EAST HANOVER, N.J., Dec. 12 New data from two earlyclinical studies show that RAD001(R) (everolimus) may overcome resistance toHerceptin(R) (trastuzumab)* in women with HER2-positive metastatic breastcancer. These results support the initiation of a Phase III clinical trialprogram to fully explore the potential of RAD001 (proposed brand nameAfinitor(R)) in breast cancer.
Two Phase I studies were presented today during the CTRC-AACR San AntonioBreast Cancer Symposium. Initial results from both studies were releasedearlier this year at the American Society of Clinical Oncology (ASCO) annualmeeting.
Updated results from the first Phase I trial show that the combination ofRAD001 with Herceptin and weekly Taxol(R) (paclitaxel)** halted tumor growthin 77% of patients with HER2-positive metastatic breast cancer with documentedresistance to Herceptin. In addition, the data demonstrated the first completeresponse in the trial.
In addition, updated data from the second Phase I study show promisinganticancer activity for RAD001 in combination with Herceptin and Navelbine(R)(vinorelbine)*** in heavily pretreated Herceptin-resistant patients withHER2-positive metastatic breast cancer. In the study, RAD001 in combinationwith Herceptin and Navelbine halted tumor growth in 62% of patients.
"Data presented at this meeting affirm the potential of RAD001 to reverseHerceptin resistance and restore patient response to treatment," said RuthO'Regan, MD, Emory University School of Medicine, Atlanta, GA. "These findingsare important for patients with HER2-positive metastatic breast cancer whodevelop resistance to Herceptin."
Preclinical data have shown that RAD001, an inhibitor of mTOR, acts on thepathway that mediates Herceptin resistance and has the potential to helprestore response in these patients. RAD001 works through direct antitumoractivity and through its influence on two of the most important pathways forbreast cancer, the erbB receptor and the HER2 pathways.
"We are encouraged by the benefit RAD001 provided to advanced breastcancer patients in these early trials," said Alessandro Riva, MD, ExecutiveVice President & Global Head of Development, Novartis Oncology. "Novartis iscommitted to further evaluating the potential of RAD001 in combination withHerceptin as a new treatment regimen in breast cancer, as well as studying itsrole in treating other tumor types."
Novartis will initiate a worldwide Phase III clinical trial program tofurther evaluate the potential of RAD001 in combination with Herceptin andchemotherapy in patients with HER2-positive metastatic breast cancer. To learnmore about the trial, please visit http://mail.breastcancerresearchstudy.com/,or speak to your doctor.
Study details: abstract #3119
An open-label, multicenter Phase I dose escalation trial evaluated dailyRAD001 (5 mg, 10 mg) and weekly RAD001 (30 mg, 50 mg and 70 mg) regimens incombination with Taxol (80 mg/m2 IV over 60 min on days 1, 8 and 15 every 28days) and Herceptin (2 mg/kg IV over 30 min) in heavily pretreated patientswith HER2-positive metastatic breast cancer with prior resistance toHerceptin.
Across treatment arms, there was an overall disease control rate of 77%(complete response/ partial response/ stable disease greater than or equal to16 weeks). Twenty-two heavily pretreated patients were evaluable for efficacy:treatment arms included five patients assigned to RAD001 5 mg daily, eight toRAD001 10 mg daily and nine to RAD001 30 mg weekly. Among the five patientsevaluated in the 5 mg daily treatment arm, one patient had a complete responseand four patients had partial responses. In the 10 mg daily treatment arm, onepatient had a partial response, six patients had stable disease and onepatient had progressive disease. Among the nine patients evaluated in the 30mg weekly treatment arm, three patients had partial responses, five patientshad stable disease and one patient had progressive disease. The critical dose-limiting toxicities occurring in the first cycle of treatment included febrileneutropenia, oral mucositis and confusion occurring in the 5 mg daily, 10 mgdaily and 30 mg weekly treatment groups, respectively. The most commonlyreported grade 3/4 adverse events (greater than or equal to 10%) suspected ofbeing related to study treatment were neutropenia, lymphopenia, stomatitis,leukopenia, alopecia and anemia.
Study details: abstract #406
An open-label, multicenter Phase I trial evaluated daily RAD001 (2.5 mg, 5mg and 10 mg) and weekly RAD001 (20 mg, 30 mg, 50 mg and 70 mg) in combinationwith Navelbine (25 mg/m2 IV over 10-15 min on days 1 and 8 every 21 days) andHerceptin (2 mg/kg IV over 30 min). All patients entering the study hadprogression on, or shortly after, treatment with Herceptin and all hadreceived prior taxane. The median number of prior chemotherapy regimens was 3(range: 1-5).
Across treatment arms, there was an overall disease control rate of 62%.Thirty-four heavily pretreated patients were evaluated to date (fifteenpatients assigned to 5 mg daily, six to 20 mg weekly, and thirteen to 30 mgweekly). Among the fifteen patients in the 5 mg daily treatment arm, onepatient had a complete response, two patients had partial responses, ninepatients had stable disease and three patients had progressive disease. Amongthe six patients in the 20 mg weekly treatment arm, one patient had a partialresponse, three patients had stable disease and two patients had progressivedisease. Among the thirteen patients evaluated in the 30 mg weekly treatmentarm, two patients had partial responses, nine patients had stable disease andtwo patients had progressive disease. The critical dose-limiting toxicities(i.e., dose-limiting toxicities in cycle 1) occurring in the 5 mg dailytreatment group included grade 3/4 neutropenia, grade 3 stomatitis, grade 3fatigue and grade 3 anorexia. In the 30 mg weekly treatment group, grade 3/4neutropenia was the only critical dose-limiting toxicity. There were nocritical dose-limiting toxicities in the 20 mg weekly RAD001 treatment arm.The most commonly reported grade 3/4 adverse events (greater than or equal to10%) suspected of being related to study treatment were neutropenia,stomatitis and leukopenia.
About breast cancer
In the US, invasive breast cancer affects one in eight women. It is thesecond most common cancer among women in the US and the second leading causeof cancer-related death in women. Breast cancer is expected to claim the livesof approximately 40,500 women in 2008.
Inside a breast there are many lobes, ducts and vessels that supportseveral important functions in the body, including reproductive needs andfighting infection. In breast cancer, some of the cells in the breast begingrowing abnormally and divide more rapidly than healthy cells. The quickdivision of cells may cause spreading through the breast, to the lymph nodesor to other parts of the body.
RAD001, an oral once-daily inhibitor of mTOR, is an investigational drugbeing studied in multiple tumor types. In cancer cells, RAD001 providescontinuous inhibition of mTOR, a protein that acts as a central regulator oftumor cell division, cell metabolism and blood vessel growth.
The safety and efficacy profile of RAD001 has not yet been established inoncology and there is no guarantee that RAD001 will become commerciallyavailable for oncology indications. The active ingredient in RAD001 iseverolimus. The active ingredient everolimus, is available in differentdosage strengths under the trade name Certican(R) for the prevention of organrejection in heart and kidney transplant recipients. Certican was firstapproved in the EU in 2003. Certican is not approved in the US.
In addition to breast cancer, RAD001 is being evaluated as a single agentor in combination with existing therapies in renal cell carcinoma,neuroendocrine tumors, lymphoma, gastric, lung and other cancers, as well astuberous sclerosis complex.
The foregoing release contains forward-looking statements that can beidentified by terminology such as "potential," "to start," "to explore,""may," "to fully explore," "promising," "encouraged," "committed," "will," "tofurther evaluate," or similar expressions, or by express or implieddiscussions regarding potential regulatory filings or marketing approvals forRAD001 or regarding potential future revenues from RAD001. You should notplace undue reliance on these statements. Such forward-looking statementsreflect the current views of management regarding future events, and involveknown and unknown risks, uncertainties and other factors that may cause actualresults with RAD001 to be materially different from any future results,performance or achievements expressed or implied by such statements. There canbe no guarantee that RAD001 will be approved for sale for any oncologyindication in any market. Nor can there be any guarantee that RAD001 willachieve any particular levels of revenue in the future. In particular,management's expectations regarding RAD001 could be affected by, among otherthings, unexpected clinical trial results, including unexpected new clinicaldata and unexpected additional analysis of existing clinical data; unexpectedregulatory actions or delays or government regulation generally; the company'sability to obtain or maintain patent or other proprietary intellectualproperty protection; competition in general; government, industry and generalpublic pricing pressures; the impact that the foregoing factors could have onthe values attributed to the Novartis Group's assets and liabilities asrecorded in the Group's consolidated balance sheet, and other risks andfactors referred to in Novartis AG's current Form 20-F on file with the USSecurities and Exchange Commission. Should one or more of these risks oruncertainties materialize, or should underlying assumptions prove incorrect,actual results may vary materially from those anticipated, believed, estimatedor expected. Novartis is providing the information in this press release as ofthis date and does not undertake any obligation to update any forward-lookingstatements contained in this press release as a result of new information,future events or otherwise.
About Novartis Pharmaceuticals Corporation
Novartis Pharmaceuticals Corporation researches, develops, manufacturesand markets leading innovative prescription drugs used to treat a number ofdiseases and conditions, including those in the cardiovascular, metabolic,cancer, organ transplantation, central nervous system, dermatological, GI andrespiratory areas. The company's mission is to improve people's lives bypioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporationis an affiliate of Novartis AG which provides healthcare solutions thataddress the evolving needs of patients and societies. Focused solely onhealthcare, Novartis offers a diversified portfolio to best meet these needs,innovative medicines, cost-saving generic pharmaceuticals, preventivevaccines, diagnostic tools and consumer health products. Novartis is the onlycompany with leading positions in these areas. In 2007, the Group's continuingoperations (excluding divestments in 2007) achieved net sales of USD 38.1billion and net income of USD 6.5 billion. Approximately USD 6.4 billion wasinvested in R&D activities throughout the Group. Headquartered in Basel,Switzerland, Novartis Group companies employ approximately 97,000 full-timeassociates and operate in over 140 countries around the world. For moreinformation, please visit http://www.novartis.com.
* In the US, Herceptin is a registered trademark of Genentech, Inc.Internationally, Herceptin is a registered trademark of Roche.
** Taxol is a registered trademark of Bristol-Myers Squibb Company.
*** Navelbine is a registered trademark of Pierre Fabre PharmaceuticalsInc.Novartis Media Relations Media only: Investors only: Geoffrey Cook Jill Pozarek Novartis Oncology Novartis Corporation P: +1 862 778 2675 P: +1 212 830 2445 F: +1 973 652 7927 Dana Kahn Cooper P: +1 732 817 1800 F: +1 732 817 1834
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