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2015-09-01

Novartis International AG: Novartis receives EU approval for Tafinlar® and Mekinist®, first combination approved for patients with aggressive form of melanom

Novartis International AG / Novartis receives EU approval for Tafinlar® and
Mekinist®, first combinationapproved for patients with aggressive form of
melanoma . Processed and transmitted by NASDAQ OMX Corporate Solutions.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...

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