Full Prescribing Information, including Boxed Warnings

Date	Event
1975		Georges Köhler and César Milstein, scientists at the Medical Research Council, Laboratory of Molecular Biology (Cambridge, UK), discovered the potential of using antibodies in vitro to fight disease.
1976		The research of Michael Bishop and Harold Varmus at the University of California San Francisco showed that disturbances in one or more members of a family of genes can lead to the transformation of a normal cell into a cancer cell.
1976		Genentech was founded by venture capitalist Robert A. Swanson and biochemist Dr. Herbert W. Boyer.
1981		Genentech scientists cloned a portion of the HER2 gene.
1984		Robert Weinberg and his team of scientists at the Massachusetts Institute of Technology discovered a rat gene that produced cancer features in transfected cells and named it "neu." "Neu" later would be known as "Her-2/neu" or "HER2."
1984		Georges Köhler and César Milstein win the Nobel Prize in Medicine, "for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies."
1984		Genentech scientists Axel Ullrich and Peter Seeberg, in collaboration with Mike Waterfield at the Imperial Cancer Research Fund and Joseph Schlesinger at the Weizmann Institute, published the complete human EGF-R sequence in Nature.
1985		Following work that began in the early 1980s, a Genentech team of scientists, including Axel Ullrich and Art Levinson, clone the first full-length human HER2 gene. This achievement is described in a paper published in Science.
1985		Stu Aaronson at the National Institute of Health showed that the HER2/neu gene is frequently amplified in human breast tumors.
1987		Axel Ullrich of Genentech, Dr. Dennis Slamon et al at UCLA, and colleagues at the University of Texas Health Science Center published in Science the link between HER2 overexpression with a more aggressive type of breast cancer in approximately 25 percent of patients.
1989		Michael Bishop and Harold Varmus were awarded the Nobel Prize in Medicine for their discovery that normal cells contain genes capable of becoming cancer genes.
1990		Len Presta and Paul Carter of Genentech humanized a mouse antibody directed at HER2.
1992		Genentech filed an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA) and Phase I clinical trials were initiated.
1993		Genentech initiated two Phase II clinical trials that evaluated the investigational anti-HER2 antibody as a single agent and in combination with chemotherapy in the relapsed setting.
1995		Genentech began enrollment of the Phase III pivotal trials for patients with HER2 over-expressing metastatic breast cancer. Pivotal trial 648, double-blind, placebo-controlled study of the investigational anti-HER2 antibody plus chemotherapy to include 450 women with newly diagnosed metastatic breast cancer Trial 649, study of the investigational anti-HER2 antibody as a single agent to include 200 women whose metastatic disease had failed to respond to one or two rounds of chemotherapy Trial 650, study of the investigational anti-HER2 antibody to include 200 women who had newly diagnosed metastatic breast cancer but did not want chemotherapy Genentech worked closely with breast cancer patient advocates to design an expanded access program to ensure the investigational agent is available to patients with no other therapeutic alternatives. Genentech advanced the construction of a new manufacturing facility that would produce the anti-HER2 antibody.
1996		Critical efforts are undertaken to enroll patients into the trials, including: Genentech clinicians and outside investigators spearheaded an amendment to the study protocol of pivotal trial 648 to include paclitaxel chemotherapy as an alternative to doxorubicin chemotherapy and traveled across the country to inform investigators to spur interest in the trial; Genentech and patient advocates worked together to publicize the trials to the breast cancer community.
March 1996		Researchers at Memorial Sloan Kettering co-authored a paper titled, "Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2-neu-overexpressing metastatic breast cancer," which showed that the antibody was well-tolerated and clinically active in women with HER2-neu-overexpressing metastatic breast cancer who had received prior therapy. The study provided evidence that targeting growth factor receptors can cause regression of human cancer.
December 1996		Genentech initiated a partnership with diagnostics company DAKO to develop a commercial test to identify patients who overexpress the HER2 gene.
March 1997		Genentech completed enrollment of the Phase III pivotal trials for the anti-HER2 antibody (now known as Herceptin® (Trastuzumab)).
May 1998		Genentech submitted a biologic license application (BLA) for Herceptin, and DAKO submitted a pre-market approval (PMA) application to the FDA for approval of the diagnostic HercepTest™. The FDA designated Herceptin as a "Fast Track" product for the treatment of metastatic breast cancer.
May 1998		Results from a Phase III investigational clinical trial of Herceptin were presented at the American Society of Clinical Oncology (ASCO) annual meeting. Results showed that Herceptin, in combination with chemotherapy, increased time to disease progression and response rates.
July 1998		Genentech and Roche signed a licensing agreement giving Roche exclusive marketing rights for Herceptin outside of the United States.
September 1998		Herceptin received FDA approval for use in women with metastatic breast cancer who have tumors that overexpress the HER2 protein. It is indicated for treatment of patients both as first-line therapy in combination with paclitaxel chemotherapy and as a single agent for those who have received one or more chemotherapy regimens. Dako's HercepTest is approved simultaneously to aid in the identification of patients for Herceptin treatment. Herceptin was the first therapeutic antibody targeted to a specific (HER2) cancer-related molecular marker to receive FDA approval.
May 2000		Genentech issued a letter to healthcare providers about reports of serious adverse events, including hypersensitivity, infusion and pulmonary reactions.
August 2000		European Commission approved Herceptin for the treatment of HER2-positive metastatic breast cancer.
December 2000		Enrollment of two Phase III clinical trials evaluating the potential use of Herceptin for the adjuvant treatment of early-stage HER2-positive breast cancer was initiated. Adjuvant therapy is given to women with early-stage (localized) breast cancer who have had initial treatment — surgery with or without radiation therapy — with the goal of reducing the risk of cancer recurrence and/or the occurrence of metastatic disease. The studies are sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and conducted by a network of researchers led by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the North Central Cancer Treatment Group (NCCTG).
March 2001		Further data from a pivotal Phase III clinical trial were published in the New England Journal of Medicine (NEJM) that showed a significant increase in survival for women with HER2-positive metastatic breast cancer who received Herceptin and chemotherapy over chemotherapy alone.
March 2001		HERA, the third adjuvant trial of Herceptin, began enrollment.
December 2001		Genentech received FDA approval to include, in the product label, data that showed an improved median overall survival for women with HER2-positive metastatic breast cancer treated initially with Herceptin and chemotherapy, compared to chemotherapy alone (median 25.1 months compared to 20.3 months).
December 2001		BCIRG 006, the fourth adjuvant trial of Herceptin, began enrollment.
August 2002		Genentech received FDA approval to include information about a breast cancer gene-detection test method called FISH (fluorescence in situ hybridization) in the Herceptin product labeling.
May 2005		Results from a joint analysis of the Phase III NSABP and NCCTG clinical trials evaluating the addition of Herceptin to standard adjuvant therapy for early-stage HER2-positive breast cancer were presented at the ASCO annual meeting. According to this 3-year planned joint analysis, Herceptin in combination with chemotherapy significantly reduced the risk of cancer recurrence.
August 2005		Genentech issued a letter to healthcare providers informing them of updated cardiotoxicity information related to the use of Herceptin, obtained from the Phase III NSABP study (B-31).
February 2006		Based on results from the joint analysis of the NSABP and NCCTG trials, Genentech filed a supplemental Biologics License Application (sBLA) with the FDA for Herceptin for the adjuvant treatment of early-stage HER2-positive breast cancer.
November 2006		The FDA approved Herceptin as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of patients with early-stage HER2-positive, node-positive breast cancer based on the joint analysis of the NSABP and NCCTG studies.
December 2006		Genentech submitted an sBLA with the FDA based on the global HERA study to potentially expand Herceptin's use in the adjuvant treatment of early-stage HER2-positive breast cancer.
June 2007		Genentech submitted two sBLAs to the FDA based on the global BCIRG 006 trial to potentially expand Herceptin's use in the adjuvant treatment of early-stage HER2-positive breast cancer.
January 2008		Based on the HERA one-year data, the FDA approved Herceptin as a single agent for the adjuvant treatment of early-stage HER2-positive node-positive breast cancer or node-negative (ER/PR-negative or with one high-risk feature) following multi-modality, anthracycline-based therapy. Herceptin also may be administered as a single agent in an every-three-week dosing schedule for one year.
May 2008		Based on the results of the BCIRG 006 study, the FDA approved two new Herceptin-containing regimens for the adjuvant treatment of early-stage HER2-positive node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer. The first regimen is in combination with docetaxel and carboplatin, (also known as TCH for Taxotere®, carboplatin, and Herceptin) which does not contain an anthracycline (doxorubicin) component. The second is part of a treatment regimen containing anthracycline (doxorubicin), cyclophosphamide, and docetaxel (AC-TH). In comparison to AC-TH, TCH provided a similarly effective treatment option.
October 2008		More than 420,000 women with HER2-positive breast cancer have been treated with Herceptin worldwide.

Boxed WARNINGS and Additional Important Safety Information Cardiotoxicity and Cardiac Monitoring

• Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF).
• The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens.
• Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.
• Patients should undergo monitoring for decreased left ventricular function before Herceptin treatment, and frequently during and after Herceptin treatment.
• More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricular cardiac dysfunction.
• In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin containing regimens.

Infusion Reactions, Pulmonary Toxicity and Neutropenia

• Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported.
• In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension.
• Patients should be monitored until signs and symptoms completely resolve.
• Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
• Exacerbation of chemotherapy-induced neutropenia has also occurred.

Pregnancy Category D Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman.

Most Common Adverse Events The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

Please see the Herceptin full prescribing information including Boxed WARNINGS and additional important safety information.