By Kim Coghill
SILVER SPRING, Md. ¿ A government panel Wednesday tended to lean on the side of patients and researchers when it discussed conducting clinical trials for customized therapies.
The FDA¿s Oncologic Drugs Advisory Committee (ODAC) tackled issues surrounding the future of targeted therapies and how trials involving assays such as immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) should be conducted.
Problems have arisen in the past few years interpreting IHC and FISH tests, according to the FDA. In particular, the agency said there are discrepancies in cutoff points in assay scores to define positive vs. negative results, interlaboratory variability and derivations from recommended package inserts.
The general consensus among panel members is that the assays have worked in the past, but the question remains whether will they continue to work as technology progresses.
That point was proven when panel members voted unanimously to recommend that Vysis Inc.¿s PathVysion HER2 DNA Probe Kit, which uses FISH technology, is an appropriate method to assist in the selection of patients for Genentech Inc.¿s breast cancer therapy, Herceptin (trastuzumab).
In discussions about the future of such technologies in other therapies, ODAC members debated whether detailed or standardized instructions on diagnostic assays would stop some misinterpretations on the laboratory level.
Stacy Nerenstone, ODAC¿s chairman, said, ¿You want us to read the directions, don¿t you? I think the more information you put in, the less time someone is going to spend looking at it.¿
Nerenstone, of Oncology Associates P.C., Helen & Harry Gray Cancer Center at Hartford Hospital, in Hartford, Conn., is an associate professor of oncology.
Another member suggested that his colleagues consider trial participants before forwarding any decisions on using central laboratories for pivotal trials, and on whether patients should submit tissue to be banked and later tested.
¿I¿m just throwing this out there,¿ said Stephen George, ODAC member and professor of biostatistics at the Department of Biostatistics and Bioinformatics at Duke University in Durham, N.C. ¿I¿m not saying this is my opinion, but trials should be simpler for patients. We don¿t want delays or expensive trials, because people who might have entered may not want to, if they have to submit to extra tests.¿
PathVysion, a diagnostic test using FISH technology developed by Vysis Inc., of Downer¿s Grove, Ill., is designed to detect HER2 (human epidermal growth factor receptor-2), which is both a normal gene and one that has the ability to cause cancer.
PathVysion consists of two DNA probes that are labeled with a fluorescent marker that binds to target DNA or a particular gene with a tumor cell nucleus. The technology allows for direct visualization of the gene.
The FDA makes the final decision and is not bound by the panel¿s recommendation.
¿Clearly the test is imperfect,¿ said Musa Mayer, a panel member. ¿But I think it can provide information in making a treatment decision for women with breast cancer who don¿t have many choices. If there is some way of accepting this test with the caveat of further testing, I think it would be beneficial.¿
Scott Lippman, ODAC member and professor of medicine and cancer prevention at the University of Texas Anderson Cancer Center, in Houston, said FISH, ¿done the right way, is useful, and immunohistochemistry done in the right way is useful. But I don¿t think we have data to say which is better. I think we should leave that up to the physicians.¿
Vysis and Genentech, of South San Francisco, last year entered a collaborative agreement under which PathVysion would be used to assess patients for whom Herceptin therapy is being considered. Financial terms were not disclosed. (See BioWorld Today, May 24, 2000.)
PathVysion already is approved to detect HER2/neu gene amplification as an adjunct to existing clinical and pathologic information that is used as prognostic factors in node-positive, Stage II breast cancer.
Herceptin, a monoclonal antibody, works by targeting HER2 protein overexpressing cells. It inhibits cancer cell division and growth by seeking out extra HER2 protein receptors on the surface of cancer cells, attaching itself to these areas and preventing the HER2 growth response. By binding to the receptor sites, Herceptin has been shown to slow the growth and spread of tumors that have an overabundance of HER2 protein.
Given as a weekly infusion in a doctor¿s office, Herceptin was approved by the FDA in September 1998 for use in women with metastatic breast cancer who have tumors that overexpress the HER2 protein. (See BioWorld Today, Sept. 29, 1998.)
Vysis, a genomics disease management company, is being purchased by Abbott Laboratories, of Abbott Park, Ill., in a cash tender offer worth about $355 million. (See BioWorld Today, Oct. 25, 2001.)
Genentech notes that research has shown that women with HER2 positive disease breast cancer have a more aggressive disease, greater likelihood of recurrence, poorer prognosis and approximately have the life expectancy of women with HER2 negative breast cancer.