Phase III Novartis data show potential benefit of Afinitor® plus Sandostatin® LAR® in patients with advanced neuroendocrine tumors
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Novartis International AG /
Phase III Novartis data show potential benefit of Afinitor® plus Sandostatin®
LAR® in patients with advanced neuroendocrine tumors
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* Everolimus plus octreotide LAR extended time without tumor growth from 11.3
to 16.4 months versus octreotide LAR alone in advanced NET (carcinoid)
patients[1]
* The study did not reach its primary endpoint of progression-free survival[1]
()
* Analyses to adjust for imbalances in the treatment arms show everolimus plus
octreotide LAR significantly reduced risk of disease progression[1]
()
* Worldwide regulatory filings for everolimus planned this year based on study
as well as results from a separate Phase III study in patients with
pancreatic NET
Basel, October 11, 2010 - A Novartis Phase III study of Afinitor(®) (everolimus)
tablets in combination with Sandostatin(®) LAR(®) (octreotide acetate for
injectable suspension) extended median progression-free survival (PFS), or time
without tumor growth, in patients with advanced neuroendocrine tumors (NET)
compared to taking octreotide LAR alone. The study, RADIANT-2 (RAD001 In
Advanced Neuroendocrine Tumors), was presented at the 35(th) European Society
for Medical Oncology (ESMO) Congress and is part of the largest clinical trial
program in patients with advanced NET[1].
Everolimus is not approved in this patient population. Octreotide LAR is
indicated for the treatment of symptoms associated with functional
gastroenteropancreatic-NET (GEP-NET)[2].
The study did not meet its primary endpoint of PFS based on central radiologic
review of the data (p=0.026 versus p=0.024 predefined). Findings demonstrated
that everolimus plus octreotide LAR provided a clinically meaningful extension
in the median time without tumor growth from 11.3 to 16.4 months when compared
with placebo plus octreotide LAR (hazard ratio=0.77 [95% confidence interval,
0.59 to 1.00]; p=0.026)[1].
Further analyses of the study data were conducted using a well-established
statistical model to adjust for imbalances in baseline characteristics between
the two treatment arms and inconsistencies between the review of radiology scans
for disease progression. The results show that everolimus plus octreotide LAR
provided a statistically significant reduction in the risk of disease
progression by 40% (hazard ratio=0.60 [95% confidence interval, 0.44 to 0.84];
p=0.0014) versus octreotide LAR alone[1].
Patients examined in the study had advanced NET that originated in the
gastrointestinal (GI) tract, lungs and other locations in the body[1], also
known as carcinoid tumors, which are the most common form of NET[3].
Neuroendocrine tumors are a rare cancer that can cause symptoms such as flushing
and diarrhea[4]. Most patients with NET are not diagnosed until their disease
has advanced, meaning the cancer has spread to other parts of the body and has
become more difficult to treat[5]. Patients with advanced NET usually have a
five year survival rate of less than 35%[6].
"A key goal of treating patients with advanced NET is to extend time without
tumor growth," said Prof Marianne Pavel, MD, Leader, Section for Neuroendocrine
Tumors and Clinical Trial Unit in Neuroendocrine Tumors, Charité University
Medicine, Berlin, and primary investigator of the RADIANT-2 trial. "This Phase
III study is important because it shows that everolimus plus octreotide LAR may
provide a viable new treatment approach for patients with advanced NET, where
there is a high unmet need."
Results from the Phase III RADIANT-3 trial, which were also presented at the
ESMO Congress, show that everolimus more than doubled median time without tumor
growth from 4.6 to 11.0 months when compared with placebo in patients with
advanced pancreatic NET (hazard ratio=0.35 [95% confidence interval, 0.27 to
0.45]; p<0.0001)[7]. Findings from this study were also presented earlier this
year at the 12(th) World Congress on Gastrointestinal Cancer in Barcelona.
"Results from the RADIANT trials, the largest and broadest in patients with
advanced NET, will form the basis for regulatory filings later this year and
demonstrate the ongoing commitment Novartis has to the NET community," said
Hervé Hoppenot, President, Novartis Oncology.
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
octreotide LAR versus placebo plus octreotide LAR in 429 patients with advanced
NET. Patients who met the study's entry criteria were randomized 1:1 to receive
either 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[1].
The primary endpoint of RADIANT-2 is PFS. Secondary endpoints from the trial
include safety, overall response rate and overall survival[1].
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. A well established statistical
model, inverse probability of censoring weighted analysis, was used to adjust
for the imbalances and censoring[1].
In the study, the most frequent all grade drug-related adverse events with
everolimus plus octreotide LAR were stomatitis, rash, fatigue and diarrhea; most
were grade one or two. Grade three and four adverse events (?5%) with everolimus
plus octreotide LAR were stomatitis (6.5%), fatigue (6.5%), diarrhea (6%),
infections/infestations (5.1%) and hyperglycemia (5.1%)[1].
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 best supportive care (BSC) versus placebo plus BSC in
410 patients with advanced pancreatic NET, also known as islet cell tumors.
Patients who met the study entry criteria were randomized 1:1 to receive either
daily everolimus (10 mg) or daily placebo orally[7].
The primary endpoint of RADIANT-3 is PFS. Secondary endpoints include safety,
objective response rate and overall survival[7].
In the study, the most frequent all grade drug-related adverse events with
everolimus were stomatitis (64%), rash (53%), diarrhea (34%), fatigue (31%) and
infections (23%); most were grade one or two. Stomatitis (6.9%), anemia (6%) and
hyperglycemia (5%) were the most common grade three or four events. Median
exposure to everolimus was 2.3-fold longer than exposure to placebo (38 versus
16 weeks)[7].
About neuroendocrine tumors (NET)
Neuroendocrine tumors arise from cells that can produce and secrete a variety of
hormones that regulate bodily functions[8]. There are many types of NET that can
occur throughout the body; however, most are found in the GI tract, pancreas and
lungs[6],[9].
Because NET are relatively rare, there is no routine screening and patients
often experience delays of five to seven years before receiving an accurate
diagnosis. As a result of this, patients with NET often have advanced disease
when diagnosed. The most recent available data show that in 2004, NET were
diagnosed in approximately five cases per 100,000 per year. Although considered
a rare cancer, the incidence of NET is increasing dramatically, having more than
quadrupled in the past 30 years[5],[6].
About Afinitor (everolimus)
Approved in more than 55 countries globally, 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. In the United
States (US), Afinitor is approved for the treatment of patients with advanced
RCC after failure of treatment with sunitinib or sorafenib.
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.
With once-daily dosing Afinitor works by targeting mTOR in cancer cells, a
protein that acts as an important regulator of tumor cell division, blood vessel
growth and cell metabolism.
As an investigational compound the safety and efficacy profile of everolimus has
not yet been established in NET. Access to everolimus for NET has been carefully
controlled and monitored in clinical trials designed to better understand the
potential benefits and risks of the compound. For more information about ongoing
everolimus clinical trials, healthcare professionals can visit
www.theWIDEprogram.com. Because of the uncertainty of clinical trials, there is
no guarantee that everolimus will become commercially available for NET anywhere
in the world.
Afinitor (everolimus) tablets important safety information
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.
Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated
with Afinitor. Monitoring of renal function, blood glucose and complete blood
counts is recommended prior to initiation and periodically during treatment.
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.
Avoid concurrent treatment with strong CYP3A4 and PgP inhibitors and use caution
with moderate inhibitors. Avoid concurrent treatment with strong CYP3A4 or PgP
inducers.
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,
dyspnea and dysgeusia. Common adverse reactions (?1 to <10%) include headache,
dry mouth, pyrexia, weight loss, hand-foot syndrome, abdominal pain, erythema,
insomnia, dyspepsia, dysphagia, hypertension, increased daytime urination,
dehydration, chest pain, hemoptysis and exacerbation of diabetes mellitus.
Uncommon adverse reactions (<1%) include ageusia, congestive cardiac failure,
new-onset diabetes mellitus, impaired wound healing, grade 1 hemorrhage and
hepatitis B reactivation.
About Sandostatin LAR
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.
Sandostatin LAR important safety information
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 "potential," "planned," "may," "will," "commitment," or
similar expressions, or by express or implied discussions regarding potential
new indications or labeling for Afinitor and Sandostatin LAR or regarding
potential future revenues from Afinitor and Sandostatin LAR. 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 and Sandostatin LAR will be submitted or approved
for any additional indications or labeling in any market. Nor can there be any
guarantee that Afinitor and Sandostatin LAR will achieve any particular levels
of revenue in the future. In particular, management's expectations regarding
Afinitor and Sandostatin LAR could be affected by, among other things,
unexpected clinical trial results, including unexpected new clinical data and
unexpected additional analysis of existing clinical data; unexpected regulatory
actions or delays or government regulation generally; 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 2009, the Group's continuing operations achieved net sales of
USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D
activities throughout the Group. Headquartered in Basel, Switzerland, Novartis
Group companies employ approximately 102,000 full-time-equivalent 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] 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). 35(th) European
Society for Medical Oncology Congress. October 9, 2010.
[2] Sandostatin(®) LAR(®) (octreotide acetate) Basic Prescribing Information.
Basel, Switzerland: Novartis International AG; November 2007.
[3] Memorial Sloan-Kettering Cancer Center. Gastrointestinal Carcinoid Tumors.
Available at:http://www.mskcc.org/mskcc/html/92542.cfm. Accessed September
29, 2010.
[4] Caring for Carcinoid Foundation. What is Carcinoid Cancer? Available
at:http://caringforcarcinoid.org/patient-caregiver-resources/neuroendocrine-
tumor-information/carcinoid-cancer. Accessed September 29, 2010.
[5] Modlin, et al. Priorities for Improving the Management of
Gasteroenteropancreatic Neuroendocrine Tumors. J Natl Cancer Inst
2008;100:1282-1289.
[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] Yao et al. A randomized, double-blind, placebo-controlled, multicenter phase
III trial of everolimus in patients with advanced pancreatic neuroendocrine
tumors (pNET) (RADIANT-3). 35(th) European Society for Medical Oncology
Congress. October 9, 2010.
[8] National Library of Medicine and the National Institutes of Health.
Neuroendocrine Tumor. Available
at:http://www.cancer.gov/dictionary/?CdrID=44904. Accessed September 29, 2010.
[9] American Cancer Society Detailed Guides. What are the key statistics about
gastrointestinal carcinoid tumors? Available
at:http://www.cancer.org/Cancer/GastrointestinalCarcinoidTumor/DetailedGuide/gas
trointestinal-carcinoid-tumors-key-statistics. Accessed September 29, 2010.
# # #
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