Novartis Drug Afinitor® Extends Progression-Free Survival in Patients With Advanced Pancreatic NET, Study Published in NEJM Shows

EAST HANOVER, N.J., Feb. 9, 2011 /PRNewswire/ -- The New England Journal of Medicine (NEJM) published a study today that shows Afinitor® (everolimus) tablets plus best supportive care (BSC) more than doubled progression-free survival (PFS), or time without tumor growth, versus placebo plus BSC in patients with advanced pancreatic neuroendocrine tumors (NET)(1).

Data from the study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), were first presented last year at the 12th World Congress on Gastrointestinal Cancer in Barcelona(2). Regulatory submissions for everolimus to treat this patient population are underway worldwide.

Results from the trial showed that everolimus more than doubled median PFS from 4.6 to 11.0 months when compared with placebo and reduced the risk of cancer progression by 65% (hazard ratio [HR] =0.35 [95% confidence interval (CI), 0.27 to 0.45]; p<0.001) in patients with advanced pancreatic NET. After 18 months, 34% of patients treated with everolimus (95% CI, 26 to 43) were alive and progression-free versus 9% of those treated with placebo (95% CI, 4 to 16), showing a more prolonged benefit for patients treated with everolimus(1).

Pancreatic NET originates from the islet cells of the pancreas and can grow aggressively(3). It is a distinct and uncommon disease that is different from what is generally referred to as pancreatic cancer or pancreatic exocrine cancer(4). At time of diagnosis the majority of patients have advanced disease, meaning the cancer has spread to other parts of the body and has become more difficult to treat(3),(5). The median survival duration for patients with advanced pancreatic NET is 24 months(6).

"A patient diagnosed with advanced NET may have limited treatment options," said James Yao, MD, Associate Professor of Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. "Results from the RADIANT-3 trial are encouraging and demonstrate the potential benefit of treating advanced pancreatic NET with the mTOR inhibitor everolimus."

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism(7). Preclinical and clinical data have established the role of mTOR in the development and progression of several types of tumors, including pancreatic NET.

The US Food and Drug Administration (FDA) has granted everolimus priority review designation for the application of advanced NET of gastrointestinal (GI), lung or pancreatic origin based on results of RADIANT-3 and another Phase III trial, RADIANT-2. Priority review status is granted to therapies that offer major advances in treatment or provide a treatment where no adequate therapy exists(8).

This status accelerates the standard review time for everolimus from 10 to six months(8). Since the data included in the submission may require further discussion, the FDA is likely to call an Advisory Committee meeting, which could result in the FDA extending the review period. Worldwide regulatory filings for everolimus in this indication are also underway.

About RADIANT-3

RADIANT-3 is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus BSC versus placebo plus BSC in 410 patients with advanced, low- or intermediate-grade pancreatic NET, also known as islet cell tumors. Patients who met the study entry criteria were randomized 1:1 to receive either everolimus 10 mg once-daily (n=207) or daily placebo (n=203) orally, both in conjunction with BSC(1).

The primary endpoint of RADIANT-3 is PFS. Secondary endpoints include safety, objective response rate (confirmed according to RECIST), duration of response and overall survival(1).

In the study, everolimus maintained a safety profile consistent with the prescribing information and previous studies of the drug. The most frequent all grade, drug-related adverse events (greater than or equal to 20%) were stomatitis/oral mucositis/ulcers (64% everolimus vs. 17% placebo; includes stomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), infections (23% vs. 6%), nausea (20% vs. 18%), peripheral edema (20% vs. 3%) and decreased appetite (20% vs. 7%); most were grade one or two. Grade three and four adverse events (greater than or equal to 5%) include stomatitis/oral mucositis/ulcers (7% vs. 0%; includes stomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). Median exposure to everolimus was 2.3-fold longer than exposure to placebo (38 vs. 16 weeks)(1).

About RADIANT-2

RADIANT-2 is a Phase III randomized, double-blind, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus Sandostatin® LAR Depot (octreotide acetate for injectable suspension) versus placebo plus octreotide LAR in 429 patients with advanced carcinoid tumors. Patients who met the study's entry criteria were randomized 1:1 to receive either oral everolimus (10 mg daily) plus octreotide LAR (30 mg intramuscularly every 28 days) or placebo daily plus octreotide LAR. Patients had radiological documentation of disease progression within 12 months prior to randomization(9).

The study did not meet its primary endpoint of PFS as assessed by independent radiological review (p=0.026 vs. p=0.0246 predefined) (hazard ratio=0.77 [95% CI, 0.59 to 1.00]). Secondary endpoints from the trial include safety, overall response rate and overall survival(9).

In the initial review of the data an imbalance in baseline characteristics was observed between the two treatment arms, including prior treatment with chemotherapy, primary tumors located in the lung and a poorer World Health Organization (WHO) performance status (an assessment of each patient's functional/physical performance). Further, inconsistencies were found between analyses of radiology scans, which resulted in censoring of patients from the trial. These imbalances and the censoring of data seem to favor the control arm and may have impacted the outcome of the study. Additional analyses to adjust for imbalances in the treatment arms show everolimus plus octreotide LAR significantly reduced risk of disease progression (HR=0.60 [95% CI, 0.44 to 0.84])(9).

In the study, the most frequent all grade drug-related adverse events with everolimus plus octreotide LAR were stomatitis, rash, fatigue, diarrhea, nausea and infections; most were grade one or two. Grade three and four adverse events (greater than or equal to 5%) with everolimus plus octreotide LAR were stomatitis (7%; includes stomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), fatigue (7%), diarrhea (6%), infections/infestations (5%) and hyperglycemia (5%)(9).

About neuroendocrine tumors (NET)

Neuroendocrine tumors arise from cells that can produce and secrete a variety of hormones that regulate bodily functions(10). There are many types of NET that can occur throughout the body; however, most are found in the GI tract, pancreas and lungs(6),(11). Many patients with NET have no symptoms or nonspecific symptoms, such as flushing and diarrhea, which often lead to delays in diagnosis of five to seven years(12),(13). As a result, many patients with NET often have advanced disease when diagnosed, meaning the cancer has spread to other parts of the body and has become more difficult to treat(3),(5). Approximately 64% of patients with pancreatic NET are diagnosed in advanced stages(6).

About Afinitor (everolimus)

Afinitor® (everolimus) tablets is approved in the US for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib and in the European Union (EU) for the treatment of patients with advanced RCC whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy.

Afinitor is also approved in the US to treat patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative 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.  Novartis has submitted marketing applications for everolimus to the European Medicines Agency (EMA) and the Swiss Agency for Therapeutic Products (Swissmedic), and additional regulatory submissions are underway worldwide.

Afinitor is available in the US in 2.5 mg, 5 mg and 10 mg tablet strengths. With once-daily dosing, Afinitor targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism.

In the US, everolimus is available in different dosage strengths under the trade name Zortress® for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. In the EU, everolimus is available in different dosage strengths under the trade name Certican® for the prevention of organ rejection in heart and kidney transplant recipients.

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. As an investigational compound the safety and efficacy profile of everolimus has not yet been established in NET. 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. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for NET or any additional indications anywhere 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 or infections.  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, difficulty breathing or wheezing. Patients may need to stop taking Afinitor for a while or use a lower dose.

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. In patients taking Afinitor for advanced kidney cancer, 44% of patients developed mouth ulcers/sores and in patients taking Afinitor for SEGA, 86% of patients 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.

Patients will have regular blood tests before they start and as needed during their treatment with Afinitor. These tests will monitor how their kidneys and liver are working, their blood sugar and cholesterol levels as well as the number of blood cells in their body. 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 8 weeks after stopping treatment.

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.

About Sandostatin LAR Depot (octreotide acetate for injectable suspension)

Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors in patients in whom initial treatment with immediate-release Sandostatin® (octreotide acetate) Injection has been shown to be effective and tolerated. In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and Sandostatin LAR Depot on tumor size, rate of growth, and development of metastases has not been determined.

Important Safety Information for Sandostatin LAR Depot

Warnings and precautions: Treatment with Sandostatin LAR Depot may affect gallbladder function, sugar metabolism, thyroid and heart function, and nutritional absorption, which may require monitoring by your doctor.

Before taking Sandostatin LAR Depot: Tell your doctor if you have a history of heart disease or are taking other medications, including: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine.

Common side effects: Most patients experience side effects at some time. Some common side effects you may experience include: back pain, fatigue, headache, abdominal pain, nausea, and dizziness.

Other information: Patients with carcinoid tumors and VIPomas should adhere closely to their scheduled return visits for reinjection in order to minimize exacerbation of symptoms.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "encouraging," "potential," "priority review," "likely, "could," "will," or similar or similar expressions, or by express or implied discussions regarding potential submissions or approvals for new indications or labeling for Afinitor, or regarding the potential timing of any such approvals, or regarding potential future revenues from Afinitor. 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 Afinitor to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Afinitor will be submitted or approved for any additional indications or labeling in any market. Nor can there be any guarantee that Afinitor will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Afinitor 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; 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 healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, the Novartis Group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis Group is the only company with leading positions in each of 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. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 119,000 full-time-equivalent associates (including 16,700 Alcon associates) and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.

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

References

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2. Yao, et al. Everolimus versus placebo in patients with advanced pancreatic neuroendocrine tumors (pNET) (RADIANT-3). 12th World Congress on Gastrointestinal Cancer, Barcelona. July 1, 2010.
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9. Pavel et al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NET) (RADIANT-2). 35th European Society for Medical Oncology Congress. October 9, 2010.
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