Novartis pivotal Phase III trial shows Afinitor® significantly delays tumor growth in HER2 positive advanced breast cancer
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Novartis pivotal Phase III trial shows Afinitor® significantly delays tumor
growth in HER2 positive advanced breast cancer
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* A 22% reduction in the risk of disease progression was seen with the
addition of everolimus, an mTOR inhibitor, to trastuzumab and vinorelbine in
heavily pretreated patients[1]
* First Phase III study showing that inhibition of HER2 positive receptor and
mTOR provides significant benefit in HER2 positive advanced breast
cancer[1]
* Everolimus is currently approved as Afinitor in more than 65 countries for
the treatment of HR+/HER2 negative advanced breast cancer[2]
Basel, June 2, 2013 - Novartis today presented results from a pivotal Phase III
trial of a treatment regimen including Afinitor(®) (everolimus) tablets in women
with human epidermal growth factor receptor-2 positive (HER2 positive) advanced
breast cancer who received prior taxane therapy and whose disease is resistant
to prior trastuzumab (Herceptin(®*)) treatment. The findings showed that adding
everolimus, an mTOR inhibitor, to trastuzumab and vinorelbine significantly
extended progression-free survival (PFS) when compared to treatment with placebo
plus trastuzumab and vinorelbine,meeting the study's primary endpoint[1].
The BOLERO-3 (Breast cancer trials of OraL EveROlimus-3) findings were presented
at the 49(th) Annual Meeting of the American Society of Clinical Oncology
(ASCO)[1]. Final PFS results showed that adding everolimus to the standard
treatment of trastuzumab and vinorelbine reduced the risk of disease progression
by 22% (hazard ratio=0.78 [95% confidence interval (CI): 0.65 to 0.95];
p<0.01)[1]. Median time to progression was 7.0 months in the everolimus
combination arm and 5.8 months in the placebo combination arm[1]. All patients
were resistant to trastuzumab-containing regimens and 27% of the patient
population was pretreated with a lapatinib-containing regimen[1]. Findings on
overall survival, the key secondary endpoint of the trial, are not yet
mature[1].
"These encouraging data demonstrate that everolimus has a meaningful impact in
heavily pretreated HER2 positive advanced breast cancer patients," said Ruth
O'Regan, Professor and Vice-Chair for Educational Affairs, Department of
Hematology and Medical Oncology, Emory University School of Medicine and lead
study author. "Everolimus works differently than available treatment options for
HER2 positive advanced breast cancer by inhibiting mTOR, and may offer an
important new option for physicians and their patients."
Adverse events were consistent with the known safety profile of everolimus[1].
The most common all-grade adverse reactions (incidence >=30%) were neutropenia,
stomatitis, anemia, leukopenia, fatigue, pyrexia, diarrhea, nausea, decreased
appetite and constipation[1]. The most common Grade 3-4 adverse reactions
(incidence >=2%) were neutropenia, leukopenia, anemia, stomatitis, fatigue,
febrile neutropenia, diarrhea, pyrexia, nausea, hyperglycemia and
thrombocytopenia[1].
The number of on-treatment deaths (2.5% per arm) and the number of deaths due to
adverse events (0.7% per arm) were similar across treatment groups[1].
Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many
types of cancers[3]. mTOR is a protein that acts as an important regulator of
cell division, blood vessel growth and cell metabolism[4]. Previously released
data indicate that the mTOR inhibitor everolimus can provide significant benefit
when added to certain existing advanced breast cancer treatments[2],[4].
"Our previous advanced breast cancer studies have proven that everolimus plays a
key role in treating women with hormone-receptor positive, HER2 negative
advanced breast cancer, and now we know it may have a substantial impact in HER2
positive advanced breast cancer," said Alessandro Riva, Global Head, Oncology
Development & Medical Affairs, Novartis Oncology. "We plan to share the BOLERO-
3 data with regulatory health authorities worldwide."
Everolimus is approved as Afinitor in more than 65 countries including the
United States and the countries of the European Union to treat postmenopausal
women with hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced
breast cancer in combination with exemestane, after recurrence or progression
following a non-steroidal aromatase inhibitor[2]. The specific indications vary
by country[2]. HR+/HER2 negative advanced breast cancer is the most common form
of the disease[5]. Approximately 70% of all invasive breast cancers are positive
for HR expression at the time of diagnosis[6].
Study design
BOLERO-3 is a Phase III, randomized, double-blind study of everolimus plus
trastuzumab and vinorelbine conducted at 159 clinical trial sites globally[1].
The trial included 569 women with HER2 positive locally advanced or metastatic
breast cancer who were previously treated with a taxane and were resistant to
trastuzumab[1]. Participants were randomized 1:1 to receive either everolimus 5
mg/day orally or placebo, plus weekly vinorelbine 25 mg/m[2] IV and weekly
trastuzumab 2 mg/kg IV following a loading dose of 4 mg/kg[1].
The primary endpoint of the trial is PFS[1]. Secondary endpoints include overall
survival, objective response rate, time to deterioration of performance status,
changes in quality-of-life scores over time, clinical benefit rate, duration of
response, time to response, safety and pharmacokinetics[1].
About advanced breast cancer
Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally
advanced breast cancer (stage III)[7]. Metastatic breast cancer is the most
serious form of the disease and occurs when the cancer has spread to other parts
of the body, such as the brain, bones or liver[7]. Locally advanced breast
cancer occurs when the cancer has spread to lymph nodes and/or other tissue in
the area of the breast, but not to distant sites in the body[7].
Overactivation of the PI3K/AKT/mTOR pathway has been associated with disease
progression in women with advanced breast cancer[4]. Eighty percent of advanced
breast cancer is either HR+ and/or HER2 positive[2],[8].
HR+ advanced breast cancer is the most common type of advanced breast cancer,
with an estimated 220,000 women diagnosed globally each year[2]. HR+ advanced
breast cancer is characterized by hormone receptor-positive tumors, a group of
cancers that express receptors for certain hormones such as estrogen and
progesterone. Cancer cell growth can be driven by these hormones[9].
In HER2 positive advanced breast cancer, overexpression of the HER2 gene
activates signaling pathways, such as the mTOR pathway, leading to the
uncontrolled growth and division of cancer cells[2],[10]. Globally, an estimated
140,000 women are living with HER2 positive advanced breast cancer[2].
About Afinitor(®) (everolimus)
Everolimus is approved as Afinitor(®) in the European Union for the treatment of
hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast
cancer, in combination with exemestane, in postmenopausal women without
symptomatic visceral disease after recurrence or progression following a non-
steroidal aromatase inhibitor. In the United States, Afinitor is approved for
the treatment of postmenopausal women with advanced hormone receptor-positive,
HER2 negative breast cancer (advanced HR+/HER2 negative breast cancer) in
combination with exemestane after failure of treatment with letrozole or
anastrozole.
Afinitor (everolimus) tablets is approved in more than 100 countries, including
the United States and throughout the European Union, in the oncology settings of
advanced renal cell carcinoma following progression on or after vascular
endothelial growth factor (VEGF)-targeted therapy, and in the United States and
European Union for locally advanced, metastatic or unresectable progressive
neuroendocrine tumors of pancreatic origin.
Everolimus is also available from Novartis for use in certain non-oncology
patient populations under the brand names Afinitor(®) or Votubia(®), Certican(®)
and Zortress(®) and is exclusively licensed to Abbott and sublicensed to Boston
Scientific for use in drug-eluting stents.
Indications vary by country and not all indications are available in every
country. 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 about Afinitor (everolimus) tablets
Afinitor/Votubia can cause serious side effects including lung or breathing
problems, infections (including sepsis), and kidney failure, which can lead to
death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia
can affect blood cell counts, kidney and liver function, and blood sugar,
cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in
pregnant women. Highly effective contraception is recommended for women of
child-bearing potential while receiving Afinitor/Votubia and for up to eight
weeks after ending treatment. Women taking Afinitor/Votubia should not breast
feed. Fertility in women and men may be affected by treatment with
Afinitor/Votubia.
The most common adverse drug reactions (incidence >=10 percent) are mouth
ulcers, skin rash, feeling tired or weak, diarrhea, nausea, decreased appetite,
infections (including upper respiratory tract infection), low level of red blood
cells, abnormal taste, inflammation of lung tissue, weight loss, swelling of
extremities or other parts of the body, nose bleeds, itching, vomiting, high
level of blood cholesterol, headache, high level of blood sugar, cough,
spontaneous bleeding or bruising, and breathlessness. The most common Grade 3-4
adverse drug reactions (incidence >=2 percent) are mouth ulcers, feeling tired
or weak, infections, inflammation of lung tissue, diarrhea, spontaneous bleeding
or bruising, low white blood cells (a type of blood cell that fights infection),
and breathlessness. Cases of hepatitis B reactivation, blood clots in the lung
or legs, and menstruation disorders such as absence of periods have been
reported. Abnormalities were observed in hematology and clinical chemistry
laboratory tests.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "encouraging," "may," "plan," "will," 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 submitted or
approved for any new 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
Novartis 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 2012, the Group
achieved net sales of USD 56.7 billion, while R&D throughout the Group amounted
to approximately USD 9.3 billion (USD 9.1 billion excluding impairment and
amortization charges). Novartis Group companies employ approximately 129,000
full-time-equivalent associates and operate in more than 140 countries around
the world. For more information, please visit http://www.novartis.com.
Novartis is on Twitter. Sign up to follow (at)Novartis at
http://twitter.com/novartis.
* Herceptin(®) is a registered trademark of Genentech, Inc.
References
[1] O'Regan R. Phase 3, Randomized, Double-blind, Placebo-controlled
Multicenter Trial of Daily Everolimus Plus Weekly Trastuzumab and
Vinorelbine in Trastuzumab-resistant, Advanced Breast Cancer (BOLERO-
3). 2013 American Society of Clinical Oncology Annual Meeting. Oral
Presentation Abstract No. 505. Presented June 2, 2013.
[2] Novartis Data on File.
[3] Baselga J. Everolimus in Postmenopausal Hormone-Receptor-Positive
Advanced Breast Cancer. New England Journal of Medicine. December 2011.
[4] Advani SH. Targeting mTOR Pathway: A New Concept in Cancer Therapy.
Indian Journal Medical Pediatric Oncology. Oct-Dec 2010.
[5] Buckley N, Isherwood A. Breast Cancer. Decision Resources. March 2011.
[6] Dobrescu A, et al. Study of Estrogen Receptor and Progesterone Receptor
Expression in Breast Ductal Carcinoma In Situ by Immunohistochemical
Staining in ER/PgR-Negative Invasive Breast Cancer. International
Scholarly Research Network. 2011.
[7] American Cancer Society. How Do You Determine the Stage of Breast Cancer?
Available at
http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-
staging. Accessed on May 21, 2013.
[8] Arnedos M, Bihan C, Delaloge S and Andre F. Triple-negative Breast
Cancer: Are We Making Headway at Least? Therapeutic Advances in Medical
Oncology. July 2012.
[9] National Cancer Institute. What You Need to Know About Breast Cancer.
Available at
http://www.cancer.gov/cancertopics/wyntk/breast/wyntk_breast.pdf.
Accessed on May 24, 2013.
[10] Prat A, Baselga J. The Role of Hormonal Therapy in the Management of
Hormonal-Receptor-Positive Breast Cancer With Co-Expression of HER2.
Nature Clinical Practice Oncology. 2008.
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Datum: 02.06.2013 - 15:01 Uhr
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News-ID 265450
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