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Genentech, Dako Submit Applications to FDA for Herceptin in HER2-Positive Stomach Cancer

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By Turna Ray

This article was posted May 27.

Genentech recently submitted a supplemental biologics license application with the US Food and Drug Administration for Herceptin (trastuzumab) in addition to chemotherapy as a treatment for HER2-positive stomach cancer, including cancer that affects the gastroesophageal junction.

If approved by the FDA, Herceptin stands to be the first personalized cancer treatment for stomach cancer patients who overexpress the HER2 protein.

"This application reflects our commitment to developing more personalized medicines for people with cancer. By using diagnostics to help identify the right patients for our medicines, it is our hope that Herceptin used with chemotherapy will become the first targeted option for advanced HER2-positive stomach cancer," Hal Barron, Genentech's chief medical officer, said in a statement announcing the sBLA submission last month. "We look forward to working with the FDA and [Dako] on this application."

Dako announced in August 2009 that it was working with Genentech to submit to the FDA two genetic tests — the immunohistochemistry-based HercepTest and the HER-2 FISH pharmDx test — as companion diagnostics for Herceptin for the treatment of gastric cancer (PGx Reporter 08/12/09). A Genentech spokesperson told Pharmacogenomics Reporter this week that Dako submitted its applications to the FDA's diagnostics division for the companion tests on April 21, a few days after Genentech filed its sBLA for the new Herceptin indication to the agency's drug review arm on April 19.

"The application requests priority review, which, if granted, takes approximately six months for a decision (compared to 10 months for a standard review)," Krista Pellegrino, Genentech's product communications manager, said in an e-mail. However, the FDA hasn't issued a decision about its review timeline.

The company's filing was based on positive results from a Phase III study, known as ToGA, or the Trastuzumab with chemotherapy in HER2-positive advanced Gastoesophageal Cancer trial, which showed that people treated with Herceptin and chemotherapy had a survival advantage compared to those receiving chemotherapy alone.

In the study, all patients were tested to establish their HER2 status using a diagnostic test from Dako. According to Genentech, approximately 22 percent of patients in ToGA had HER2-positive stomach cancer.

ToGA was an international Phase III study that enrolled 594 people with locally advanced or metastatic HER2-positive stomach cancer who were randomized to receive Herceptin plus chemotherapy (Genentech's Xeloda or intravenous 5-flourouracil and cisplatin) or receive just chemotherapy.

The primary endpoint of the study was overall survival, which was "significantly improved" in patients who received Herceptin plus chemo, compared to those who received chemo alone (HR=0.74, p=0.0046, median OS 13.8 vs. 11.1 months). The objective response rate was 47 percent in the trastuzumab/chemo arm and 35 percent in the chemo arm.

Researchers reported no new or unexpected adverse events in the Herceptin patient group. Specifically, "no statistically significant difference in symptomatic congestive heart failure was seen between the two groups," the researchers reported. One person in the Herceptin group and two in the comparator arm experienced heart failure.

Genentech, a subsidiary of the Roche Group, presented Phase III data from the ToGA trial at the American Society for Clinical Oncology's annual meeting last year. At the time, the company had expressed its intention to expand Herceptin's indication into stomach cancer (PGx Reporter 06/03/09).

Gastric cancer is hard to diagnose since most patients don't show symptoms in the early stages of the disease. In 2009, 10,600 people in the US died from the disease.

"There are several unique aspects of HER2 testing for stomach cancer that differ from breast cancer, which may lead to a HER2-positive or HER2-negative diagnosis, so it will be important for physicians and pathologists to be informed of these differences to allow for accurate and rapid diagnosis," Pellegrino said.

If FDA approves Genentech's sBLA for Herceptin as a treatment for stomach cancer, then the drug's use will be expanded from its current indication as a treatment for HER2-overexpressing breast cancer.

The FDA encourages companies to ink drug/diagnostic partnerships as early as possible in the development cycle of a drug. Additionally, in an effort to advance pharmacogenomic personalized medicine products, the agency is aligning its drug and diagnostics divisions to allow for simultaneous review of the drug and companion diagnostic (PGx Reporter 11/11/09).

Herceptin, first approved by the FDA in 1998, is often cited as the first example of a personalized medicine product that entered the market with a companion test for gauging HER2 status in breast cancer patients. In the drug's label, the FDA informs that HER2 testing may be conducted by several agency-cleared tests, including Dako's HercepTest and Roche's Pathway HER-2/neu IHC assays, as well as Abbott's FISH-based PathVysion and Dako's HER2 FISH pharmDx.

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