A targeted-medicine hopeful is in trouble.
After reviewing recent data showing no survival benefit for patients taking the cancer drug Iressa, the US Food and Drug Administration this week urged current consumers of the drug to see their doctors and consider changing prescriptions, a development that may spell the end of the drug unless responders can be reliably identified. The company’s manufacturer, AstraZeneca, is currently discussing the drug’s fate with the FDA.
“The problem is that we don’t have a good test to detect which patients will respond” to Iressa and its competitor, Tarceva, co-developed by OSI Pharmaceuticals and Genentech, said Jorge Leon, who heads Leomics, the Princeton, NJ, molecular-diagnostics consulting firm . But, he added, there are “very powerful technologies on the horizon that are going to address it.”
Iressa was cleared in May under the FDA’s accelerated-approval program, requiring further study to “verify the expected clinical benefit,” according to an FDA statement. It was during that verification of 1,692 patients that the company found no “statistically significant survival benefit” compared to placebo, although it did find a “statistically significant improvement” in tumor shrinkage, AstraZeneca said in a Dec. 17 statement.
Iressa’s future may well depend on hints found in initial analysis of the data. A preliminary analysis found “statistically significant” survival among some patients of Asian descent and nonsmokers, said AstraZeneca spokesperson Mary Lynn Carver. In addition, only the initial results of the study have been released, and some information may prove to be favorable for the drug — for example, by showing an improvement in the quality of patients’ lives, said Carver. “All of the subanalyses and subprotocols have not been completed yet.”
Quality-of-life analysis and biomarker analysis are still ongoing, and the company expects results “definitely” by the first half of 2005, Carver said. The “extensive” biomarker studies conducted by AstraZeneca involve evaluations of the relationship between EGFR status and Iressa response, she added.
The company is “suspending promotional activities,” meaning that AstraZeneca will no longer advertise Iressa, and its sales force will no longer promote it. “It’s our intention to continue to provide this drug for the patients that it benefits,” said Carver. “We just have to do a lot more work to find out who those patients are.”
The search for valid biomarkers linked to Iressa response is going on “all over the world”, Carver said, including research conducted at Vanderbilt University, MD Anderson Cancer Center, Cedars-Sinai Medical Center, and Massachusetts General Hospital.
In Search of a Diagnostic
“My understanding is that this is something that would be available within 24 months,” said Joseph Ferrara, executive VP of consulting at Boston Healthcare.
A fundamental change is about to occur in EGFR therapies, said Jorge Leon. “[There exists] a new technology … that is showing very, very powerful results in selecting patients that respond to Iressa,” said Leon. “The studies are being conducted; I have seen the data personally.”
Leon pointed to ViroLogic’s eTag technology, which the company acquired along with Aclara Biosciences, as the most promising EGFR diagnostic. “The eTag technology has already shown that it can detect patients that will respond to [EGFR inhibitors] — or will not respond — better than any other test,” Leon said. ViroLogic’s data has yet to be validated and published, he added.
The Iressa savior, it seems, may be a year or two in coming. ViroLogic CEO Bill Young told Pharmacogenomics Reporter last week that the company’s eTag diagnostics would roll out in 2005 or 2006. Young said the company will focus first on EGF-family drugs (see Pharmacogenomics Reporter, 12/16/2004).
Currently, there is no FDA-approved diagnostic to identify responders to Iressa or Tarceva. An immunohistochemistry diagnostic by Denmark-based DakoCytomation links EGFR overexpression to a statistically unreliable benefit for Tarceva, according to Tarceva product information supplied by Genentech [https://www.tarceva.com/tarceva/product/index.jsp].
“The DakoCytomation test is a terrible test — it has nothing to do with clinical response,” said Leon.
Enter the Competition
“The question is, ‘Which drug are you going to hand out?” said Herman Kattlove, a retired medical oncologist who works with the American Cancer Society. “I think the physicians are going to go for Tarceva at this point, because Iressa has bad press,” he said.
Like Iressa, Tarceva shows a significant response among nonsmokers, according to Genentech. Tarceva also seems to work better in patients of Asian descent than in non-Asians, although there is no statistically significant association yet, the company said.
But Tarceva’s advantage may be insurmountable, even though it is the more expensive of the two at $2,000 per month, compared to about $1,800 for Iressa, according to Frost and Sullivan. Phase III trials showed an overall survival benefit for patients taking Tarceva.
When doctors can instead prescribe Tarceva for non-small cell lung cancer, the recent study results may be Iressa’s “death knell,” said Denise Anderson, an analyst who covers AstraZeneca for Kepler Equities. But the seriousness of lung cancer may still make the drug attractive to patients, if not AstraZeneca, should Iressa eventually show a clear benefit for a small number of people, Anderson said.
“Certainly this recent study is really devastating for Iressa,” Leon said. In a situation with few choices, like that of lung cancer patients, “I would do it,” he said.
“I don’t know if Iressa will be back, because that depends a lot on the competition — if you’ve got Erbitux showing better data with lung and colon [cancer]” people will switch to Erbitux, said Leon. Currently, Erbitux is indicated only for colorectoral cancer, and it is about twice as expensive than Iressa, he added. “I don’t know how this is going to pan out.”
For colon, lung, and breast cancer-related EGFR-family diagnostics, the market size is approximately $250 million, assuming one-quarter of patients opt for tests, said Leon.
Iressa sales for the first nine months of 2004 were $300 million, with about half of that from sales in the United States, according to AstraZeneca.
But the intended market for Iressa was always supposed to be larger than non-small cell lung cancer, said Kepler’s Anderson. “But when you add together all the other cancers, that’s what the hope was [in the market] … over $1 billion.” If Iressa had been intended solely for non-small cell lung cancer, it would have never been a blockbuster drug, she said.
AstraZeneca shares dropped 7.7 percent to $37.10 on the day of the announcement. Meanwhile, OSI stocks rose 45 percent to $68.38, and Genentech jumped 5.9 percent to $51.36.
Investors want to have their cake and to eat it too, said Joseph Ferrara of Boston Healthcare. “They’ve got a situation where they invest in the promise of pharmacogenomics, but they still want a blockbuster drug,” he said. “I think they probably punished AstraZeneca more than they should have, because there may indeed be a survival benefit for a smaller percentage of patients than the overall study population,” he said. “It’s definitely going to be a matter of proving to the investment community that the drug works well for whatever the target population is.”