Novartis drug Afinitor® significantly improves progression-free survival in advanced nonfunctional gastrointestinal and lung NET

EAST HANOVER, N.J., Sept. 26, 2015 /PRNewswire/ -- Novartis announced today results of a Phase III pivotal study showing Afinitor^® (everolimus) tablets reduced the risk of progression by 52% (hazard ratio [HR] = 0.48; 95% confidence interval [CI], 0.35-0.67; p<0.00001) vs placebo in patients with advanced, progressive, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin. The study, RADIANT-4, will be presented at the European Cancer Congress (ECC) 2015 in Vienna, Austria, and was highlighted in the ECC press conference on Saturday, September 26¹.

Additionally, the data show everolimus, a mammalian target of rapamycin (mTOR) inhibitor, extended median progression free survival (PFS) by 7.1 months: median PFS by central review was 11.0 months (95% CI, 9.23-13.3) in the everolimus arm and 3.9 months (95% CI, 3.58-7.43) in the placebo arm. Overall survival (OS) was a key secondary endpoint of the trial. While the OS data are not mature, the first interim analysis showed a trend favoring the everolimus arm. Additional OS analyses are planned. Another secondary endpoint was best overall response rate; the study found that 64% of patients receiving everolimus experienced at least some degree of tumor shrinkage compared to 26% of those on placebo¹.

Safety was also a secondary endpoint of the trial and adverse events (AEs) were consistent with the known safety profile of everolimus. The most common treatment-related grade 3/4 AEs (>5%) for everolimus and placebo, respectively, were stomatitis (9.0% vs 0.0%), diarrhea (7.0% vs 2.0%) and infections (7.0% vs 0.0%)¹.

"Advanced, progressive, nonfunctional NET of GI or lung origin are rare and aggressive cancers, with limited treatment options," said James Yao, MD, Professor of Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, and the study's principal investigator. "These pivotal trial results demonstrate strong evidence for the efficacy of the mTOR inhibitor everolimus in this patient population."

NET are a rare type of cancer that originate in neuroendocrine cells found throughout the body, and are most often found in the GI tract, lungs or pancreas⁵. NET can be functional or nonfunctional: functional NET produce symptoms caused by the secretion of hormones and other substances; nonfunctional NET may produce symptoms caused by the tumor's growth, such as intestinal blockage, pain and bleeding^5,6,7,8. At time of diagnosis, 5%-44% of patients with NET in the GI system and 28% of patients with lung NET have advanced disease, meaning the cancer has spread to other parts of the body and is more difficult to treat⁵.

"These results show that everolimus has the potential to be a new, clinically meaningful therapy for patients with advanced, progressive, nonfunctional GI or lung NET, which typically have poor prognoses," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "Our work with the RADIANT clinical program demonstrates our long-term commitment to NET and has yielded important data that have led to improved outcomes for patients with different types of NET."

The results of the RADIANT-4 study—part of the largest clinical trial program in patients with advanced NET—will serve as the basis of worldwide regulatory submissions for Afinitor for the treatment of advanced, progressive, nonfunctional GI and lung NET. Afinitor is already approved in more than 95 countries worldwide for locally advanced, metastatic or unresectable progressive NET of pancreatic origin.

About RADIANT-4
RADIANT-4 (RAD001 In Advanced Neuroendocrine Tumors) is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus best supportive care (BSC) vs placebo plus BSC in 302 patients with progressive, well-differentiated, nonfunctional, advanced NET of GI or lung origin. All patients received BSC during treatment, which excluded antitumor agents such as somatostatin analogues (SSAs). Patients were required to have ceased treatment with SSAs for 4 weeks before study entry. Everolimus demonstrated similar efficacy regardless of whether the patient had prior SSA therapy or not. Patients had no history or active symptoms of carcinoid syndrome, and had documented disease progression within the previous 6 months. Patients were randomized 2:1 to receive either daily everolimus 10 mg or daily placebo orally¹.

The primary endpoint of RADIANT-4 was PFS by central radiology review. Secondary endpoints included safety, OS, best overall response rate (defined as complete response plus partial response) and disease control rate¹.

The safety profile of everolimus was consistent with what has been observed in previous studies of this drug. The most common treatment-related AEs included stomatitis, diarrhea, peripheral edema, fatigue, and rash. At the time of the data analysis cutoff date, the primary reasons for treatment discontinuation were disease progression (37% in the everolimus arm vs 72% in the placebo arm) and adverse events (29% in the everolimus arm vs 7% in the placebo arm). A trend towards improved survival was observed at the time of interim OS analysis [HR=0.64; 95% CI, 0.40-1.05; p=0.037], with a total of 70 deaths recorded at the time of the data cutoff (42 [20.5%] in the everolimus arm and 28 [28.6%] in the placebo arm). The result was not statistically significant, since interim analysis significance threshold was p=0.000213¹.

About Afinitor^® (everolimus) tablets
Afinitor is a prescription medicine used to treat adults with a type of pancreatic cancer known as pancreatic neuroendocrine tumor (pNET) that has progressed and cannot be treated with surgery. Afinitor is not for use in people with carcinoid tumors that actively produce hormones.

Important Safety Information
Patients should not take Afinitor if they are allergic to Afinitor or to any of its ingredients. Patients should tell their health care 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 health care provider's instructions.

In some patients, lung or breathing problems may be severe and can even lead to death. Patients should tell their health care 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 health care 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 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.

Afinitor can cause incisions to heal slowly or not heal well. Patients should tell their health care provider if their incision is red, warm, or painful; if they have blood, fluid, or pus in their incision; or if their incision opens up or is swollen.

Common side effects include mouth ulcers. Afinitor 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 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 words such as "underway," "will," "planned," "potential," "commitment," "yet," or similar terms, 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 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. Nor can there be any guarantee that everolimus will be commercially successful in the future. In particular, management's expectations regarding everolimus 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 safety issues; unexpected manufacturing or quality 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 Pharmaceuticals Corporation researches, develops, manufactures and markets innovative prescription drugs used to treat a number of diseases and conditions, including cardiovascular, dermatological, central nervous system, bone disease, cancer, organ transplantation, psychiatry, infectious disease and respiratory. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

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 over-the-counter products. Novartis is the only global company with leading positions in these areas. In 2014, the Group achieved net sales of USD 58 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 130,000 full-time-equivalent associates.  Novartis products are available in more than 180 countries around the world. For more information, please visit http://www.novartis.com.

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References

1.  Yao J, et al. Everolimus in advanced, nonfunctional neuroendocrine tumors of lung or gastrointestinal origin: Efficacy and safety results from the placebo-controlled, double-blind, multicenter, Phase 3 RADIANT-4 study. European Cancer Congress (ECC) 2015, Vienna, Austria.

2.  American Cancer Society. Gastrointestinal Carcinoid Tumors. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003102-pdf.pdf. Accessed September 2015.

3.  American Cancer Society. Lung Carcinoid Tumors. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003117-pdf.pdf. Accessed September 2015.

4.  Halfdanarson T.R., et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc. 2008; 19: 1727-1733.

5.  Yao J, et al. One hundred years after "Carcinoid:" Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008; 26: 3063-72.

6.  Akerstrom G, et al. Timing and extent of surgery in symptomatic and asymptomatic neuroendocrine tumors of the pancreas in MEN 1. Langenbecks Arch Surg. 2002; 386:558-69.

7.  Modlin I, et al. Priorities for improving the management of gasteroenteropancreatic neuroendocrine tumors. J Natl Cancer Inst. 2008;100: 1282-1289.

8.  Modlin I, et al. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128 :1717-1751.

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