Genentech BioOncology Product Portfolio Genentech is working to fundamentally change the way cancer is treated by developing a broad oncology portfolio of innovative targeted therapies designed to improve and extend the lives of cancer patients.

Marketed Products Avastin® (bevacizumab) Avastin is a therapeutic antibody that is believed to work by targeting and inhibiting the function of a natural protein called "vascular endothelial growth factor" (VEGF) that stimulates new blood vessel formation, a process known as angiogenesis. Researchers have shown in preclinical models that anti-VEGF agents like Avastin may work by causing the following changes to occur in the blood vessels supporting tumor growth (tumor vasculature):

• Regression of existing microvessels — helps arrest tumor growth and reduce tumor size
• "Normalization" of surviving mature vasculature — makes the tumor vasculature more conducive to effective anti-cancer therapy
• Inhibition of vessel growth and neovascularization (e.g., the sprouting of new micro-vasculature from existing vessels)

Avastin is currently approved for use in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum, and has been shown to extend survival in this patient population. Avastin is also approved in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC). It was the first anti-angiogenesis therapy approved by the U.S. Food and Drug Administration (FDA).

Based on data showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a broad development program for Avastin that currently includes more than 300 clinical trials in 20 different tumor types. Avastin is being evaluated in Phase III clinical trials for its potential use in adjuvant and metastatic colorectal, renal cell (kidney), breast, pancreatic, non-small cell lung, prostate and ovarian cancers.

Avastin Safety Profile The most serious adverse events associated with Avastin across all trials were GI perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure. The most common adverse events seen in patients receiving Avastin across all studies were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.

Herceptin® (Trastuzumab) Herceptin is a targeted therapeutic antibody treatment for women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, an especially aggressive form of the disease that affects approximately one-fourth of women with breast cancer. Special testing is required to identify women who have HER2-positive breast cancer and who may be candidates for treatment with Herceptin.

Herceptin received FDA approval in September 1998 for use in women with metastatic breast cancer, who have tumors that overexpress the HER2 protein. It is indicated for weekly treatment of patients both in combination with paclitaxel and as a single agent in second- and third-line therapy. In clinical trials of HER2-positive metastatic breast cancer patients, Herceptin has shown a survival benefit when used in combination with chemotherapy. Nearly 400,000 women with HER2-positive metastatic breast cancer have been treated with Herceptin worldwide. In November 2006, the FDA approved Herceptin as part of a treatment regimen containing doxorubicin, cyclophosphamide and paclitaxel, for the adjuvant treatment of patients with HER2-positive, node-positive breast cancer. In January 2008, the FDA approved Herceptin, as a single agent, for the adjuvant treatment of HER2-overexpressing node-negative (ER/PR-negative or with one high risk feature) or node-positive breast cancer, following multi-modality anthracycline-based therapy.

Herceptin Safety Information Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction. Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. Exacerbation of chemotherapy-induced neutropenia has also occurred. Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman. 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.

Rituxan® (Rituximab) Rituxan, the first therapeutic antibody approved for cancer in the United States, targets and selectively depletes CD20, a protein found on the surface of B-cells. Normal B-cells are an important component of the immune system, but uncontrolled B-cell growth and replication can give rise to several types of blood cancers, such as non-Hodgkin's lymphoma (NHL). Rituxan works by binding to a specific protein (CD20 antigen) on the surface of B-cells. From there, it is believed that Rituxan works with the body's own immune system to attack and kill the marked B-cells. Rituxan does not target stem cells, B-cell progenitors in the bone marrow that lack the CD20 protein, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.

Rituxan is approved in the United States for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma (NHL) as a single agent; for previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens; for previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy; and for the treatment of non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent, after first-line CVP chemotherapy.

Rituxan Safety Information: The most important serious adverse reactions of Rituxan are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.

Tarceva® (erlotinib) Tarceva is a small molecule designed to target the human epidermal growth factor receptor 1 (EGFR/HER1) pathway, which is one of the factors critical to cell growth in non-small cell lung cancer (NSCLC). EGFR/HER1 is a component of the HER signaling pathway, which plays a role in the formation and growth of numerous cancers. Tarceva is designed to inhibit the tyrosine kinase activity of the HER1 signaling pathway inside the cell, which may block tumor cell growth. Tarceva is the first and only HER1/EGFR-targeted therapy proven to prolong survival in advanced second-line NSCLC.

Tarceva is an oral tablet currently approved for use as a monotherapy in advanced non-small cell lung cancer for patients whose disease has progressed after one or more courses of chemotherapy (at a recommended dose of 150 mg/day). Results from two randomized, placebo-controlled clinical trials in first-line advanced NSCLC patients showed no clinical benefit with concurrent administration of Tarceva with doublet platinum-based chemotherapy (carboplatin and paclitaxel or gemcitabine and cisplatin) and its use is not recommended in that setting. Tarceva is also indicated in combination with gemcitabine for the treatment of locally advanced or metastatic pancreatic cancer in patients who have not received previous chemotherapy (at a recommended dose of 100 mg/day). Additional early-stage trials of Tarceva are being conducted in other solid tumors.

Tarceva NSCLC Safety Information: The most common side effects in patients with NSCLC receiving Tarceva monotherapy were mild-to-moderate rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9 and 6 percent of Tarceva-treated patients, respectively, with each resulting in 1 percent of patients discontinuing the single-agent Phase III trial. Historically, there have been infrequent reports of serious interstitial lung disease (ILD), including fatalities, in patients receiving Tarceva for treatment of NSCLC or other advanced solid tumors. In the trial, severe pulmonary reactions, including potential cases of interstitial lung disease, were infrequent (0.8 percent) and were equally distributed between treatment arms. The overall incidence of ILD in Tarceva-treated patients from all studies was approximately 0.6 percent. There are no adequate and well-controlled studies in pregnant women using Tarceva. Women of childbearing potential should be advised to avoid pregnancy and breastfeeding while on Tarceva.

Tarceva Pancreatic Safety Information: In the Phase III study in pancreatic cancer, the most common adverse events reported were fatigue, rash, nausea, anorexia and diarrhea. Rash was reported in 69 percent of patients who received Tarceva plus gemcitabine and in 30 percent of patients who received gemcitabine plus placebo. Diarrhea was reported in 48 percent of patients who received Tarceva plus gemcitabine and in 36 percent of patients who received gemcitabine plus placebo. Two percent of the patients discontinued Tarceva because of rash and 2 percent because of diarrhea. In addition, severe and potential fatal adverse events included interstitial lung disease-like complications, myocardial infarction or ischemia, cerebrovascular accident, and microangiopathic hemolytic anemia with thrombocytopenia.

Pipeline Projects Genentech's pipeline continues to grow and includes both breakthrough innovations and new indications for existing, well-understood products that my fight more than one disease or more than one form of a disease.

In oncology, we are focusing our efforts in four primary areas: HER signaling, anti-angiogenesis, apoptosis and B-cell biology. We are studying our marketed products Avastin, Herceptin, Rituxan and Tarceva in numerous new oncology indications as well as conducting combination trials including a Phase III trial of Avastin plus Tarceva in lung cancer. In addition, we are investigating a number of new molecules as cancer therapies, including:

• Pertuzumab, the first in a new class of investigational agents known as HER dimerization inhibitors (HDIs), is being investigated in Phase II studies in combination with other therapies in ovarian cancer, and Phase III studies in combination with Herceptin in HER2-positive metastatic breast cancer are planned;
• Apo2L/TRAIL, a recombinant soluble human protein designed to selectively induce apoptosis (programmed cell death), is being evaluated in collaboration with Amgen in Phase I studies in combination with Rituxan in indolent NHL; and
• Trastuzumab-DM1, a HER2 antibody-drug conjugate which comprises a cell-killing agent linked to a HER2 therapeutic antibody that targets overexpression of the HER2 protein, is being evaluated in HER2-positive metastatic breast cancer.