Thursday, May 15, 2008
South San Francisco, Calif. -- May 15, 2008 --Genentech, Inc. (NYSE:DNA) today announced results from studies of several investigational agents targeting the biological cancer pathways of HER (human epidermal growth factor receptor) signaling, Hedgehog signaling and apoptosis (programmed cell death). These data will be presented during the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) taking place May 30 to June 3 in Chicago. Results will be presented from a Phase II study of pertuzumab in HER2-positive metastatic breast cancer and Phase I studies of trastuzumab-DM1 (T-DM1), an investigational HER2 antibody-drug conjugate; GDC-0449, a small molecule antagonist of the Hedgehog pathway; and two novel agents designed to trigger apoptosis, ABT-263 and Apo2L/TRAIL.
"Early clinical data with these investigational anti-cancer agents reflects our significant research effort and demonstrates Genentech's commitment to discovering the next cancer breakthroughs," said Susan Desmond-Hellmann, M.D., M.P.H., president, Product Development. "By exploring new cellular targets and cancer growth pathways, we hope this research may ultimately lead to improved treatment options for people with cancer."
Results of a Phase II Trial of Trastuzumab and Pertuzumab in Patients with HER2-Positive Metastatic Breast Cancer Who had Progressed During Trastuzumab Therapy (Abstract #1026)
Karen Gelmon, M.D., British Columbia Cancer Agency, Vancouver, Canada; Tuesday, June 3, 2008, 11:00 a.m. - Noon CDT; E354a
Updated results from an ongoing Roche-sponsored Phase II study of the combination of two HER2-targeted monoclonal antibodies, pertuzumab and Herceptin® (trastuzumab), without concurrent chemotherapy in women with HER2-positive metastatic breast cancer whose disease progressed following previous treatment with Herceptin and chemotherapy will be presented.
At the time of abstract submission, preliminary data from 66 patients treated with the combination of pertuzumab and Herceptin showed objective responses in six of 33 evaluable patients (one complete response, five partial responses). Seven patients had stable disease lasting more than six months and 10 patients had stable disease lasting less than six months. The most common adverse events included diarrhea, pain, mucositis (inflammation of mucous membrane lining the digestive tract) and nausea/vomiting. Serious Grade 3 adverse events that resolved without discontinuation of treatment included one case of diarrhea, one case of pruritic rash due to contrast dye allergic reaction and a central line infection. No significant cardiac toxicity was reported and no patients withdrew from the study due to treatment-related or cardiac adverse events. Updated efficacy and safety data will be reported at the meeting.
"These encouraging preliminary data suggest that combining two HER2-directed therapies with complementary mechanisms of action may provide greater inhibition of the HER signaling pathway," said Jose Baselga, M.D., chairman and professor of medicine, Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain and one of the study authors. "The treatment responses observed to date in this study validate the need to further investigate the combination of these two targeted agents and we look forward to presenting the updated data at the meeting."
Pertuzumab, a HER dimerization inhibitor, is designed to bind to the HER2 receptor a protein found on the surface of cells that line the internal and external surfaces of the body and prevent the pairing (dimerization) of HER2 with other HER family receptors on the surface of cancer cells. This receptor pairing is believed to play an important role in the growth and formation of several different cancer types.
A global Phase III study (CLEOPATRA) investigating the combination of pertuzumab and Herceptin plus docetaxel chemotherapy in first-line HER2-positive metastatic breast cancer is currently enrolling patients..
A Phase I Study of Trastuzumab-DM1, a First-in-Class HER2 Antibody-Drug Conjugate (ADC), in Patients with Advanced HER2-Positive Breast Cancer (Abstract #1028)
Muralidhar Beeram, M.D., South Texas Oncology & Hematology, San Antonio, Texas; Tuesday, June 3, 2008, 11:00 a.m. - Noon CDT; E354a
Twenty-four patients with HER2-positive metastatic breast cancer whose disease had progressed during prior Herceptin therapy have been enrolled in a Phase I study of single-agent trastuzumab-DM1 (T-DM1) administered every three weeks. The maximum tolerated dose of T-DM1 with this schedule was 3.6 mg/kg IV. Dose-limiting, rapidly reversible, Grade 4 thrombocytopenia (lowered platelet levels) was observed at 4.8 mg/kg. No other Grade 4 adverse events and no cardiac-specific toxicity have been observed to date. The most common adverse events reported with this dosing schedule were Grade 1/2 thrombocytopenia, fatigue, nausea, elevated liver enzymes, anemia, headache and constipation.
The confirmed response rate in patients with measurable disease treated at or below the maximum tolerated dose was 36 percent (5/14). A total of 15 patients were treated at the recommended Phase II dose (3.6 mg/kg) and median progression-free survival in this group was 9.8 months. Nine of these patients had measurable disease, four (44 percent) of whom had a confirmed partial response. Treatment is ongoing for six patients.
Results from a weekly dosing schedule will also be presented at the meeting (Abstract #1029), which demonstrated similar efficacy and safety as observed with the every-three-week dosing schedule.
In 2007, Genentech initiated a Phase II trial of single-agent T-DM1 administered every three weeks in patients with HER2-positive metastatic breast cancer who have progressed on a Herceptin-containing regimen. Genentech is developing T-DM1 under a collaboration agreement with ImmunoGen, Inc.
A First-in-Human, First-in-Class, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC- 0449, in Patients with Advanced Solid Tumors (Abstract #3516)
Patricia LoRusso, D.O., Karmanos Cancer Center, Wayne State University, Detroit, Mich.; Oral Presentation; Sunday, June 1, 2008, 8:00 a.m. - 8:15 a.m. CDT; W375a
Interim results will be presented from a Phase I study evaluating the safety, tolerability and pharmacokinetic profile of GDC-0449, a small molecule antagonist of the Hedgehog signaling pathway, in 19 patients with refractory solid tumors that have not responded to prior treatment. GDC-0449 demonstrated a favorable pharmacokinetic profile, with high sustained micromolar plasma concentrations and a terminal half-life of greater than seven days. No dose-limiting adverse events were observed at the three dose levels of GDC-0449 studied.
Two cases of reversible drug-related Grade 3 hyponatremia (lowered serum sodium level) and one case of reversible Grade 3 drug-related fatigue were reported. Stable disease was achieved in two patients with adenocystic carcinoma (a rare cancer most commonly found in the salivary glands) and partial responses were observed during this study in two patients with advanced basal cell carcinoma (BCC).
Data were reported earlier this year (American Association for Cancer Research, April 2008) for nine patients with advanced BCC, including the two advanced BCC patients described here, from an expansion cohort of this study. Stable disease or partial responses were achieved in eight out of nine patients (six partial responses, two stable disease) without significant toxicity.
This is the first study to evaluate a systemic Hedgehog antagonist in human clinical trials. Abnormal activation of the Hedgehog pathway appears to be an important mechanism for tumors to survive and grow. Mutations of the Hedgehog pathway have been implicated in the development of several tumors, such as BCC. Additionally, the progression of several solid tumor cancers has been associated with over-expression of the Hedgehog ligand, including colorectal cancer.
Genentech is initiating three Phase II studies of GDC-0449 this year. A Phase II study in first-line metastatic colorectal cancer began enrolling patients in Q2 2008 and other studies are planned in advanced BCC and an advanced epithelial tumor. Genentech is developing GDC-0449 under a collaboration agreement with Curis, Inc.
A Phase I Study Evaluating the Safety, Pharmacokinetics and Efficacy of ABT-263 in Subjects with Refractory or Relapsed Lymphoid Malignancies (Abstract #8511)
Wyndham Wilson, M.D., National Cancer Institute, Bethesda, Md.; Oral Presentation; Sunday, June 1, 2008, 9:45a.m. - 10:00 a.m. CDT; E354b
Updated data will be presented from an interim analysis of a Phase I study evaluating the safety, pharmacokinetic profile and efficacy of single-agent ABT-263 in 30 patients with refractory or relapsed lymphoid malignancies. At the time of abstract submission, preliminary trial data indicated five of the 30 enrolled patients showed a response to single-agent ABT-263. Two patients with bulky chronic lymphocytic leukemia (CLL), one patient with bulky CLL/small lymphocytic lymphoma (SLL), one patient with follicular lymphoma and one patient with natural killer (NK)/T-cell lymphoma experienced tumor reductions (99 percent, 36 percent, 75 percent, 20 percent and 75 percent, respectively). Adverse events included two cases of Grade 3 dose-limiting toxicity (upper respiratory infection and elevated liver enzymes) and five cases of Grade 3 thrombocytopenia (lowered platelet level) without any signs of bleeding. Dose-escalation continues in this trial and updated information will be presented at the meeting.
ABT-263 is a small molecule Bcl-2 family protein antagonist, being co-developed by Genentech and Abbott, that is designed to restore apoptosis in cancer cells. These proteins are expressed at high levels in many tumors and promote tumor formation and growth by blocking the normal process of apoptosis. ABT-263 is being studied in Phase I/II clinical trials as a single agent in patients with relapsed or refractory CLL, relapsed or refractory lymphoid malignancies, small cell lung cancer and other non-hematologic malignancies.
Phase Ib Study of Recombinant Human (rh)Apo2L/TRAIL in Combination with Paclitaxel, Carboplatin and Bevacizumab in Patients with Advanced Non-Small Cell Lung Cancer (Abstract #3539)
Jean-Charles Soria, M.D., Institute Gustave Roussy, Villejuif, France; Saturday, May 31, 2008, Noon - 1:00 p.m. CDT; W375a
Interim results from a Phase Ib study evaluating the safety and pharmacokinetic profile of Apo2L/TRAIL added to Avastin® (bevacizumab) in combination with paclitaxel and carboplatin chemotherapy as first-line treatment in 24 patients with advanced, non-squamous, non-small cell lung cancer (NSCLC) will be reported at the meeting.
At the time of abstract submission, preliminary trial data indicated that the addition of Apo2L/TRAIL to Avastin and chemotherapy showed an overall response rate of 56 percent among 18 patients who had completed the study at the time of data analysis (one complete response and nine partial responses). No dose-limiting toxicities were observed and the maximum tolerated dose had not been reached. Grade 2 or greater adverse events possibly related to Apo2L/TRAIL included rhinitis (runny nose), arthralgia (sore joints) and epistaxis (nose bleed). Updated data will be presented at the meeting. In addition, a population pharmacokinetic analysis of Apo2L/TRAIL in a Phase Ia study in advanced cancer and lymphoma will be presented (Abstract #2525). Data identifying potential biomarkers of tumor susceptibility to Apo2L/TRAIL will be published.
Apo2L/TRAIL is designed to activate two pro-apoptotic receptors, DR4 and DR5, and is being co-developed by Genentech and Amgen, Inc. A Phase Ib/II study of Apo2L/TRAIL in combination with Rituxan® (rituximab) in patients with follicular and other low-grade CD20+ B-cell non-Hodgkin's lymphoma is currently enrolling patients. Genentech and Amgen are also studying Apo2L/TRAIL in an ongoing Phase II study in combination with paclitaxel and carboplatin with Avastin (or without Avastin in ineligible patients) for the first-line treatment of advanced NSCLC.
Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines for patients with significant unmet medical needs. The company has headquarters in South San Francisco, California and is listed on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit http://www.gene.com.
For the full prescribing information and Boxed Warnings for Avastin, Herceptin and Rituxan please visit http://www.gene.com.
This press release contains forward-looking statements regarding the potential of our investigational agents and the initiation of clinical trials. Such statements are predictions and involve risks and uncertainties such that actual results may differ materially. Actual results may be affected by a number of factors including, but not limited to, unexpected safety, efficacy or manufacturing issues, difficulty enrolling patients in clinical trials, the need for additional data or clinical studies, FDA actions or delays, failure to obtain or maintain FDA approval, competition, pricing, reimbursement, the ability to supply product, product withdrawals, new product approvals and launches, and intellectual property or contract rights. Please also refer to the risk factors described in Genentech's periodic reports filed with the Securities and Exchange Commission. Genentech disclaims, and does not undertake, any obligation to update or revise any forward-looking statements in this press release.