Novartis gains FDA approval for Afinitor® in advanced breast cancer marking a significant milestone for women battling this disease

EAST HANOVER, N.J., July 20, 2012 /PRNewswire/ -- The US Food and Drug Administration (FDA) has approved Afinitor^® (everolimus) tablets for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole².

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"Afinitor is the first and only treatment that boosts the effectiveness of endocrine therapy, significantly extending the time women with advanced breast cancer live without tumor progression," said Gabriel Hortobagyi, MD, Chair of Breast Medical Oncology, University of Texas MD Anderson Cancer Center. "This approval redefines the treatment and management of advanced hormone receptor-positive breast cancer, offering a critical new option for physicians and patients."

Each year, an estimated 220,000 women globally will be diagnosed with advanced HR+ breast cancer, the most common form of the disease^2,3. In the United States, nearly 40,000 people are expected to be newly diagnosed with advanced breast cancer this year alone⁴. Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis³.

The approval was based on a randomized, double-blind, placebo-controlled, multi-center trial called BOLERO-2 (Breast cancer trials of OraL EveROlimus-2), which evaluated 724 postmenopausal women with advanced HR+ breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole².

This pivotal Phase III study found that treatment with Afinitor plus exemestane more than doubled median progression-free survival (PFS) to 7.8 months, compared to 3.2 months with exemestane alone (hazard ratio=0.45 [95% Cl: 0.38 to 0.54]; p<0.0001) by local investigator assessment². An additional analysis based on an independent central radiology review showed Afinitor plus exemestane extended median PFS to 11.0 months compared to 4.1 months (hazard ratio=0.38 [95% CI: 0.31 to 0.48]; p<0.0001) with exemestane alone². The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, rash, fatigue, diarrhea and decreased appetite². The most common grade 3-4 adverse reactions (incidence greater than or equal to 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis and diarrhea².

"The approval of Afinitor in advanced breast cancer marks a very proud day for the breast cancer community and Novartis. We are bringing a highly-effective treatment to women and their physicians who are in need of new approaches in the battle against this disease," said Herve Hoppenot, President, Novartis Oncology. "This milestone is a result of an extensive collaboration with researchers around the world who have helped study Afinitor in advanced breast cancer, as well as the more than 700 women who participated in the trial."

While endocrine therapy remains the cornerstone of treatment for these women, most will eventually develop treatment resistance⁵. Therapeutic resistance has been associated with overactivation of the PI3K/AKT/mTOR pathway⁵. Afinitor targets the mTOR pathway, which is hyperactivated in many types of cancer cells. mTOR is a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism⁵.

Marking the fifth indication for Afinitor, this is the first FDA approval for an mTOR inhibitor in the treatment of advanced HR+ breast cancer in the United States³. Afinitor is also being studied in HER2-positive breast cancer in two ongoing Phase III trials. On June 21, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Afinitor in the HR+/HER2-negative population⁶. Additional regulatory submissions are being reviewed by health authorities worldwide.

About Advanced Breast Cancer

Advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ breast cancer) is comprised of 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 bones or liver⁷. 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 body⁷.

It is estimated that women with metastatic breast cancer have a life expectancy of approximately 18-36 months after diagnosis⁸, and median survival for women with stage III disease is less than five years⁹.

Advanced HR+ breast cancer is characterized by hormone receptor tumors, a group of cancers that express receptors for certain hormones, such as estrogen and progesterone. Cancer cell growth can be driven by these hormones⁷. The presence of estrogen receptor (ER) and/or progesterone receptor (PgR) is one of the most important predictive and prognostic markers in human breast cancers, and is collectively referred to as hormone receptor-positive.

About Afinitor (everolimus)

Afinitor^® (everolimus) is approved in the United States for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole³.

For more information visit www.AFINITOR.com or call 1-888-4-AFINITOR. US patients who may be eligible for financial assistance can learn about the Novartis Patient Assistance Now Oncology (PANO) reimbursement support program by contacting 1-800-282-7630 or visiting the Afinitor website.

In the United States, Afinitor tablets is approved for the treatment of adult patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib and for the treatment of progressive neuroendocrine tumors of pancreatic origin in adult patients with unresectable, locally advanced or metastatic disease. The US Food and Drug Administration (FDA) determined that the safety and effectiveness of Afinitor in the treatment of patients with carcinoid tumors have not been established.

Afinitor is approved in the United States to treat adult patients with renal angiomyolipomas and tuberous sclerosis complex (TSC), who do not require immediate surgery. The effectiveness of Afinitor in treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes. Afinitor is also approved in the United States to treat adult and pediatric patients, three years of age or older, with SEGA associated with TSC, who require therapeutic intervention but are not candidates for surgical resection. The effectiveness of Afinitor is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been shown.

In the United States, Afinitor is available from Novartis in different dosage strengths and for different uses in non-oncology patient populations under the trade name Zortress^®. Everolimus is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Not all indications are available in every country. Access to Afinitor outside of the approved indications has been carefully controlled and monitored in clinical trials designed to better understand the potential benefits and risks of the compound. As an investigational compound, the safety and efficacy profile of Afinitor has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that Afinitor will become commercially available for additional indications anywhere else in the world.

About Novartis Patient Access NOW Oncology (PANO)

Novartis is committed to providing access to our medications for those most in need. Through a variety of resources, including the Novartis Oncology Patient Assistance Program, the Novartis Oncology Reimbursement Hotline, and our support of independent Charitable Co-pay foundations, Novartis has made a firm commitment to enable patients in need to access medicines. For more information, please visit www.novartisoncology.us/reimbursement.

Afinitor^® Important Safety Information

Patients should not take Afinitor^® if they are allergic to Afinitor or to any of its ingredients. Patients should tell their healthcare provider before taking Afinitor if they are allergic to sirolimus (Rapamune^®) or temsirolimus (Torisel^®).

Afinitor can cause serious side effects including lung or breathing problems, infections and kidney failure, which can even lead to death. If patients experience these side effects, they may need to stop taking Afinitor for a while or use a lower dose. Patients should follow their healthcare provider's instructions.

In some patients, lung or breathing problems may be severe, and can even lead to death. Patients should tell their healthcare provider right away if they have any of these symptoms: new or worsening cough, shortness of breath, chest pain, difficulty breathing, or wheezing.

Afinitor may make patients more likely to develop an infection, such as pneumonia, or a bacterial, fungal, or viral infection. Viral infections may include reactivation of hepatitis B in people who have had hepatitis B in the past. In some people these infections may be severe, and can even lead to death. Patients may need to be treated as soon as possible. Patients should tell their healthcare provider right away if they have a temperature of 100.5 degrees F or above, chills, or do not feel well. Symptoms of hepatitis B or infection may include the following: fever, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stool or dark urine, yellowing of the skin, or pain in the upper right side.

Afinitor may cause kidney failure. In some people this may be severe and can even lead to death. Patients should have tests to check their kidney function before and during their treatment with Afinitor.

Common side effects include mouth ulcers. Afinitor can cause mouth ulcers and sores. Other common side effects include infections, rash, feeling weak or tired, diarrhea loss of appetite, nausea, weight loss, cough, abnormal taste, shortness of breath, headache, and joint pain.

Please see full Prescribing Information for Afinitor available at www.AFINITOR.com.

Rapamune^® (sirolimus) and Torisel^® (temsirolimus) are registered trademarks of Wyeth LLC.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "expected," "will," "ongoing," "positive opinion," "are being reviewed," 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 additional 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; government, industry and general public pricing pressures; competition in general; 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

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which 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 2011, the Group's continuing operations achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 124,000 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. Redmond C. Breast Cancer Hormone Therapy Options. Available at: http://christine-redmond.suite101.com/breast-cancer-hormone-therapy-options-a197304. Accessed April 27, 2012.
2. Novartis Data on File.
3. Buckley N, Isherwood A. Breast Cancer. Decision Resources, March 2011.
4. Dobrescu, Andrei. Study of Estrogen Receptor and Progesterone Receptor Expression in Breast Ductal Carcinoma In Situ by Immunohistochemical Staining in ER/PgR-Negative Invasive Breast Cancer. May 9, 2011. Available at: http://www.isrn.com/journals/oncology/2011/673790/. Accessed on April 9, 2012.
5. Baselga, J. Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer. New England Journal of Medicine. February 9, 2012.
6. European Medicines Agency. Summary of opinion for Afinitor. June 21, 2012.
7. National Cancer Institute. "What You Need to Know About Advanced Breast Cancer." Available at: http://www.cancer.gov/cancertopics/wyntk/breast/WYNTK_breast.pdf. Accessed on March 8, 2012.
8. Giordano, S. Update on Locally Advanced Breast Cancer. The Oncologist, 2003.
9. Eniua A, Palmierib F and Perez E: Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer. The Oncologist, 2005.

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