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2016-06-06

Novartis International AG: Novartis combination therapy Tafinlar® + Mekinist® demonstrates overall survival benefit at three-year follow-up in patients with a

Novartis International AG / Novartis combination therapy Tafinlar® + Mekinist®
demonstrates overall survivalbenefit at three-year follow-up in patients with
advanced melanoma . Processed and transmitted by NASDAQ OMX Corporate
Solutions.The issuer is solely responsible for the content of this
announcement.
* Study is longest Ph III survival follow-up to date of BRAF V600E/K
mutation-positive melanoma patients who received a targeted combination
therapy
* Latest data show an estimated 44% of patients alive after receiving
Tafinlar®+ Mekinist®combination therapy[1]
* Of those patients still enrolled at three years, 58% were receiving the
Tafinlar + Mekinist combination[1]

Basel, June 6, 2016
- Novartis today announced data from a Phase III study showing a significant
survival benefit for patients with BRAF V600E/K mutation-positive advanced
melanoma when treated with the first-line combination of
Tafinlar®(dabrafenib) + Mekinist®(trametinib) compared to Tafinlar
monotherapy[1]. The results from the COMBI-d three-year follow-up analysis
represent one of the longest survival follow-up studies to date with BRAF
mutation-positive advanced melanoma patients. Results are being presented
today at the 52ndAnnual Meeting of the American Society of Clinical Oncology
(ASCO) in Chicago.

"BRAF mutation remains the critical genetic feature in advanced melanoma that
guides patients' treatment options," said Keith T. Flaherty, MD, Director of
the Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts
General Hospital Cancer Center and Professor of Medicine, Harvard Medical
School. "These results confirm that long-term survival can be achieved with
this combination and it should be an important consideration for patients
with BRAF mutation-positive advanced melanoma. It is particularly striking to
note the excellent outcome for those with lower burden of disease at
baseline."

Results from the COMBI-d study of 423 patients found the estimated three-year
survival rate to be 44% for patients receiving the combination of Tafinlar +
Mekinist (95% CI, 36.4%-50.5%) compared with 32% who received Tafinlar alone
(95% CI, 25.4%-38.3%)[1]. There were 26 patients who crossed over from the
monotherapy arm to the combination arm after the combination demonstrated a
significant overall survival (OS) benefit in a prior analysis[1].
Additionally, the estimated three-year progression-free survival rate was 22%
(95% CI, 16.2%-28.0%) for the combination arm and 12% (95% CI, 7.1%-18.0%)
for the monotherapy arm[1]. In an analysis of patients with normal lactate
dehydrogenase (LDH) levels and fewer than three disease sites, the three-year
survival rate for combination was 62% (95% CI, 49.3%-72.0%) compared with 45%
who received Tafinlar alone (95% CI, 34.9%-55.1%)[1]. In advanced melanoma, a
patient's LDH level is often predictive of prognosis and may be a predictor
of treatment response[2].

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[1]. The most common adverse
events (>=20%) in the combination arm were pyrexia, fatigue, nausea,
headache, chills, diarrhea, rash, vomiting, joint pain (arthralgia),
hypertension, cough and peripheral edema[1].

"Novartis is committed to improving outcomes for advanced melanoma patients,
and we are gratified to see that these data show that we are extending the
lives of many patients receiving therapy with Tafinlar + Mekinist," said
Alessandro Riva, MD, Global Head, Oncology Development&Medical Affairs. "This
data is also a strong example of the importance of rationally combining
targeted therapies and identifying those patients who are likely to benefit
from our medicines beyond three years. This type of treatment approach is not
only helping to grow the practice of precision oncology, but has the
potential to fundamentally change the way we treat cancer."

About the COMBI-d Study

COMBI-d is a pivotal Phase III randomized, double-blinded study (NCT01584648)
comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK
inhibitor, Mekinist, to single agent therapy with Tafinlar and placebo as
first-line therapy in patients with unresectable (Stage IIIC) or metastatic
(Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study
randomized 423 patients from 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 were 26 patients who crossed over from the
monotherapy group to the combination group after the combination demonstrated
a significant OS benefit in a prior analysis[1].

At three years of follow up, the combination of Tafinlar + Mekinist continued
to demonstrate a benefit on the measures of DoR and ORR, in line with results
seen at the two-year follow up analysis[1]. 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[1].

About Melanoma

Metastatic melanoma is the most serious and life-threatening type of skin
cancer and is associated with low survival rates[3],[4]. Only about 20% of
people will survive for at least five years following a diagnosis with
late-stage disease[3]. There are about 200,000 new cases of melanoma
diagnosed worldwide each year[5], approximately half of which have BRAF
mutations, a key target in the treatment of metastatic melanoma[3],[6]. Gene
tests can determine whether a tumor has a BRAF mutation[3],[7].

About Tafinlar and 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 non-small cell lung cancer (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.

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.

Important Safety Information for Tafinlar + Mekinist Combination for
Metastatic Melanoma

Tafinlar + Mekinist combination may cause serious side effects.

Tafinlar in combination with Mekinist should only be used to treat melanoma
with a change (mutation) in the BRAF gene; therefore, doctors should test
their patients before treatment, as patients without a BRAF mutation and with
a RAS mutation can be at risk of increased cell proliferation in the presence
of a BRAF inhibitor.

Doctors should also consider other treatment options for their patients if
they had been previously treated with a BRAF inhibitor as single agent, as
the limited data available have shown that the efficacy of Tafinlar +
Mekinist is lower in these patients.

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.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe
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, or either drug alone, 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.

Tafinlar in combination with Mekinist, or Tafinlar alone, 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 38.5oC (101.3oF) while taking Tafinlar.

Tafinlar in combination with Mekinist, or Mekinist alone, can affect how well
the heart pumps blood. 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 in combination with Mekinist, or Tafinlar alone, can cause abnormal
kidney function or inflammation of the kidney. Abnormal kidney function may
happen more often for patients with fever or too much fluid loss. Patients
should be advised to call their healthcare provider right away if they have a
fever above 38.5oC (101.3oF), decreased urine, fatigue, loss of appetite or
discomfort in lower abdomen or back. Tafinlar has not been studied in
patients with renal insufficiency (defined as creatinine> 1.5 x ULN)
therefore caution should be used in this setting.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause abnormal
liver function. A patient may feel tired, lose appetite, yellow skin, dark
urine colour, or discomfort in abdomen. The liver function abnormality needs
to be assessed by laboratory test of the blood. Patients should consult their
healthcare provider if they have such experience. Administration of Tafinlar
or Mekinist should be done with caution in patients with moderate to severe
hepatic impairment.

Elevations in blood pressure have been report...

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