Novartis drug Afinitor® extends progression-free survival in patients with advanced pancreatic NET, study published in NEJM shows
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Novartis drug Afinitor® extends progression-free survival in patients with
advanced pancreatic NET, study published in NEJM shows
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* RADIANT-3 trial shows everolimus more than doubled median progression-free
survival from 4.6 to 11.0 months versus placebo[1]
* No tumor growth after 18 months in 34% of the patients treated with
everolimus versus in 9% of those treated with placebo[1]
* These data, previously reported at oncology congresses, support worldwide
regulatory submissions for treatment of advanced neuroendocrine tumors
(NET), which has received priority review designation by US FDA
Basel, February 9, 2011 - 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=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 (>=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 (>=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® (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 (hazard ratio=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
(>=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 European Union (EU) for the
treatment of patients with advanced renal cell carcinoma (RCC) whose disease has
progressed on or after treatment with vascular endothelial growth factor (VEGF)-
targeted therapy and also in the US for the treatment of patients with advanced
RCC after failure of treatment with sunitinib or sorafenib.
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.
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. 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.
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 about Afinitor (everolimus) tablets
Afinitor is contraindicated in patients with hypersensitivity to everolimus, to
other rapamycin derivatives or to any of the excipients.
Cases of non-infectious pneumonitis have been described; some of these have been
severe and occasionally fatal. Management of pneumonitis may require dose
adjustment and/or interruption, or discontinuation of treatment and/or addition
of corticosteroid therapy.
Afinitor is immunosuppressive. Localized and systemic bacterial, fungal, viral
or protozoal infections (e.g., pneumonia, aspergillosis, candidiasis, hepatitis
B reactivation) have been described; some of these have been severe and
occasionally fatal. Pre-existing infections should be treated prior to starting
treatment. Patients and physicians should be vigilant for symptoms and signs of
infection; in case of emergent infections, appropriate treatment should be
promptly instituted and interruption or discontinuation of Afinitor should be
considered. Patients with systemic invasive fungal infections should not receive
Afinitor.
Hypersensitivity reactions have been observed.
Mouth ulcers, stomatitis and oral mucositis have been seen. Topical treatments
are recommended; alcohol- or peroxide-containing mouthwashes should be avoided.
Monitoring of renal function, blood glucose and complete blood counts is
recommended prior to initiation and periodically during treatment. Cases of
renal failure, some fatal, have been observed.
Afinitor is not recommended in patients with severe hepatic impairment.
Use of live vaccines should be avoided.
Afinitor is not recommended during pregnancy or for women of childbearing
potential not using contraception. Afinitor may cause fetal harm in pregnant
women. Women taking Afinitor should not breast feed. Male fertility may be
compromised by Afinitor.
Avoid concurrent treatment with strong CYP3A4 and PgP inhibitors and use caution
with moderate inhibitors. Avoid concurrent treatment with strong CYP3A4 or PgP
inducers.
In advanced RCC, the most common adverse reactions (>=10%) include stomatitis,
rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation,
vomiting, cough, infections, peripheral edema, dry skin, epistaxis, pneumonitis,
pruritus and dyspnea. Common adverse reactions (>=1 to <10%) include headache,
dysgeusia, dry mouth, pyrexia, weight loss, hand-foot syndrome, abdominal pain,
erythema, insomnia, dyspepsia, dysphagia, hypertension, increased daytime
urination, dehydration, chest pain, renal failure, hemoptysis and exacerbation
of diabetes mellitus. Uncommon adverse reactions (<1%) include ageusia,
congestive cardiac failure, new-onset diabetes mellitus, impaired wound healing,
and grade 1 hemorrhage.
Cases of hepatitis B reactivation and pulmonary embolism have been reported.
In patients with SEGA, the most common adverse reactions (>=10%) include
infections, hypertriglyceridaemia, cough, stomatitis, diarrhoea, acneiform
dermatitis, acne, pyrexia, and decreased white blood cell count. Common adverse
reactions (>=1 to <10%) include pharyngeal inflammation, gastritis, vomiting,
mucosal inflammation, increased blood triglycerides, anxiety, somnolence,
hypertension, respiratory disorders, dry skin, pityriasis rosea, proteinuria,
fatigue, peripheral oedema, ocular hyperaemia, and decreased blood
immunoglobulin G.
About Sandostatin LAR (octreotide acetate for injectable suspension)
Sandostatin® LAR® is a long-acting, injectable depot formulation of octreotide
acetate that is indicated for the treatment of patients with acromegaly who are
adequately controlled on s.c. treatment with Sandostatin; in whom surgery or
radiotherapy is inappropriate or ineffective; or in the interim period until
radiotherapy becomes fully effective and for the treatment of patients with
symptoms associated with functional GEP-NET in whom symptoms are adequately
controlled on s.c. treatment with Sandostatin.
Sandostatin LAR was first approved in France in June 1995 and is currently
approved in 85 countries. For more than a decade, Sandostatin LAR has achieved a
long-standing track record of sustained efficacy with a well-established safety
profile.
Not all indications are approved in every country.
Important Safety Information about Sandostatin LAR
Patients who have a known hypersensitivity to octreotide or to any of the
excipients should not take Sandostatin LAR. Dose adjustments of drugs, such as
beta-blockers, calcium channel blockers or agents to control fluid and
electrolyte balance may be necessary. Caution should be used in patients with
insulinomas; patients with diabetes mellitus. Thyroid function should be
monitored if receiving prolonged treatment with octreotide. Patients receiving
Sandostatin LAR should receive periodic examination of the gallbladder; and
patients who have a history of vitamin B12 deprivation should have their vitamin
B12 levels monitored. Caution should be used in patients who are pregnant;
patients should be advised to use adequate contraception, if necessary. Patients
should not breast-feed during Sandostatin LAR treatment. The use of Sandostatin
LAR may increase the bioavailability of bromocriptine, impair intestinal
absorption of cyclosporin and delay that of cimetidine. Drugs mainly metabolized
by CYP3A4 and that have a low therapeutic index should be used with caution.
Very common (>=1/10) adverse drug reactions in clinical studies with Sandostatin
LAR were diarrhea, abdominal pain, nausea, constipation, flatulence, headache,
cholelithiasis, hyperglycemia and injection-site localized pain. Common
(>=1/100, <1/10) adverse drug reactions were dyspepsia, vomiting, abdominal
bloating, steatorrhea, loose stools, discoloration of feces, dizziness,
hypothyroidism, thyroid dysfunction (e.g., decreased thyroid stimulating
hormone, decreased Total T4 and decreased Free T4), cholecystitis, biliary
sludge, hyperbilirubinemia, hypoglycemia, impairment of glucose tolerance,
anorexia, elevated transaminase levels, pruritus, rash, alopecia, dyspnea and
bradycardia.
The uncommon (>=1/1000, <1/100) adverse drug reactions were dehydration and
tachycardia. The following adverse reactions have been reported postmarketing:
anaphylaxis, allergy/hypersensitivity reactions, urticaria, acute pancreatitis,
acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis,
jaundice, cholestatic jaundice, arrhythmia, increased alkaline phosphatase
levels and increased gamma glutamyl transferase levels.
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
Novartis provides healthcare solutions that address the evolving needs of
patients and societies. Focused solely on healthcare, Novartis offers a
diversified portfolio to best meet these needs: innovative medicines, cost-
saving generic pharmaceuticals, preventive vaccines, diagnostic tools and
consumer health products. Novartis is the only 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.
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 visithttp://www.novartis.com.
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References
[1] Yao, et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. New
Eng J Med 2011;364:514-23.
[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.
[3] National Library of Medicine and the National Institutes of Health.
Pancreatic islet cell tumor. Available
athttp://www.nlm.nih.gov/medlineplus/ency/article/000393.htm. Accessed February
2011.
[4] American Cancer Society Detailed Guides. Pancreatic Cancer. Available
athttp://www.cancer.org/Cancer/PancreaticCancer/DetailedGuide/pancreatic-cancer-
what-is-pancreatic-cancer. Accessed February 2011.
[5] Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence,
prognosis and recent trend toward improved survival. Annals of Onc
19: 1727-1733, 2008.
[6] Yao, et al. One Hundred Years After "Carcinoid:" Epidemiology of and
Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United
States. Journal of Clinical Oncology. June 20 2009; vol. 26, number 18.
[7] Motzer, et. al. Phase 3 Trial of Everolimus for Metastatic Renal Cell
Carcinoma. Cancer 2010 Sep; 116(18):4256-4265.
[8] US Food and Drug Administration. Fast Track, Accelerated Approval and
Priority Review. Available
athttp://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesst
oimportantnewtherapies/ucm128291.htm. Accessed February 2011.
[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.
[10] National Library of Medicine and the National Institutes of Health.
Neuroendocrine Tumor. Available athttp://www.cancer.gov/dictionary/?CdrID=44904.
Accessed February 2011.
[11] American Cancer Society Detailed Guides. Gastrointestinal Carcinoid Tumors.
Available
athttp://www.cancer.org/Cancer/GastrointestinalCarcinoidTumor/DetailedGuide/
gastrointestinal-carcinoid-tumors-key-statistics. Accessed February 2011.
[12] Modlin, et al. Priorities for Improving the Management of
Gastroenteropancreatic Neuroendocrine Tumors. J Natl Cancer Inst
2008;100:1282-1289.
[13] National Library of Medicine and the National Institutes of Health.
Carcinoid syndrome. Available
athttp://www.nlm.nih.gov/medlineplus/ency/article/000347.htm. Accessed February
2011.
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