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The Miracle of Iressa®

Editor-in-Chief, The Oncologist
Clinical Director, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts

Despite its compelling logic, molecularly targeted drug (MTD) therapy of cancer has been slow to realize its great potential. The one resounding success, imatinib mesylate (Gleevec^®; Novartis Pharmaceuticals Corporation; East Hanover, NJ), for chronic myelogenous leukemia, may or may not be a cure for that disease; it is too soon to tell, and the slow but steady increase in the relapse of patients over time may be telling us that even this disease cannot be cured by a single drug. Antibodies have had a significant impact on breast cancer, lymphoma, and colon cancer, and newer antiangiogenic drugs, such as SU-011248 and Bayer 43-4009, are clearly active in renal cancer. However, with the exception of Gleevec^®, a minority of patients responds, few, if any, are cured, and the cost is extremely high. The epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa^®; AstraZeneca Pharmaceuticals; Wilmington, DE) is a classic example. With response rates of 10%–15% as third-line therapy, it is an expensive and mostly futile treatment for a relentlessly lethal disease. Interestingly, the few responders may have remarkable benefits in terms of symptom relief and prolongation of disease regression. If there were only a test to select the subset of patients that respond, it would truly be a "miracle" drug. But isn’t this the essential problem of cancer therapy? Most of our cytotoxic agents produce responses in fewer than half the patients treated and, with the exception of the hormonal agents and antibodies, we have been unable to devise tests to distinguish the subset of responders.

In landmark studies released on April 29, one from the Massachusetts General Hospital (MGH) Cancer Center [1] and the other from our partner institution, the Dana Farber Cancer Institute [2], researchers identified a mutation in the EGFR that is strongly associated with response to Iressa^®. Thirteen of 14 responders in the two studies had a variety of mutations in the binding pocket of the intracellular catalytic domain of the receptor. None of the 11 nonresponders had such mutations. The overall incidence of such mutations in random lung cancer specimens was about 10% in U.S. patients, but 26% in Japanese patients, figures that correlate closely with the response rates in non-small cell lung carcinoma in those countries. Most of the responders were women and nonsmokers with bronchoalveolar features in their tumor histology, a spectrum previously associated with Iressa^® response. As molecular studies have disclosed in virtually all categories of cancer, this finding suggests that there are significant subsets of tumors within the broad category of lung cancer, each with its own driving oncogenic changes and its own susceptibility to therapy.

The MGH group further showed that the mutations, when transfected into cell lines, increased sensitivity to Iressa^® many-fold and seemed to confer a more sustained response to the epidermal growth factor, the stimulatory ligand. It is possible that the mutation is, in itself, a transforming event in this particular subset of lung cancer patients, distinct from the complex series of mutations induced by carcinogens in smokers, something akin to the bcr-abl of lung cancer. Another possibility is that the mutation, an antiapoptotic event, is selected for by exposure to chemotherapy. An intriguing observation in the recently analyzed erlotinib (Tarceva^TM; Genentech, Inc.; South San Francisco, CA) study is that that drug confers a survival benefit as third-line therapy. The biostatisticians feel that this could not be explained by a benefit confined to 10% of the patients. Likewise, it is the impression of most lung cancer doctors that more than 10% of patients experience symptomatic benefit and a fraction have prolonged disease stabilization. Perhaps the incidence of the mutation in tumors after failing chemotherapy is actually higher than 10%. At present, we lack information on the incidence of mutation after cytotoxic therapy.

Clearly, follow-up trials are required. We need to confirm the finding, determine the true incidence in untreated and treated tumors, and determine whether, in mutation-positive patients, combined-modality therapy with cytotoxics is beneficial. It is even attractive to imagine that Iressa^® or Tarceva^TM will become useful drugs in adjuvant therapy for the subset of mutation-positive patients, as their toxicities are modest and easily handled. Whatever the stage of disease or the line of therapy, it is likely that the use of these drugs in the future will depend on the results of mutation testing in tumor samples. Until the test for mutations (at present sequencing of the affected exons of the EGFR) is widely available, patients will continue to receive Iressa^® when they fail chemotherapy. The test is possible to do, but not straightforward or uniformly successful, when carried out on paraffin blocks. It works best with fresh tissue. The discoverers are actively seeking collaborators to carry out routine testing and to refine the methods.

Beyond the immediate and practical implications of this research, these findings have enormous implications for cancer drug use and for drug development. The cost of new MTDs is staggering, particularly when there is no element of rational patient selection involved. Most agents cost $2,000–$5,000 per month. Antibodies may cost as high as $15,000 per month, an overwhelming burden in view of the low rate of response. With the mutation test in hand, the patient population receiving the drug would fall significantly, and response rates would immediately increase to >90%, representing a tremendous savings in money and time on useless treatment.

Secondly, tests such as this could greatly simplify the problem of drug development and approval. If the search for such mutations was initiated early in the clinical development of a drug, subsequent trials could be much smaller and truly targeted to the affected population. The resulting high response rates would convince the U.S. Food and Drug Administration to grant early approval. In most cases, there would be no need for large randomized phase III trials and the final benefit, as in the case of the EGFR mutations, would be that we would gain remarkable new insights into the mechanisms of tumor progression and drug resistance. Surely, even better therapies would result.

This series of studies, beginning with Stanley Cohen’s discovery of the EGFR [3] and culminating in the studies of the inhibitors, represents a major breakthrough in understanding solid tumor biology and therapeutics. Miracles do happen. It just takes time.

REFERENCES

1. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. Available at: http://content.nejm.org/cgi/reprint/NEJMoa040938v1.pdf. Accessed April 29, 2004.
2. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004 (in press).
3. Cohen S. Nobel lecture. Epidermal growth factor. Biosci Rep 1986;6:1017–1028.[CrossRef][Medline]

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