Novartis receives EU approval for Tafinlar® and Mekinist®, first combination approved for patients with aggressive form of melanoma
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Novartis International AG /
Novartis receives EU approval for Tafinlar® and Mekinist®, first combination
approved for patients with aggressive form of melanoma
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The issuer is solely responsible for the content of this announcement.
* Approval based on two Phase III studies demonstrating statistically
significant overall survival benefit with combination therapy vs BRAF
inhibitor monotherapy
* Targeted combination offers BRAF V600 mutation-positive melanoma patients in
the EU new first-line option with improved efficacy and manageable safety
profile
Basel, September 1, 2015 - Novartis today announced that the European Commission
has approved the combination of Tafinlar(®) (dabrafenib) and Mekinist(®)
(trametinib) for the treatment of adult patients with unresectable or metastatic
melanoma with a BRAF V600 mutation. This is the first targeted therapy
combination approved in the EU to treat patients with the most aggressive form
of skin cancer[1], demonstrating improved overall survival versus the current
standard of care with BRAF inhibitor monotherapy in two Phase III studies[2,3].
"We look forward to making the Tafinlar and Mekinist targeted combination
treatment, which demonstrated a significant overall survival benefit in two
robust clinical trials, available across Europe as soon as possible," said Bruno
Strigini, President, Novartis Oncology. "Today's EU approval further
demonstrates our ongoing commitment to deliver medicines that can further
enhance outcomes for patients with metastatic melanoma."
Metastatic melanoma is the most serious and life-threatening type of skin
cancer[4] and is associated with low survival rates[1]; approximately one out of
every five people will survive for five years following a diagnosis with late-
stage disease[1]. There are about 200,000 new cases of melanoma diagnosed
worldwide each year[5], approximately half of which have BRAF mutations[1,6].
Gene tests can determine whether a tumor has a BRAF mutation, and results can
play a key role in prognosis and determining appropriate treatment[1].
Marketing authorization is based on results from the Phase III COMBI-d and
COMBI-v studies, in which the Tafinlar/Mekinist combination demonstrated overall
survival (OS) benefit compared to Tafinlar and Zelboraf monotherapies
respectively in patients with BRAF V600 mutation-positive unresectable or
metastatic melanoma[2,3].
The COMBI-d study showed that the combination of Tafinlar and Mekinist achieved
a statistically significant OS benefit compared to Tafinlar monotherapy (median
of 25.1 months vs 18.7 months; Hazard Ratio [HR] 0.71 [95% Confidence Interval
(CI), 0.55-0.92], p=0.011). In those who received Tafinlar in combination with
Mekinist, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for those
who received Tafinlar only, respectively. Safety results from the COMBI-d study
were consistent with the profile observed to date for the combination; no new
safety concerns were observed. The most common adverse events (>=20%) in the
combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash,
joint pain (arthralgia), hypertension, vomiting, cough, and peripheral edema[2].
Adverse events or toxicities were generally manageable with appropriate
intervention, as described in the product labelling submitted with the
application. Updated results from COMBI-v will be presented at an upcoming
medical congress.
The European Commission approval applies to all 28 EU member states, plus
Iceland, Norway and Liechtenstein.
In the US, the Food and Drug Administration (FDA) granted priority review in
July 2015 for regular approval of the Tafinlar and Mekinist combination in BRAF
V600 mutation-positive metastatic melanoma. Since January 2014, the combination
of Tafinlar and 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 V600 mutation.
About the COMBI-d Study
COMBI-d is a pivotal Phase III, randomized, double-blinded study comparing the
combination of the BRAF inhibitor, Tafinlar, and the MEK inhibitor, Mekinist, to
single agent therapy with Tafinlar and placebo in patients with unresectable
(Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous
melanoma. The study randomized 423 patients at investigative sites in Australia,
Europe and North and South America. The primary endpoint of this study was
investigator-assessed progression-free survival (PFS). Secondary endpoints
included overall survival (OS), overall response rate (ORR), duration of
response (DoR), and safety. There was no crossover between treatment arms[2].
Updated results from the COMBI-d study showed that the combination of Tafinlar
and Mekinist achieved a statistically significant OS benefit compared to
Tafinlar monotherapy (median of 25.1 months vs 18.7 months; HR 0.71 [95% CI,
0.55-0.92], p=0.011). In those who received the Tafinlar and Mekinist
combination, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for
those who received Tafinlar only, respectively. The analysis for the combination
also showed median PFS of 11.0 months, ORR of 69%, and median DoR of 12.9
months. The safety results were consistent with the profile observed to date for
the combination and consistent with the profile observed for Tafinlar
monotherapy; no new safety concerns were observed. The most common adverse
events (>=20%) in the combination arm were pyrexia, fatigue, nausea, headache,
chills, diarrhea, rash, joint pain (arthralgia), hypertension, vomiting, cough,
and peripheral edema. More patients had AEs leading to dose modifications in the
combination arm compared to Tafinlar monotherapy. Increased incidence (57% vs
33%) and severity (grade 3, 7% (n=15) vs 2% (n=4)) of pyrexia occurred with
combination treatment as compared to Tafinlar monotherapy. There was a lower
incidence of cutaneous squamous cell carcinoma (cuSCC) including keratoacanthoma
with the combination arm (3% (n=6)) compared to the Tafinlar monotherapy arm
(10% (n=22)). Discontinuation of treatment due to adverse events occurred in
11% (n=24) vs 7% (n=14) of patients in the combination group and the monotherapy
group, respectively[2].
About the COMBI-v Study
COMBI-v was a two-arm, open-label, Phase III study comparing the combination of
Tafinlar and Mekinist combination therapy with vemurafenib monotherapy in
patients with BRAF V600 mutation-positive unresectable or metastatic
melanoma. The primary endpoint of this study was OS[3]. Updated results from
COMBI-v will be presented at an upcoming medical congress.
About Tafinlar and Mekinist Combination
Combination use of Tafinlar and Mekinist in patients with unresectable or
metastatic melanoma who have BRAF V600E/K mutation is approved in the US,
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
effectively compared with either drug alone. The combination of Tafinlar and
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 and Mekinist combination has not
yet been established outside the approved indication.
Tafinlar and Mekinist are also indicated as single agents to treat patients with
unresectable or metastatic melanoma with a BRAF V600 mutation in more than 35
countries worldwide, including the US and EU.
Tafinlar and Mekinist Combination Important Safety Information for Metastatic
Melanoma
Tafinlar and 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 and 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 and
Mekinist combination. For more information, patients should ask their doctor or
pharmacist.
Patients should take Tafinlar and Mekinist combination exactly as their health
care provider tells them. Patients should not change their dose or stop taking
Tafinlar and 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 and 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 "look forward," "ongoing," "commitment," "can," "will,"
"upcoming," "priority review," "being investigated," "yet," or similar terms, or
by express or implied discussions regarding potential marketing approvals or new
indications or labeling for Tafinlar and Mekinist, either in combination or as
single agents, 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 Tafinlar
and Mekinist, either in combination or as single agents, 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 Tafinlar and Mekinist,
either in combination or as single agents, 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, in combination and 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.
Novartis is on Twitter. Sign up to follow (at)Novartis at
http://twitter.com/novartis.
References
[1.] Melanoma Skin Cancer. American Cancer Society. Available at:
http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf.
Accessed August 26, 2015.
[2.] Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus
dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-
blind, phase 3 randomised controlled trial [published online May 30, 2015].
Lancet. 2015.
[3.] Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in
melanoma with combined dabrafenib and trametinib. N Engl J Med.
2015;372(1):30-39.
[4.] A Snapshot of Melanoma. National Cancer Institute. Available at:
http://www.cancer.gov/research/progress/snapshots/melanoma. Accessed August
26, 2015.
[5.] 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.
[6.] Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity in V600R
metastatic melanoma. Eur J Cancer. 2013; 49(5):1073-1079.
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Datum: 01.09.2015 - 07:15 Uhr
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