New Data Confirms Novartis Drug Afinitor® Significantly Extends Time Women With Advanced Breast Cancer Live Without Tumor Growth

EAST HANOVER, N.J., Dec. 7, 2011 /PRNewswire/ -- Updated results of a Phase III study of Afinitor® (everolimus) tablets plus exemestane, a hormonal therapy, show everolimus provided additional time women with advanced breast cancer lived without their disease progressing (progression-free survival)(1).

The study findings, which represent an additional five months of follow-up, were presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS). Simultaneously, initial results of BOLERO-2 were published today in The New England Journal of Medicine (NEJM) and were first presented at the 2011 European Multidisciplinary Cancer Congress (EMCC)(2).

"These data provide longer-term evidence of the benefit of adding everolimus to hormonal therapy in patients whose disease progressed while on or following initial hormonal treatment, representing a major paradigm shift in the management of ER+HER2- breast cancer," said Gabriel Hortobagyi, MD, Chair of Breast Medical Oncology, University of Texas MD Anderson Cancer Center and lead study author. "Everolimus is the first treatment to enhance the efficacy of hormonal therapy in this patient population, where there remains a significant unmet need."  

Updated findings from the BOLERO-2 study presented at SABCS showed treatment with everolimus plus hormonal therapy more than doubled progression-free survival (PFS) to 7.4 months compared to 3.2 months with hormonal therapy alone (hazard ratio=0.44 [95% confidence interval (CI): 0.36 to 0.53]; p<1x10-16) by local investigator assessment. Twelve-month estimates of patients without disease progression were 31% and 10% in the everolimus and exemestane, and exemestane-alone arms, respectively. An additional analysis based on an independent central radiology review showed everolimus extended PFS to 11.0 months compared to 4.1 months (hazard ratio=0.36 [95% CI: 0.28 to 0.45]; p<1x10-16)(1).

Response rates and clinical benefit rates (patients with complete response, partial response, or stable disease for greater than six months) were higher in the combination arms (12.0% vs. 1.3% and 50.5% vs. 25.5%; p<0.0001), respectively(1,3). The results with everolimus were favorable regardless of the presence of visceral disease, prior use of chemotherapy or number of prior therapies. In addition, patients with only bone metastases benefited from the combination. These results represent an additional five months of follow-up (median duration of follow-up of 17.5 months) and are supportive of previously presented outcomes(1).

"Despite the significant progress in treating women with breast cancer, there have been no new treatment advances for women living with ER+HER2- advanced breast cancer in more than 15 years," said Herve Hoppenot, President, Novartis Oncology. "The results of BOLERO-2 are the first to show everolimus combined with hormonal therapy enabled women with this type of breast cancer to live significantly longer without their tumor progressing."

The original results published in NEJM today showed that at a pre-planned interim analysis, BOLERO-2 met its primary endpoint of PFS showing treatment with everolimus plus hormonal therapy extended PFS to 6.9 months compared to 2.8 months with hormonal therapy alone (hazard ratio=0.43 [95% CI: 0.35 to 0.54]; p<0.001) by local investigator assessment. Additional analysis by an independent central radiology review committee showed everolimus extended PFS to 10.6 months compared to 4.1 months (hazard ratio=0.36 [95% CI: 0.27 to 0.47]; p<0.001)(2).

The side effects observed were consistent with those previously reported with everolimus with the most common Grade 3 or 4 adverse events including: stomatitis (8% vs. 1%), anemia (7% vs. 1%), hyperglycemia (5% vs. <1%), dyspnea (4% vs. 1%), fatigue (4% vs. 1%) and pneumonitis (3% vs. 0%) for the combination and exemestane-only arms, respectively(1). At the time of updated analysis, 137 patients died, constituting 17.2% of patients in the everolimus plus exemestane arm and 22.7% of those in the exemestane-only arm(3).

Hormonal therapy remains the cornerstone of treatment for women with advanced breast cancer but almost all patients who respond eventually develop resistance(2). Everolimus targets the mTOR pathway in cancer cells. mTOR is a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism(4). Resistance to hormonal therapy in breast cancer has been associated with over-activation of the mTOR pathway(2).

Each year, around 220,000 women globally will be diagnosed with ER+HER2- advanced breast cancer(5,6). Everolimus is also being investigated for the treatment of patients with HER2+ advanced breast cancer(7,8).

Regulatory submissions for everolimus based on the BOLERO-2 results are planned by the end of 2011.

About BOLERO-2

BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) is a Phase III, randomized, double-blind, placebo-controlled, multicenter study that examined the safety and efficacy of everolimus in combination with exemestane versus exemestane alone in postmenopausal women with ER+HER2- advanced breast cancer who recurred or progressed while on or following previous treatment with the hormonal therapies letrozole or anastrozole(2). The trial was conducted at 189 sites worldwide, in 24 countries and enrolled 724 patients(2). Patients who met the study criteria were randomized (2:1) to receive either everolimus 10 mg/day orally (n=485), or placebo, plus oral exemestane 25 mg/day (n=239). Novartis provided financial support for the study(1).

The primary endpoint was PFS based on local investigator radiology assessment. Other endpoints include overall survival, overall response rate, safety, patient reported outcome, clinical benefit rate and changes in markers of bone metabolism(1).

In the data presented at SABCS, no difference in time to deterioration of quality of life was observed and everolimus increased exemestane steady-state Cmin and Cmax levels by 45% and 64%, respectively, with no difference in estradiol levels. Serum markers of bone resorption and bone formation increased in the exemestane arm and generally decreased in the everolimus plus exemestane arm(1).

About everolimus

In the US, Afinitor® (everolimus) tablets is approved for the treatment of progressive neuroendocrine tumors of pancreatic origin (pNET) in patients with unresectable, locally advanced or metastatic disease and for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. 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 also approved in the US to treat patients with SEGA associated with TS who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of everolimus 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 US, everolimus 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 everolimus 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 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 for Afinitor (everolimus) tablets

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 lead to death. If patients experience these serious side effects, they may need to stop taking Afinitor for a while or use a lower dose. 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 can cause mouth ulcers and sores, which are the most frequently occurring side effects occurring in approximately 44%-70% advanced kidney cancer and advanced pancreatic NET patients taking Afinitor. Eighty-six percent of patients taking Afinitor for SEGA developed mouth ulcers/sores. Patients should tell their healthcare provider if they have pain, discomfort or open sores in their mouth. Their healthcare provider may tell them to use a special mouthwash or mouth gel that does not contain alcohol or peroxide.

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.

Patients will have regular blood tests before they start and as needed during their treatment with Afinitor. These tests will include tests to check the patient's blood cell count, kidney and liver function and blood sugar levels. Patients who receive Afinitor for the treatment of SEGA will need regular blood tests to measure how much Afinitor is in their blood since this will help their doctor decide how much Afinitor they need to take.

Afinitor may affect the way other medicines work, and other medicines can affect how Afinitor works. Using Afinitor with other medicines can cause serious side effects. Patients should tell their healthcare provider about all of the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements such as: St. John's Wort, and medicine for fungal infections, bacterial infections, tuberculosis, seizures, HIV-AIDS, heart conditions or high blood pressure and medicines that suppress their immune system. Patients should not drink grapefruit juice or eat grapefruit during their treatment with Afinitor as it may make the amount of Afinitor in their blood increase to a harmful level.

Patients should not take Afinitor tablets which are broken or crushed. Patients should not chew or crush the tablets.

The amount of Afinitor in the blood was increased in patients who had liver problems.  Patients should tell their healthcare provider about all their medical conditions, including if they have or have had liver problems, diabetes or high blood sugar, high cholesterol levels, infections, hepatitis B or other medical conditions.

Patients should tell their healthcare provider if they are scheduled to receive any vaccinations. Patients should not receive a live vaccine or be around people who have recently received a live vaccine during treatment with Afinitor.

It is not known if Afinitor will harm an unborn baby. Women should use effective birth control while using Afinitor and for eight weeks after stopping treatment.

Common side effects of Afinitor in patients with advanced pancreatic neuroendocrine tumors include mouth ulcers, rash, diarrhea, swelling of arms, hands, feet, ankles, face or other parts of the body, abdominal pain, nausea, fever and headache. Common side effects of Afinitor in patients with advanced kidney cancer include mouth ulcers, infections, feeling weak or tired, cough and diarrhea. Common side effects of Afinitor in patients with SEGA include mouth ulcers, infections of the respiratory tract, sinuses and ears and fever.

Please see full Prescribing Information for Afinitor.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "may," "planned," "will," "potential," 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 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; 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, 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 2010, the Group's continuing operations achieved net sales of USD 50.6 billion, while approximately USD 9.1 billion (USD 8.1 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 121,000 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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# Rapamune® (sirolimus) and Torisel® (temsirolimus) are registered trademarks of Wyeth Pharmaceuticals Inc.

References

(1) Hortobagyi GN. Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. 2011 San Antonio Breast Cancer Symposium. Updated late breaking abstract No. S3-7. December 7, 2011.  

(2) Baselga, J. et al. Improved Clinical Outcome With the mTOR Inhibitor Everolimus for Postmenopausal Women With Hormone Receptor-Positive Advanced Breast Cancer. New Eng J Med. Published online December 7, 2011.

(3) Hortobagyi GN. Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. 2011 San Antonio Breast Cancer Symposium. Presentation of late-breaking abstract No. S3-7. December 8, 2011.

(4) Motzer, et. al. Phase 3 Trial of Everolimus for Metastatic Renal Cell Carcinoma. Cancer 2010 Sep; 116(18):4256-4265.

(5) Buckley N. et al. Decision Resources: Breast Cancer. March 2011.

(6) World Cancer Report. International Agency for Research on Cancer. Available at http://globocan.iarc.fr/factsheets/populations/factsheet.asp?uno=900. Accessed September 2011.

(7) Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer (BOLERO-1). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00876395?term=bolero-1&rank=1. Accessed November 2011.

(8) Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With   Locally Advanced or Metastatic Breast Cancer (BOLERO-3). Available at: http://clinicaltrials.gov/ct2/show/NCT01007942?term=BOLERO-3&rank=1. Accessed November 2011.

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