameters such as female gender, non-smoker, and Asian background, in general, are as accurate as biomarkers in predicting who is going to respond to EGFR TKI treatment. Why do the remaining patients with NSCLC not respond to these agents? The answer is that lung cancer is a heterogeneous disease, so the female, non-smoker, and Asian groups quite possibly have a completely different disease from that of the male, heavy smoker, Western population with NSCLC. The most likely hypothesis is that the EGFR-sensitive population has had very little exposure to carcinogenic load compared with males who are heavy smokers. The less-damaged genome in the female, non-smoker Asian populations may be part of the explanation for why they do well both on chemotherapy and with EGFR TKIs.

What about the results of the V-15-32 study? How do we explain the fact that two similarly designed trials, INTEREST and V-15-32, had very different outcomes? One can argue that the results of the Japanese study of gefitinib versus docetaxel were confounded by the disproportionate number of patients who crossed over from the docetaxel arm to the gefitinib arm (53%) versus those gefitinib-treated patients who crossed over to docetaxel post-randomization (36%). We know from the BR.21 study and also from ISEL that a significant number of people respond to third-line EGFR TKIs. Therefore, the crossover likely accounted for the two arms performing more or less equivalently in the V-15-32 study. In the INTEREST study, however, third-line therapy following the experimental treatment was equivalent in both arms, and was therefore less likely to have influenced the survival results.

Erlotinib has single-agent activity in older patients with advanced or metastatic non?small cell lung cancer

The TRUST study was a large open-label, non-randomized phase IV study with a final analysis based on more than 5,000 patients with NSCLC. The survival data compare very well with data from the BR.21 trial, which gives us more comfort with the latter trial’s results. The adverse event profile was as anticipated; however, the number of patients who could not tolerate the erlotinib (6%) was high.

The median survival of 6.2 months the Target trial compares favourably with the results of the perspective randomized trials of single agent chemotherapy versus best supportive care in the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) and MILES studies where the median overall survival was 27 weeks and 30 weeks, respectively.

Molecular characterization of EGFR inhibition: EGFR, but not KRAS, mutations are important for EGFR inhibition

It should be noted that the above correlates mutational status with response and not survival and confirms the results of a number of trials. Mutational status as a predictor of survival still needs to be definitively evaluated in a perspective randomized trial that is powered to answer this question.