Patients with aggressive form of melanoma lived for more than two years on average when taking Novartis therapies Tafinlar® + Mekinist®
(Thomson Reuters ONE) -
Novartis International AG /
Patients with aggressive form of melanoma lived for more than two years on
average when taking Novartis therapies Tafinlar® + Mekinist®
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* Phase III data showed median overall survival of 25.6 months in patients
with BRAF+ V600E/K metastatic melanoma who received Tafinlar + Mekinist
* Tafinlar + Mekinist combination also demonstrated significant improvement in
health-related quality of life vs vemurafenib monotherapy in this Phase III
study
* Metastatic melanoma is a serious, life-threatening skin cancer, and long-
term survival rates are low for patients with late-stage disease[1],[2]
Basel, September 28, 2015 - Novartis today announced updated data from the Phase
III COMBI-v study showing a significant overall survival benefit for patients
with BRAF V600E/K mutation-positive metastatic melanoma when treated with the
combination of Tafinlar(®) (dabrafenib) + Mekinist(®) (trametinib) compared to
vemurafenib monotherapy. The combination also demonstrated significant health-
related quality of life improvements in the trial, including overall health,
physical and social functioning. Results are being presented at the European
Cancer Congress 2015 in Vienna.
"It is remarkable to see so many patients with BRAF V600E/K mutation-positive
metastatic melanoma having long term responses and obtaining a significant
decrease of the risk of death as compared with vemurafenib monotherapy," said
Caroline Robert, MD, PhD, Head of Dermatology, Institute Gustave-Roussy. "This
is the second Phase III trial of Tafinlar + Mekinist combination therapy to
demonstrate a significant overall survival benefit over BRAF inhibitor
monotherapy, further establishing Tafinlar + Mekinist as a standard of care for
patients fighting BRAF V600 mutation-positive metastatic melanoma."
The significant overall survival benefit of Tafinlar + Mekinist from COMBI-v is
consistent with the results demonstrated by the combination in COMBI-d, another
Phase III trial previously reported at the American Society of Clinical Oncology
(ASCO) annual meeting earlier this year.
In the COMBI-v study, the combination of Tafinlar + Mekinist achieved a
statistically significant overall survival (OS) benefit compared to vemurafenib
monotherapy (median for the combination 25.6 months vs 18.0 months; HR 0.66 [95%
CI, 0.53-0.81], p<0.001). The rate of OS at two years was 51% for those
receiving the Tafinlar + Mekinist combination and 38% for those receiving
vemurafenib monotherapy[3]. In addition, the median overall response rate (ORR)
was 65.6% in patients receiving the Tafinlar + Mekinist combination compared to
52.8% for those receiving vemurafenib monotherapy. The safety results from this
study were consistent with the profile observed to date for the combination; no
new safety concerns were observed[3].
"Helping patients live longer with our targeted combination therapy, Tafinlar
and Mekinist, is very gratifying," said Bruno Strigini, President, Novartis
Oncology. "This exemplifies our mission to transform cancer care with the
ultimate goal of identifying the right treatment for the right patient at the
right time."
Metastatic melanoma is the most serious and life-threatening type of skin
cancer[1] and only about one in five patients survives for five years following
diagnosis with late-stage disease[2]. There are about 200,000 new cases of
melanoma diagnosed worldwide each year[4], approximately half of which have BRAF
mutations[2]. Gene tests can determine whether a tumor has a BRAF mutation, and
results can play a key role in prognosis and determining appropriate
treatment[2].
In August 2015, the European Commission approved the combination of Tafinlar +
Mekinist for the treatment of adult patients with unresectable or metastatic
melanoma with a BRAF V600 mutation. The European Commission approval applies to
all 28 EU member states, plus Iceland, Norway and Liechtenstein. In July 2015,
the US Food and Drug Administration (FDA) granted priority review for an
application to obtain regular approval of the Tafinlar + Mekinist combination in
BRAF V600E/K mutation-positive metastatic melanoma. Since January 2014, the
combination of Tafinlar + Mekinist has been approved for use in the US in
patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma
as detected by an FDA-approved test. The combination was approved through the
FDA's Accelerated Approval program and reviewed under a priority review
designation. The approval was contingent on the results of the COMBI-d study,
which was designed to evaluate the clinical benefit of the combination in
patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation.
About the COMBI-v Study
COMBI-v was a two-arm, open-label, Phase III study comparing the combination of
Tafinlar + Mekinist with vemurafenib monotherapy in patients with BRAF V600E/K
mutation-positive unresectable or metastatic melanoma. The primary endpoint of
this study was OS[3].
Results from the COMBI-v study showed that the combination of Tafinlar +
Mekinist achieved a statistically significant OS benefit compared to vemurafenib
monotherapy (median for the combination 25.6 months vs 18.0 months; HR 0.66 [95%
CI, 0.53-0.81], p<0.001). A statistically significant reduction of 34% in the
risk of death among patients receiving combination therapy was observed in the
study. The analysis reported median progression free survival (PFS) of 12.6
months, ORR of 65.6%, and median duration of response (DoR) of 13.8 months for
the Tafinlar + Mekinist combination arm compared to PFS of 7.3 months, ORR of
52.8%, and median DoR of 8.5 months for the vemurafenib monotherapy arm. The
most frequent adverse events in the Tafinlar + Mekinist combination arm (>=30%)
were pyrexia, nausea, diarrhea, and chills. More patients had AEs leading to
dose modifications in the combination arm compared to the vemurafenib
monotherapy arm. For the combination group compared to the vemurafenib group,
there was a lower incidence of rash, 22% (n=76) vs 43% (n=149); photosensitivity
reaction, 4% (n=13) vs 22% (n=78); hand-foot syndrome, 4% (n=14) vs 25% (n=87);
skin papillomas, 2% (n=6) vs 23% (n=80); squamous-cell carcinomas and
keratoacanthomas, 1% (n=5) vs 18% (n=63); and hyperkeratosis, 4% (n=15) vs 25%
(n=86). Adverse events occurring more frequently in the combination arm compared
with the vemurafenib monotherapy arm included pyrexia, 53% (n=184) vs 21%
(n=73), respectively, and bleeding events, 18% (n=62) vs 7% (n=25),
respectively. Discontinuation of treatment due to adverse events was similar
between the treatment groups: 13% (n=44) for the combination group compared to
12% (n=41) for the monotherapy group[3].
Results from an analysis of the COMBI-v study of the patients' health-related
quality of life showed statistically significant and clinically meaningful
improvements among those receiving the combination of Tafinlar + Mekinist,
compared to those receiving vemurafenib monotherapy. Overall health, physical
and social functioning, and specific symptoms such as pain, insomnia, and loss
of appetite were all improved in the group receiving combination therapy[5].
About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or
metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU,
Australia, Canada and additional countries.
Tafinlar and Mekinist target different kinases within the serine/threonine
kinase family - BRAF and MEK1/2, respectively - in the RAS/RAF/MEK/ERK pathway,
which is implicated in NSCLC and melanoma, among other cancers. When Tafinlar is
used with Mekinist, the combination has been shown to slow tumor growth more
than either drug alone. The combination of Tafinlar + Mekinist is currently
being investigated in an ongoing clinical trial program across a range of tumor
types conducted in study centers worldwide.
In 2015, as part of its purchase of oncology products from GlaxoSmithKline,
Novartis obtained the worldwide exclusive rights granted by Japan Tobacco Inc.
(JT) to develop, manufacture, and commercialize trametinib. JT retains co-
promotion rights in Japan.
The safety and efficacy profile of the Tafinlar + Mekinist combination has not
yet been established outside of the approved indication.
Tafinlar and Mekinist are also indicated in more than 35 countries worldwide,
including the US and EU, as single agents to treat patients with unresectable or
metastatic melanoma with a BRAF V600 mutation.
Tafinlar + Mekinist Combination Important Safety Information for Metastatic
Melanoma
Tafinlar + Mekinist combination may cause serious side effects, such as:
When Tafinlar is used in combination with Mekinist, or when Tafinlar is
administered as monotherapy, it can cause new cancers (both skin cancer and non-
skin cancer). Patients should be advised to contact their doctor immediately for
any new lesions, changes to existing lesions on their skin, or signs and
symptoms of other malignancies.
Before taking Tafinlar in combination with Mekinist, doctors should test their
patients for BRAF wild-type melanoma, as patients without BRAF mutation and with
RAS mutation can be at risk of increased cell proliferation in the presence of a
BRAF inhibitor.
When Tafinlar is used in combination with Mekinist, it can increase the
incidence and severity of bleeding, and in some cases can lead to death.
Patients should be advised to call their healthcare provider and get medical
help right away if they have headaches, dizziness, or feel weak, cough up blood
or blood clots, vomit blood or their vomit looks like "coffee grounds," have red
or black stools that look like tar, or any unusual signs of bleeding.
Tafinlar, in combination with Mekinist, can cause blood clots in the arms or
legs, which can travel to the lungs and can lead to death. Patients should be
advised to get medical help right away if they have the following symptoms:
chest pain, sudden shortness of breath or trouble breathing, pain in their legs
with or without swelling, swelling in their arms or legs, or a cool or pale arm
or leg.
Tafinlar in combination with Mekinist can cause heart problems, including heart
failure. A patient's heart function should be checked before and during
treatment. Patients should be advised to call their healthcare provider right
away if they have any of the following signs and symptoms of a heart problem:
feeling like their heart is pounding or racing, shortness of breath, swelling of
their ankles and feet, or feeling lightheaded.
Tafinlar alone, or in combination with Mekinist, can cause severe eye problems
that can lead to blindness. Patients should be advised to call their healthcare
provider right away if they get these symptoms of eye problems: blurred vision,
loss of vision, or other vision changes, seeing color dots, halo (seeing blurred
outline around objects), eye pain, swelling, or redness.
Patients should notify their doctor if they experience any new or worsening
symptoms of lung or breathing problems, including shortness of breath or cough.
Tafinlar alone or in combination with Mekinist can cause fever, which may be
serious. When taking Tafinlar in combination with Mekinist, fever may happen
more often or may be more severe. In some cases, chills or shaking chills, too
much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems
may happen with the fever. Patients should be advised to call their healthcare
provider right away if they get a fever above 38.5(o)C (101.3(o)F) while taking
Tafinlar.
Rash is a common side effect of Tafinlar alone, or when used in combination with
Mekinist. Tafinlar alone, or in combination with Mekinist, can also cause other
skin reactions. In some cases these rashes and other skin reactions can be
severe, and may need to be treated in a hospital. Patients should be advised to
call their healthcare provider if they get any of the following symptoms: skin
rash that bothers them or does not go away, acne, redness, swelling, peeling, or
tenderness of hands or feet, skin redness.
Some people may develop high blood sugar or worsening diabetes during treatment
with Tafinlar, alone or in combination with Mekinist. For patients who are
diabetic, their healthcare provider should check their blood sugar levels
closely during treatment. Their diabetes medicine may need to be changed.
Patients should be advised to tell their healthcare provider if they have any of
the following symptoms of severe high blood sugar: increased thirst or urinating
more often than normal, or urinating an increased amount of urine.
Tafinlar may cause healthy red blood cells to break down too early in people
with G6PD deficiency. This may lead to a type of anemia called hemolytic anemia
where the body does not have enough healthy red blood cells. Patients should be
advised to tell their healthcare provider if they have any of the following
signs or symptoms of anemia or breakdown of red blood cells: yellow skin
(jaundice), weakness or dizziness, or shortness of breath.
Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a
pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.
The most common side effects of Tafinlar + Mekinist combination include fever,
nausea, tiredness, rash, chills, diarrhea, headache, vomiting, hypertension,
joint pain, peripheral edema and cough. The incidence and severity of fever is
increased when Mekinist is used in combination with Tafinlar.
Patients should tell their doctor of any side effect that bothers them or does
not go away. These are not all of the possible side effects of Tafinlar +
Mekinist combination. For more information, patients should ask their doctor or
pharmacist.
Patients should take Tafinlar + Mekinist combination exactly as their health
care provider tells them. Patients should not change their dose or stop taking
Tafinlar + Mekinist combination unless their health care provider advises them
to. Mekinist should be taken only once daily (either in the morning or evening,
at the same time as Tafinlar). The first and second dose of Tafinlar should be
taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at
least 1 hour before or 2 hours after a meal. Do not take a missed dose of
Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or
break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours
of the next dose of Mekinist.
Please see full Prescribing Information for Tafinlar and Mekinist.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by words such as "mission," "goal," "being investigated," "ongoing," "yet," or
similar terms, or by express or implied discussions regarding potential
marketing approvals or new indications or labeling for the combination of
Tafinlar plus Mekinist, or regarding potential future revenues from Tafinlar and
Mekinist, either in combination or as single agents. 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 the
combination of Tafinlar plus Mekinist will be submitted or approved for any
additional indications or labeling in any market, or at any particular time.
Neither can there be any guarantee that the combination of Tafinlar plus
Mekinist will be submitted or approved for sale in any additional markets, or at
any particular time. Nor can there be any guarantee that Tafinlar and Mekinist,
either in combination or as single agents, will be commercially successful in
the future. In particular, management's expectations regarding Tafinlar and
Mekinist, either in combination or as single agents, 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 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 and cost-saving generic pharmaceuticals. Novartis is the only global
company with leading positions in these areas. In 2014, the Group achieved net
sales of USD 58.0 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 120,000
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] A Snapshot of Melanoma. National Cancer Institute. Available at:
http://www.cancer.gov/research/progress/snapshots/melanoma. Accessed August
26, 2015.
[2] Melanoma Skin Cancer. American Cancer Society. Available at:
http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf.
Accessed August 26, 2015.
[3] Robert C. Two year estimate of overall survival in COMBI-v, a randomized,
open-label, phase III study comparing the combination of dabrafenib (D) and
trametinib (T) with vemurafenib (vem) as first-line therapy in patients (pts)
with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous
melanoma. Abstract #3301. 18th ECCO - 40th ESMO European Cancer Congress,
September 2015, Vienna, Austria.
[4] GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence
worldwide in 2012. International Agency for Research on Cancer. Available at:
http://globocan.iarc.fr/. Accessed August 26, 2015.
[5] Grob JJ. COMBI-v: health-related quality of life (HRQoL) impact of the
combination of dabrafenib and trametinib (D+T) vs vemurafenib (V) in patients
with BRAF V600 metastatic melanoma (MM). Abstract #3345. 18th ECCO - 40th ESMO
European Cancer Congress, September 2015, Vienna, Austria.
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Datum: 28.09.2015 - 00:01 Uhr
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