ODAC Backs Adding HER-2 DNA Test to Herceptin Package Insert

January 1, 2002

SILVER SPRING, Maryland-The FDA’s Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended that the agency amend the labeling of Herceptin (trastuzumab, Genentech) to include a new gene-detection test to identify women with metastatic breast cancer who are likely to benefit from the therapy. The 16-to-0 vote backed adding the PathVysion HER-2 DNA Probe Kit to the labeling. The kit is made by Vysis, Inc., now owned by Abbott Laboratories.

SILVER SPRING, Maryland—The FDA’s Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended that the agency amend the labeling of Herceptin (trastuzumab, Genentech) to include a new gene-detection test to identify women with metastatic breast cancer who are likely to benefit from the therapy. The 16-to-0 vote backed adding the PathVysion HER-2 DNA Probe Kit to the labeling. The kit is made by Vysis, Inc., now owned by Abbott Laboratories.

The FDA approved Herceptin, a humanized monoclonal antibody, in September 1998 for use in combination with paclitaxel (Taxol) as a first-line treatment for women with metastatic breast cancer whose tumors overexpress the protein HER-2, an epidermal growth factor receptor. The antibody is also approved as a single-agent therapy for HER-2-positive patients as second- and third-line therapy.

Currently, the FDA has approved two tests for selecting Herceptin patients, the HercepTest (DAKO, Inc.) and Pathway (Ventana, Inc.), although only the HercepTest is listed in the Herceptin package insert. Both tests rely on immunohistochemistry (IHC) to assess HER-2 status.

The PathVy-sion kit, on the other hand, uses fluorescence in situ hybridization (FISH), which can determine the number of HER-2 genes in a woman’s breast cancer cells. The gene codes for the HER-2 protein, and thus its amplification in a tumor cell can reveal a patient’s potential to respond to Herceptin therapy.

"A direct correlation exists between gene amplification and overexpression," said Michael Press, MD, PhD, professor of pathology, University of Southern California Norris Comprehensive Cancer Center. "Amplification, as determined by FISH, is a clinically meaningful measure associated with poor prognosis and predictive of therapeutic response."

Dr. Press described the biology of HER-2 and the ways to assess it on behalf of Genentech.

The sponsor presented two studies in support of adding PathVysion to the Herceptin package insert—a concordance study between the FISH test and the IHC test used as the Herceptin clinical trials assay and a clinical outcomes study that assessed FISH using archived tissue from Herceptin trials.

"The Herceptin pivotal trials represent the only large database available to correlate HER-2 diagnostics with treatment outcome," said Robert D. Mass, MD, Genentech’s associate director for oncology.

The first study showed a concordance of 82% between PathVysion and the clinical trials assay. "The level of concordance between PathVysion and the clinical trials assay is consistent with HercepTest," Dr. Mass said. "PathVysion will provide a similar performance compared to HercepTest when used as a surrogate for the clinical trials assay to select patients for Herceptin therapy."

The outcomes analysis presented by Genentech explored the relationship between patients’ FISH status—positive (more than two HER-2 genes) or negative (two genes or less)—and the clinical benefits of Herceptin. The retrospective study compared response rate, time to disease progression, and survival for the 96% of the 799 patients who took part in three Herceptin trials for whom FISH results were obtained.

Among 163 participants with one or two prior chemotherapy treatments, 20% of the FISH-positive but none of the FISH-negative patients showed a clinical response.

The analysis also looked at 451 patients who had no previous chemotherapy and who were treated with either chemotherapy alone or chemotherapy plus Herceptin.

Outcomes

In the FISH-positive group, 30% treated with chemotherapy-only and 54% of the chemotherapy-plus-Herceptin patients showed a clinical response. Among FISH-negative patients, the response rate was 38% for those receiving only chemotherapy and 40% for those receiving both.

FISH-positive women also did better than those found to be FISH-negative in terms of time to disease progression and survival when treated with Herceptin.

FDA medical reviewer Susan Jerian, MD, called the concordance between FISH and the clinical trials assay "moderate" and said the agency’s analysis found that between 11% and 13% of patients who test positive by IHC, and therefore might benefit from Herceptin, would not be selected by FISH.

"There are insufficient data to definitively describe the predictive capability of FISH as the first and only test to identify patients who would benefit from trastuzumab therapy," she told the committee. "Direct comparative claims or statements of equivalence or superiority between FISH and IHC cannot be made."

After several panel members suggested that the PathVysion test did offer benefit, especially among certain subpopulations, Timothy O’Leary, MD, PhD, of the Armed Forces Institute of Pathology, an ODAC voting consultant, suggested that it is important to offer physicians an additional assay choice but to carefully explain the differences between the FISH and IHC methods and results.

Several members also noted evidence of considerable variation among laboratories in the results they obtain when using FISH and questioned whether this might not lead to false positives or false negatives. But after a long discussion, the panel expressed its favorable view by recommending the addition of PathVy-sion to the Herceptin package insert.