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Assay-directed Lung Cancer Clinical Trial


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The Todd Cancer Institute at Long Beach Memorial Medical Center is the first cancer program in the nation to apply assay-directed therapy as the first-line treatment for advanced solid tumors. The Center is currently hosting clinical trials for cancers of the lung, colon, stomach, pancreas and prostate.

One of those has been Phase II assay-directed therapy in previously untreated, measurable, Stage IV NSCLC. Patients who had high activity for erlotinib in vitro and received first line single agent erlotinib had a 100% response rate.

Researchers at Rational Therapeutics and Todd Cancer Institute (Long Beach, Calif.) have reported clinical results obtained with a laboratory technique (Ex-Vivo Analysis of Programmed Cell Death - EVA-PCD) that accurately identifies patients who are candidates for targeted cancer therapy.

A team led by Robert Nagourney, M.D., laboratory director of Rational Therapeutics and medical director of the Todd Cancer Institute at Long Beach Memorial Medical Center, report that ex-vivo laboratory analysis accurately identified non-small cell lung cancer (NSCLC) patients likely to benefit from the EGFr inhibitor, Erlotinib (Tarceva). The team's findings are published in the official proceedings of the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 1-5 in Chicago.

"While targeted EGFr-TKI therapy has proven effective in treating advanced non-small cell lung cancer, response rates remain low in randomly selected patients," said Dr. Nagourney. "We have found that the EVA platform can help doctors select those patients most likely to benefit from the new generation of targeted anticancer therapies."

The researchers used ex-vivo analysis (EVA) to examine tissue from NSCLC patients as part of an IRB-approved assay-directed clinical trial. Patients found sensitive to the EGFr inhibitors received oral Erlotinib at 150mg/day as first line therapy. All of the patients selected responded to this oral therapy, with several achieving long-term remissions. This outcome demonstrates that patients whose cancer cells undergo programmed cell death in the laboratory due to EGFr inhibitor exposure are those who respond to targeted Erlotinib (Tarceva) therapy. The research team's findings are summarized in an abstract titled, "Clinical Responses to EGFr-TKI's Characterized by Drug-Induced Cell Death in Human NSCLC Primary Cultures" (ASCO Abstract # 07-AB-34058-ASCO).

Traditional anticancer drugs are toxic to both cancerous and normal cells. In contrast, targeted anticancer drugs target cancer cells with specific mutations. While such drugs hold promise, their use requires new methods to enable doctors to accurately and consistently identify patients whose particular type of cancer expresses the drug's specific target.

Dr. Nagourney explains, "Efforts to administer targeted therapies in randomly selected patients often result in low response rates at significant toxicity and cost. While researchers continue to develop molecular probes to select candidates, the ex-vivo platform used in this study serves as a functional profile capable of examining the nuances of cellular response to drugs. To exploit the full potential of targeted anticancer therapies, physicians will need laboratory tests that match patients to specific drugs. We believe the EVA PCD platform is such a test."


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Epidermal Growth Factor Receptor (EGFR) expression is associated with a poorer prognosis for many patients with solid tumors. Like HER2 expression is for Herceptin, EGFR expression is for Tarceva. In some cancer cells, EGFR triggers uncontrolled cell division.

Testing patients for EGFR to determine which patients would benefit from targeted therapies such as Iressa, Erbitux and Tarceva, was limited only to those patients whose tumors were determined to be EGFR protein positive.

There are rare patients that respond very well. However, cancer cells evolve resistance to Tarceva by multiple mechanisms related to genetic alterations both within the EGFR gene and at other sites.

Will the fact that EGFR negative patients not benefit from Tarceva and limit its usage? The FDA approved indication for Tarceva does not limit prescribing specifically to EGFR positive patients. In the drug's registration trial, determining response based on EGFR was not a major endpoint of the study.

The headlong rush to identify molecular predisposing mechanisms still does not guarantee that a drug will be effective for an individual patient. Nor can they, for any patient or even large groups of patients, discriminate the potential for clinical activity among different agents of the same class, such as Tarceva, Iressa, and Nexavar.

The growth of lung cancer appears to depend upon a variety of different growth factors. If the growth of the tumor is not entirely dependent on EGFR, an anti-angiogenic therapy directed to that growth factor alone, it may not be effective.

If there are a number of different growth factors with different influences on different tumors, then you must either isolate the predominant growth factor very specifically, or use a variety of anti-angiogenic drugs to combat various methods of tumor growth.

A "functional profiling" assay assesses the activity of a drug (or combinations of drugs) upon combined effect of "all" cellular processes, using several metabolic and morphologic endpoints. Other tests, such as those which identify DNA or RNA sequences or expression of individual proteins examine only one component of a much larger, interactive process.

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