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2015-09-27

Novartis International AG: Patients with aggressive form of melanoma lived for more than two years on average when taking Novartis therapies Tafinlar® + Mekin

Novartis International AG / Patients with aggressive form of melanoma lived
for more than two years onaverage when taking Novartis therapies Tafinlar® +
Mekinist® . Processed and transmitted by NASDAQ OMX Corporate Solutions.The
issuer is solely responsible for the content of this announcement.
* 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 advi...

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