Monday, May 14, 2001

Addition of Herceptin to Chemotherapy Demonstrates 50 Percent increase in Survival Benefit in Patients Selected by FISH

Retrospective Study Demonstrates Testing HER2 Gene Amplification by FISH as Effective Method to Identify Women with HER2 Positive Metastatic Breast Cancer

Investigational Study Evaluates New Three-Week Dosing Schedule

Investigational Study Evaluates New Three-Week Dosing Schedule

South San Francisco, Calif. -- May 14, 2001 --

Genentech (NYSE: DNA) today announced results from three retrospective studies demonstrating that FISH (fluorescence in situ hybridization) testing of tumor tissue for HER2 gene amplification appears to be an effective method for selecting women with HER2 positive metastatic breast cancer who are most likely to respond to Herceptin® (Trastuzumab) therapy. Data from these studies were presented today during two oral presentations at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO).

In the retrospective analysis of tumor tissue from women in the Phase III pivotal combination trial, those who were FISH positive for HER2 gene amplification survived 50 percent longer -- 27 months vs. 18 months -- when given Herceptin with chemotherapy as compared to those who received chemotherapy alone.

This result contrasts with the 24 percent increase in survival time seen when the same tumors tested positive for HER2 protein overexpression with immunohistochemistry (IHC) testing.

"Herceptin is one of the first examples to demonstrate the benefits of a targeted, individualized medicine," said Gwen Fyfe, M.D., Genentech's senior director of Oncology, Medical Affairs. "This retrospective analysis demonstrates that FISH testing appears to be an appropriate modality to test tumors for the specific abnormality targeted by Herceptin."

Genentech has submitted a supplemental Biological License Application (sBLA) to the U.S. Food and Drug Administration (FDA) to revise its product labeling to include FISH testing as an additional method to select patients appropriate for treatment with Herceptin.

HER2 Gene Amplification in Herceptin Combination Therapy Phase III Trial

(Abstract #85)

(Abstract #85)

In a presentation titled "Improved Survival Benefit from Herceptin (Trastuzumab) and Chemotherapy in Patients Selected by FISH," lead author Robert Mass, M.D., clinical scientist at Genentech, and colleagues retrospectively tested and analyzed tumor tissue from 458 of 469 patients from the Phase III pivotal first-line combination trial of Herceptin. The goal of the study was to determine how HER2 gene amplification, measured by FISH, compared with HER2 protein overexpression measured by IHC, in identifying patients for Herceptin therapy. Overexpression is determined on a scale of 0 to 3+, and HER2 levels of 2+ and 3+ measured by IHC were required for enrollment in the pivotal trial.

Utilizing the PathVysion? FISH assay system, developed by Vysis, HER2 gene amplification was detected in 76 percent of the study population. Eighty-nine percent of 3+ IHC samples and 31 percent of 2+ IHC samples tested positive for FISH. In this FISH-positive subgroup, the addition of Herceptin to chemotherapy resulted in an improvement in response rate to 54 percent compared to 31 percent for those women receiving chemotherapy alone. There was no improvement in response rates in women in the trial whose tumors were FISH negative for HER2 gene amplification (38 percent for Herceptin with chemotherapy versus 37.5 percent for chemotherapy alone).

"These extensive retrospective analyses show us that measuring gene amplification with FISH testing may provide more accurate information about potential tumor response rates and improvement in survival with Herceptin," said Dr. Mass.

Single Agent Herceptin Clinical Trials in First-line and Relapsed HER2 Positive Metastatic Breast Cancer (Abstract #86) Two additional retrospective FISH analyses titled "Superior Outcomes with Herceptin (Trastuzumab) in FISH-selected Patients" were presented by Charles Vogel, M.D., lead investigator from the University of Miami Cancer Center, and colleagues. In an analysis of a study in which Herceptin was given as a single agent to newly-diagnosed HER2 positive metastatic breast cancer patients, 82 of 111 IHC positive participants were also FISH-positive. Response rates for the FISH-positive subgroup were 34 percent compared with seven percent for the FISH-negative group and 26 percent for the IHC-positive patients. Time to disease progression was 4.9 months for the FISH-positive group, 1.7 months for the FISH-negative group and 3.5 months for those who were positive using IHC.

In an analysis of the single-agent pivotal trial with Herceptin given as second- or third-line therapy after disease progression following one or two chemotherapy regimens, 173 out of 209 IHC-positive patients tested FISH positive. Response rates were 19 percent in the FISH-positive group, zero percent in the FISH-negative group and 15 percent in the IHC-positive group. Time to disease progression was 3.2 months in the FISH-positive group, 1.9 months for FISH-negative and 3.1 months for IHC-positive. There was an increase in survival between the FISH-positive and FISH-negative women with the former living a median of 14.2 months and the latter 8.8 months, an increase of 5.4 months or 61 percent for women who were FISH-positive and treated with single agent Herceptin. Overall survival for women in the trial who tested positive for HER2 by IHC was 12.8 months.

"These results further highlight the important role that appropriate patient selection plays in identifying women most likely to benefit from Herceptin," said Dr. Mass.

Herceptin in Combination with Paclitaxel Every Three Weeks (Abstract #1271)

A third oral presentation on Herceptin, titled "Pharmacokinetics and Safety of Herceptin When Administered Every Three Weeks to Women with Metastatic Breast Cancer," was presented by Dr. Karen Gelmon of BCCA Vancouver Centre.

The study evaluated the use of Herceptin and paclitaxel given once every three weeks in 25 women with HER2 positive metastatic breast cancer. The participants received a "triple dose" of Herceptin [8 mg/kg as a loading dose followed by 6 mg/kg] and paclitaxel [175 mg/m2] every three weeks. Following eight cycles of paclitaxel, patients continue to receive Herceptin alone every three weeks. After two cycles, concentrations of Herceptin were similar to those obtained in the once weekly dosing studied in the pivotal trial.

The every three-week regimen did not appear to cause a clinically significant increase in adverse events as compared to those seen with the once weekly dosing regimen. Adverse events seen to date include neutropenia, alopecia, fatigue, arthralgia, myalgia and parasthesia that are common side effects of paclitaxel therapy. One patient experienced grade III heart failure.

"Clinical studies have demonstrated that Herceptin given once weekly in combination with chemotherapy provides a significant survival benefit for women with HER2 positive metastatic disease," said Dr. Fyfe. "While this study is preliminary, it suggests that administering a 'triple dose' of Herceptin one third as often, i.e. every three weeks, may prove to be a more convenient schedule for women with HER2 positive metastatic breast cancer."

About Breast Cancer

Approximately 1.6 million U.S. women are alive today with breast cancer, with approximately 225,400 new diagnoses annually, according to the National Breast Cancer Coalition. Genentech estimates there are approximately 164,000 women with metastatic breast cancer.

About Herceptin

Herceptin received FDA approval in September 1998 for the treatment of women with HER2 positive metastatic breast cancer both as a first-line therapy in combination with paclitaxel and as a single agent in second- and third-line therapy. The genetic alteration in the HER2 gene produces an increased amount of HER2 growth factor protein on tumor cell surfaces that can be inhibited with the administration of Herceptin in patients with HER2 positive disease. Routine testing in women with breast cancer is critical for identification of patients who are HER2 positive and who potentially could benefit from treatment with Herceptin.

Herceptin is generally well-tolerated. Overall, the most common adverse events were fever, hematologic toxicity and cardiac dysfunction. Infusion-associated signs and symptoms were observed but did not require antibody discontinuation. In the post-marketing setting, rare serious and fatal infusion-related events have occurred. Most patients who experienced the more serious and fatal infusion-related events had pre-existing pulmonary compromise and advanced malignancy.

The most serious adverse event was cardiac dysfunction (NYHA Grade I-IV), which occurred more frequently when Herceptin was administered with anthracycline and cyclophosphamide (AC) (27 percent) compared with AC alone (8 percent), or with Herceptin plus paclitaxel (13 percent) compared to paclitaxel alone (1 percent).

Although the NYHA Grade III/IV toxicity, which occurred in a smaller percentage of patients, was potentially severe and/or life threatening, signs and symptoms improved in 75 percent of patients and none of the patients receiving paclitaxel and Herceptin had persistent Grade III/IV cardiac dysfunction with medical management. Continued use of Herceptin was not associated with further cardiac deterioration in most patients. The only significant risk factor associated with this adverse event was advanced age.

Herceptin is marketed in the United States by Genentech and internationally by F. Hoffman-LaRoche.

Genentech, Inc. is a leading biotechnology company that discovers, develops and manufactures and markets human pharmaceuticals for significant unmet medical needs. Fourteen of the currently marketed biotechnology products stem from Genentech science, nine of which Genentech markets directly in the United States. The company has headquarters in South San Francisco, California and is traded on the New York Stock Exchange and the Pacific Exchange under the symbol DNA.

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For more information, please visit http://www.gene.com.

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