Novartis : reports data at EBCC-9 for secondary survival endpoint of Afinitor trial in HR+/HER2- advanced breast cancer »

• Everolimus plus exemestane extended overall survival, a secondary endpoint, by 4.4 months compared to exemestane alone, not reaching statistical significance[1]

• Median overall survival in everolimus arm was 31 months; the longest reported to date in a Phase III trial in HR+ advanced breast cancer following NSAI treatment[2]

• Primary endpoint results showed Afinitor plus exemestane more than doubled progression-free survival, forming basis for more than 80 worldwide approvals including most recent in Japan[2],[3]

A median overall survival duration of 31 months was seen in the combination arm versus 26.6 months for those on exemestane monotherapy, a difference of 4.4 months (hazard ratio=0.89 [95% CI: 0.73 to 1.10]; p=0.1426)[1],[2]. This secondary endpoint did not reach the threshold of statistical significance[1]. The median overall survival is the longest reported to date in a Phase III hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer trial following prior treatment with a non-steroidal aromatase inhibitor (NSAI)[2].

"The BOLERO-2 trial shows that treatment with Afinitor in combination with exemestane works against multiple target pathways to slow the progression of hormone receptor-positive advanced breast cancer, even among patients who have progressed while on or within 12 months of completing adjuvant non-steroidal aromatase inhibitor therapy," said Gabriel Hortobagyi, MD, professor, Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. "This dual approach both extends the benefits of endocrine therapy while delaying the time until the patient needs chemotherapy, which can have an important impact on patients living with this disease."

The final overall survival results were assessed as part of a prospectively planned secondary endpoint analysis. Previously reported progression-free survival (PFS) results found that treatment with everolimus plus exemestane more than doubled median PFS to 7.8 months, compared to 3.2 months with exemestane alone, meeting the study's primary endpoint (hazard ratio=0.45 [95% Cl: 0.38 to 0.54]; p<0.0001), confirmed by central assessment (11 months versus 4.1 months PFS)[3]. The most common adverse reactions (incidence >= 30%) were stomatitis, infections, rash, fatigue, diarrhea and decreased appetite[2],[3]. The most common grade 3-4 adverse reactions (incidence >= 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis and diarrhea[2],[3].

"These data, along with experience from more than 18 months of real-world use, add to the growing body of evidence regarding the use of Afinitor plus exemestane in patients with hormone receptor-positive, HER2 negative advanced breast cancer after they progress on a non-steroidal aromatase inhibitor," said Alessandro Riva, MD, President Novartis Oncology ad interim and Global Head, Oncology Development and Medical Affairs. "We continue to research the role of Afinitor in advanced breast cancer and are committed to developing other novel therapies, such as those targeting the PI3K/AKT/mTOR and CDK 4/6 pathways."

Everolimus is the first and only mTOR inhibitor approved for the treatment of HR+/HER2- advanced breast cancer[2],[4]. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism[4]. Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers[5]. Additional data presented at the meeting provide continued evidence on the important role of dual hormone receptor and mTOR inhibition in the treatment of HR+/HER2- advanced breast cancer upon NSAI failure[2].

Everolimus is approved as Afinitor in more than 80 countries to treat women with HR+/HER2- advanced breast cancer, including the most recent approval in Japan this week[2]. The specific indications vary by country.

Study design
BOLERO-2 involved more than 700 patients at more than 195 sites worldwide. Patients in the trial were randomized (2:1) to receive continuous therapy with everolimus 10 mg/day orally or placebo, plus oral exemestane 25 mg/day[5]. Patients who had received more than one prior chemotherapy regimen for advanced breast cancer were excluded from enrollment[5]. The primary endpoint was PFS[5]. Secondary endpoints included overall survival, overall response rate, incidence of adverse events, patient reported outcomes and clinical benefit rate[5].

About advanced breast cancer
Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[6]. 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[6]. 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[6].

It is estimated that women with metastatic breast cancer have a life expectancy of approximately 18-36 months after diagnosis and median survival for women with stage III disease is less than five years[7],[8]. Hyperactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer[4].

Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis[9]. HR+ advanced breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year[2],[10]. 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[11]. Cancer cell growth can be driven by these hormones[11].

About Afinitor® (everolimus)
Everolimus is approved as Afinitor® in the European Union for the treatment of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (NSAI). In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative (advanced HR+/HER2-) 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.

About the Novartis breast cancer pipeline
Novartis is currently investigating PI3K inhibitors buparlisib (BKM120) and BYL719, and CDK 4/6 inhibitor LEE011, in the treatment of drug-resistant breast cancer in combination with other targeted therapies[2].

The PI3K/AKT/mTOR pathway regulates cell metabolism, proliferation and survival, and abnormal activation of this pathway has been shown to be important in initiation and maintenance of human tumors[4]. Cyclin-dependent kinases (CDKs) drive cell cycle progression and control transcriptional processes, and the deregulation of multiple CDK proteins, including CDK 4 and 6, occur commonly in cancer[12]. Targeting these pathways could arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies[2],[4],[12].

Because they are investigational compounds, the safety and efficacy profile of BKM120, BYL719 and LEE011 have not yet been established[2]. Access to these investigational compounds is available only through carefully controlled and monitored clinical trials designed to better understand their potential benefits and risks. Because of the uncertainty of clinical trials, there is no guarantee that BKM120, BYL719 and LEE011 will ever be commercially available anywhere 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 words such as "can," "continue," "committed," "estimated," "will," "currently," "investigating," "could," "investigational," "potential," "uncertainty," "may," "should," or similar terms, or by express or implied discussions regarding potential new marketing approvals, indications or labeling for everolimus, BKM120, BYL719, or LEE011, or regarding potential future revenues from everolimus and such investigational compounds. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that everolimus will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that BKM120, BYL719, or LEE011 will be submitted or approved for sale in any market, or at any particular time. Nor can there be any guarantee that any of everolimus, BKM120, BYL719, or LEE011 will be commercially successful in the future. In particular, management's expectations regarding everolimus and such investigational compounds could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. 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 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 136,000 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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References
[1] Piccart M, et al. Everolimus plus exemestane for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (BC): overall survival results from BOLERO-2. Oral Presentation Abstract #LBA1. European Breast Cancer Conference (EBCC-9), 2014, Glasgow, Scotland.
[2] Novartis Data on File.
[3] Piccart M, et al. Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial. Abstract #559. American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL.
[4] Advani SH. Targeting mTOR Pathway: A New Concept in Cancer Therapy. Indian Journal Medical Pediatric Oncology. Oct-Dec 2010: 1-10.
[5] Baselga J. Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer. New England Journal of Medicine. December 2011.
[6] American Cancer Society. How Do You Determine the Stage of Breast Cancer? http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-staging. Accessed February 19, 2014.
[7] Eniua A, Palmierib F and Perez E. Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer. The Oncologist. 2005.
[8] Giordano, S. Update on Locally Advanced Breast Cancer. The Oncologist. 2003.
[9] Dobrescu A, et al. Study of Estrogen Receptor and Progesterone Receptor Expression in Breast Ductal Carcinoma In Situ by Immunohistochemical Staining in ER/PgR-Negative Invasive Breast Cancer. International Scholarly Research Network. 2011;2011:1-5.
[10] Buckley N, Isherwood A. Breast Cancer. Decision Resources. March 2011: 1-301.
[11] Redmond C. Breast Cancer Hormone Therapy Options. http://christineredmond.suite101.com/breast-cancer-hormone-therapy-options-a197304. Accessed February 19, 2014.
[12] Shapiro J. Cyclin-Dependent Kinase Pathways as Targets for Cancer Treatment. Journal of Clinical Oncology. January 2006.

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