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First Base 

June 17, 2004 | IRESSA, the AstraZeneca drug approved by the FDA last year (following earlier approval in Japan), produces little or no effect in the majority of lung cancer patients who receive it (following unsuccessful chemotherapy). But, as AstraZeneca CEO Sir Tom McKillop acknowledges, "there is a small group, maybe 10 to 20 percent of patients, [who] get an almost miraculous response ..."

The mystery as to why these positive responses are confined to a minority of patients has now essentially been solved by the simultaneous release last month of a pair of papers by The New England Journal of Medicine and Science. "A victory for molecular medicine" was how former NIH director and Nobel laureate Harold Varmus greeted the work.

Two teams of Boston-based researchers found that most patients who respond to Iressa have acquired mutations in the gene for the drug's natural target, EGFR. These mutations cluster in the active site of the receptor, significantly enhancing the binding of the drug and thereby increasing its inhibitory potency.

In the NEJM study, Daniel Haber and colleagues at Massachusetts General Hospital showed that eight out of nine patients who responded to Iressa have tumors with EGFR mutations (Lynch, T.J. et al. NEJM, May 20, 2004). Similar findings were reported in Science by a team at the Dana-Farber Cancer Institute led by Matthew Meyerson, Bruce Johnson, and William Sellers. They found EGFR mutations in a total of 16 out of 119 non-small-cell lung cancer patients, all of whom responded to the drug (Paez, J.G. et al. Science, April 30, 2004).

Haber's group went on to show that binding of Iressa to the mutant receptor is increased roughly tenfold, a finding the authors suggest could be "clinically relevant" given the current recommended dosage levels.

These dramatic results mean that screening in lung cancer patients must assume an elevated priority. The Massachusetts General team is already working on a diagnostic test, which could be ready by the fall. Haber's group is looking into licensing options with various companies that have expressed interest.


Screen Test 
Those who test positive would immediately warrant being placed on Iressa (or another EGFR-targeting drug), while those who are negative could potentially be spared false hope and unnecessary expense (a month's supply of Iressa costs about $2,000). However, there may still be reason to administer Iressa even in negative cases. In the Mass General study, one out of nine responders did not have an EGFR mutation.

Haber commends AstraZeneca, which was not directly involved in the new research, for its open-minded response to the study, which many would argue severely curtails the patient base. "You can't be in the molecular targeting business without being committed to following the science," he says, while noting that Iressa has potential new markets. These include adjuvant treatment of a resected lung cancer in positive-testing patients as a preventive measure, and earlier treatment (for longer duration) of therapy.

AstraZeneca maintains that Iressa still helps stem the spread of cancer in patients who test negative for EGFR mutations. Meanwhile, it is intensifying its search for mutations in patients with other forms of cancer, including brain, head-and-neck, prostate, and breast cancer. There is also encouraging news about another EGFR-targeting lung cancer drug, Tarceva. In April, the stock price of OSI Pharmaceuticals spiked more than $50, doubling its value, on promising clinical trial news regarding the drug.

Why weren't EGFR mutations examined earlier as a possible cause for the differing patient response? Haber says attention was misdirected on expression analyses and other potential surrogate markers, but now, he predicts, "there will be more focus on identifying genetic lesions in specific subtypes of cancers, and then designing narrower clinical trials aimed at this defined subset of cases."

A final caution, however. The initial Gleevec euphoria dimmed with the news of patients acquiring mutations that made them resistant to the drug. Patients receiving Iressa also tend to develop resistance over periods of months or years. As exciting as this breakthrough undoubtedly is, cancer continues to bare its claws.* 



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