In a recent post, I described the approval of taxotere as a second-line chemotherapy with a modest but survival benefit for patients previously treated with one line of chemo, usually a platinum-based doublet. Two years ago, erlotinib/tarceva, an inhibitor of a target on many NSCLC tumors called the epidermal growth factor receptor, was approved by the FDA as an additional treatment option for previously treated patients with advanced NSCLC, based on a large randomized clinical trial led by the National Cancer Institute of Canada that was published in the New England Journal of Medicine (BR.21 abstract here), demonstrating the importance of the results.

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This trial, known as BR.21 (BR stands for bronchus in the NCI Canada naming system), randomized 731 patients who had received one or two prior lines of chemotherapy to either tarceva at 150 mg by mouth daily for two thirds of patients, vs. placebo daily for the other third of patients. This showed a significant survival benefit of about two months for the recipients of tarceva, and also an improvement in the likelihood of not progressing at various time points (about 40% improvement compared with placebo). The chance of not progressing at 6 months after starting the trial was more than doubled in patients on tarceva vs. placebo. As with even our best chemo for previously treated NSCLC, tarceva showed a response rate (at least 50% shrinkage of the tumor) of 9%. Side effects were generally modest. While 76% of patients developed a rash, it was severe in less than 10% of patients on tarceva. Diarrhea was also seen in just over half of patients, but this was rarely a significant side effect. Overall, 27% had their drug held for a week or more, 19% of patients had dose reductions due to side effects, and 5% stopped tarceva due to side effects. Also interesting is the fact that 2% of patients found a placebo to be intolerably toxic.

So while some nay-sayers were not overwhelmed by the amount of benefit, most people felt that for a usually well-tolerated pill, an approximately two month survival benefit was compelling enough for FDA approval in November of 2004. Interestingly, and somewhat suprisingly, a very similarly designed trial with Iressa (vs. placebo in previously treated patients with advanced NSCLC) was reported preliminarily just a month later, leading the FDA to withdraw Iressa from the market for new prescriptions, limiting it to patients who were already on Iressa and not progressing, or clinical trials with it. So Tarceva became the major EGFR inhibitor for this setting and remains so to this time.

Among the most important questions, still controversial and very relevant to current treatment decisions, is whether the benefits of this class of drugs is broad or narrow. Are the clinical benefits from tarceva limited to and driven by a small subset of patients, whether women, patients with BAC, never-smokers, or those with EGFR mutations, who develop huge benefits while most of the other patients get no benefits. Or are the benefits more modest but better distributed among a broader population of beneficiaries. The next post will discuss the analyses of different patient subsets to help clarify who benefits from tarceva if a targeted drug is given in an "untargeted" way to everybody.