Novartis pivotal Phase III trial shows Afinitor® significantly delays tumor growth in HER2 positive advanced breast cancer

• A 22% reduction in the risk of disease progression was seen with the addition of everolimus, an mTOR inhibitor, to trastuzumab and vinorelbine in heavily pretreated patients[1] 
• First Phase III study showing that inhibition of HER2 positive receptor and mTOR provides significant benefit in HER2 positive advanced breast cancer[1] 
• Everolimus is currently approved as Afinitor in more than 65 countries for the treatment of HR+/HER2 negative advanced breast cancer[2]  

Basel, June 2, 2013 - Novartis today presented results from a pivotal Phase III trial of a treatment regimen including Afinitor^® (everolimus) tablets in women with human epidermal growth factor receptor-2 positive (HER2 positive) advanced breast cancer who received prior taxane therapy and whose disease is resistant to prior trastuzumab (Herceptin^®*) treatment. The findings showed that adding everolimus, an mTOR inhibitor, to trastuzumab and vinorelbine significantly extended progression-free survival (PFS) when compared to treatment with placebo plus trastuzumab and vinorelbine,meeting the study's primary endpoint[1].

The BOLERO-3 (Breast cancer trials of OraL EveROlimus-3) findings were presented at the 49^th Annual Meeting of the American Society of Clinical Oncology (ASCO)[1]. Final PFS results showed that adding everolimus to the standard treatment of trastuzumab and vinorelbine reduced the risk of disease progression by 22% (hazard ratio=0.78 [95% confidence interval (CI): 0.65 to 0.95]; p<0.01)[1]. Median time to progression was 7.0 months in the everolimus combination arm and 5.8 months in the placebo combination arm[1]. All patients were resistant to trastuzumab-containing regimens and 27% of the patient population was pretreated with a lapatinib-containing regimen[1]. Findings on overall survival, the key secondary endpoint of the trial, are not yet mature[1].

"These encouraging data demonstrate that everolimus has a meaningful impact in heavily pretreated HER2 positive advanced breast cancer patients," said Ruth O'Regan, Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory University School of Medicine and lead study author. "Everolimus works differently than available treatment options for HER2 positive advanced breast cancer by inhibiting mTOR, and may offer an important new option for physicians and their patients."

Adverse events were consistent with the known safety profile of everolimus[1]. The most common all-grade adverse reactions (incidence >=30%) were neutropenia, stomatitis, anemia, leukopenia, fatigue, pyrexia, diarrhea, nausea, decreased appetite and constipation[1]. The most common Grade 3-4 adverse reactions (incidence >=2%) were neutropenia, leukopenia, anemia, stomatitis, fatigue, febrile neutropenia, diarrhea, pyrexia, nausea, hyperglycemia and thrombocytopenia[1].

The number of on-treatment deaths (2.5% per arm) and the number of deaths due to adverse events (0.7% per arm) were similar across treatment groups[1].

Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers[3]. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism[4]. Previously released data indicate that the mTOR inhibitor everolimus can provide significant benefit when added to certain existing advanced breast cancer treatments[2],[4].

"Our previous advanced breast cancer studies have proven that everolimus plays a key role in treating women with hormone-receptor positive, HER2 negative advanced breast cancer, and now we know it may have a substantial impact in HER2 positive advanced breast cancer," said Alessandro Riva, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. "We plan to share the BOLERO-3 data with regulatory health authorities worldwide."

Everolimus is approved as Afinitor in more than 65 countries including the United States and the countries of the European Union to treat postmenopausal women with hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast cancer in combination with exemestane, after recurrence or progression following a non-steroidal aromatase inhibitor[2]. The specific indications vary by country[2]. HR+/HER2 negative advanced breast cancer is the most common form of the disease[5]. Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis[6].

Study design
BOLERO-3 is a Phase III, randomized, double-blind study of everolimus plus trastuzumab and vinorelbine conducted at 159 clinical trial sites globally[1]. The trial included 569 women with HER2 positive locally advanced or metastatic breast cancer who were previously treated with a taxane and were resistant to trastuzumab[1]. Participants were randomized 1:1 to receive either everolimus 5 mg/day orally or placebo, plus weekly vinorelbine 25 mg/m[2] IV and weekly trastuzumab 2 mg/kg IV following a loading dose of 4 mg/kg[1].

The primary endpoint of the trial is PFS[1]. Secondary endpoints include overall survival, objective response rate, time to deterioration of performance status, changes in quality-of-life scores over time, clinical benefit rate, duration of response, time to response, safety and pharmacokinetics[1].

About advanced breast cancer
Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[7]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[7]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[7].

Overactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer[4]. Eighty percent of advanced breast cancer is either HR+ and/or HER2 positive[2],[8].

HR+ advanced breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year[2]. HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone. Cancer cell growth can be driven by these hormones[9].

In HER2 positive advanced breast cancer, overexpression of the HER2 gene activates signaling pathways, such as the mTOR pathway, leading to the uncontrolled growth and division of cancer cells[2],[10]. Globally, an estimated 140,000 women are living with HER2 positive advanced breast cancer[2].

About Afinitor^® (everolimus)
Everolimus is approved as Afinitor^® in the European Union for the treatment of hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative breast cancer (advanced HR+/HER2 negative breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Afinitor (everolimus) tablets is approved in more than 100 countries, including the United States and throughout the European Union, in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor^® or Votubia^®, Certican^® and Zortress^® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets
Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, nausea, decreased appetite, infections (including upper respiratory tract infection), low level of red blood cells, abnormal taste, inflammation of lung tissue, weight loss, swelling of extremities or other parts of the body, nose bleeds, itching, vomiting, high level of blood cholesterol, headache, high level of blood sugar, cough, spontaneous bleeding or bruising, and breathlessness. The most common Grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, feeling tired or weak, infections, inflammation of lung tissue, diarrhea, spontaneous bleeding or bruising, low white blood cells (a type of blood cell that fights infection), and breathlessness. Cases of hepatitis B reactivation, blood clots in the lung or legs, and menstruation disorders such as absence of periods have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "encouraging," "may," "plan," "will," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for everolimus or regarding potential future revenues from everolimus. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with everolimus to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that everolimus will be submitted or approved for any new indications or labeling in any market, or at any particular time. Nor can there be any guarantee that everolimus will achieve any particular levels of revenue in the future. In particular, management's expectations regarding everolimus could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; unexpected manufacturing issues; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2012, the Group achieved net sales of USD 56.7 billion, while R&D throughout the Group amounted to approximately USD 9.3 billion (USD 9.1 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 129,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

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* Herceptin^® is a registered trademark of Genentech, Inc.

References

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