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

EAST HANOVER, N.J., June 2, 2013 /PRNewswire/ -- 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 advanced hormone-receptor positive, HER2 negative 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 advanced hormone receptor-positive, HER2 negative (advanced HR+/HER2 negative) breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole(2). The specific indications vary by country(2). Advanced HR+/HER2 negative 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/m² 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).

Advanced HR+ breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year(2). Advanced HR+ 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)
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+/HER2 negative breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

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.

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

Afinitor or Afinitor Disperz 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 or Afinitor Disperz 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 or Afinitor Disperz 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˚F or above, chills, or do not feel well. Symptoms of hepatitis B or infection may include the following: fever, chills, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stools or dark urine, yellowing of the skin, or pain in the upper right side of the stomach.

Afinitor or Afinitor Disperz 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 or Afinitor Disperz.

Common side effects include mouth ulcers. Afinitor or Afinitor Disperz can cause mouth ulcers and sores. Other common side effects include infections, feeling weak or tired, nausea and vomiting, skin problems, headache, weight loss, loss of appetite, cough, diarrhea, fever, swelling of the hands, arms, legs, feet, face, or other parts of the body, joint pain, abnormal taste, stomach-area (abdomen) pain, nose bleeds, seizure, increased blood cholesterol and sugar levels, decreased blood phosphate levels, low red and white blood cells, and the absence of menstrual periods (menstruation).

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

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

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
Located in East Hanover, NJ, Novartis Oncology 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 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.

Novartis is on Twitter. Sign up to follow @Novartis at http://twitter.com/novartis.

References

1. O'Regan R. Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Trial of Daily Everolimus Plus Weekly Trastuzumab and Vinorelbine in Trastuzumab-resistant, Advanced Breast Cancer (BOLERO-3). 2013 American Society of Clinical Oncology Annual Meeting. Oral Presentation Abstract No. 505. Presented June 2, 2013.   
2. Novartis Data on File.
3. Baselga J. Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer. New England Journal of Medicine. December 2011.
4. Advani SH. Targeting mTOR Pathway: A New Concept in Cancer Therapy. Indian Journal Medical Pediatric Oncology. Oct-Dec 2010.
5. Buckley N, Isherwood A. Breast Cancer. Decision Resources. March 2011.
6. 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.
7. American Cancer Society. How Do You Determine the Stage of Breast Cancer? Available at http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-staging. Accessed on May 21, 2013.
8. Arnedos M, Bihan C, Delaloge S and Andre F. Triple-negative Breast Cancer: Are We Making Headway at Least? Therapeutic Advances in Medical Oncology. July 2012.
9. National Cancer Institute. What You Need to Know About Breast Cancer. Available at http://www.cancer.gov/cancertopics/wyntk/breast/wyntk_breast.pdf. Accessed on May 24, 2013. 
10. Prat A, Baselga J. The Role of Hormonal Therapy in the Management of Hormonal-Receptor-Positive Breast Cancer With Co-Expression of HER2. Nature Clinical Practice Oncology. 2008.

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

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SOURCE Novartis Oncology

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