Novartis combination therapy Tafinlar® + Mekinist® demonstrates overall survival benefit at three-year follow-up in patients with advanced melanoma
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Novartis International AG /
Novartis combination therapy Tafinlar® + Mekinist® demonstrates overall survival
benefit at three-year follow-up in patients with advanced melanoma
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* 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 52(nd) Annual 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 38.5(o)C
(101.3(o)F) 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 38.5(o)C (101.3(o)F), 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 reported in association with Mekinist in
combination with Tafinlar, or with Mekinist alone, in patients with or without
pre-existing hypertension. Patients should be advised to monitor blood pressure
during treatment with Mekinist and control potential hypertension by standard
therapy, as appropriate.
Tafinlar in combination with Mekinist, or Mekinist alone, can cause inflammation
of the lung tissue. Patients should notify their doctor if they experience any
new or worsening symptoms of lung or breathing problems, including shortness of
breath or cough.
Rash is a common side effect of Tafinlar in combination with Mekinist, or with
Mekinist alone. Tafinlar in combination with Mekinist, or Mekinist alone, can
also cause other skin reactions which 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.
Tafinlar in combination with Mekinist, or Mekinist alone, can cause muscle
breakdown, a condition called Rhabdomyolysis. Patients experiencing muscle pain,
tenderness, weakness or a swelling of their muscles should contact their
healthcare provider immediately.
Tafinlar in combination with Mekinist, or Tafinlar alone, can uncommonly cause
an inflammation of the pancreas (pancreatitis). Patients should be promptly
investigated if they experience unexplained abdominal pain and closely monitored
if they re-start Tafinlar after a prior episode of pancreatitis.
Tafinlar in combination with Mekinist, or Mekinist alone, 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 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,
tiredness, nausea, headache, chills, diarrhea, rash, joint pain, high blood
pressure, vomiting 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 doses 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 "can," "committed," "helping to grow," "potential," "will,"
"being investigated," "ongoing," "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, quality or manufacturing
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 2015, the Group achieved net
sales of USD 49.4 billion, while R&D throughout the Group amounted to
approximately USD 8.9 billion (USD 8.7 billion excluding impairment and
amortization charges). Novartis Group companies employ approximately 118,000
full-time-equivalent associates. Novartis products are available in more than
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http://www.novartis.com.
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References
[1] Flaherty, K.T. Genomic Analysis and 3-Year Efficacy and Safety Update of
COMBI-d, a phase 3 study of dabrafenib + trametinib vs dabrafenib monotherapy in
patients with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma.
Abstract #9502. 2016 American Society of Clinical Oncology (ASCO) Annual
Meeting, Chicago, IL, USA.
[2] Palmer SR, Erickson LA, Ichetovkin I, et al. Circulating Serologic and
Molecular Biomarkers in Malignant Melanoma. Mayo Clinic Proceedings.
2011; 86(10):981-990.
[3] Melanoma Skin Cancer. American Cancer Society. Available at:
http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf.
Accessed May 31, 2016.
[4] A Snapshot of Melanoma. National Cancer Institute. Available at:
http://www.cancer.gov/research/progress/snapshots/melanoma. Accessed May
31, 2016.
[5] GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence
Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx.
Accessed May 31, 2016.
[6] Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity in V600R
metastatic melanoma. Eur J Cancer. 2013; 49(5):1073-1079.
[7] Heinzerling L, Kuhnapfel S, Meckbach D. Rare BRAF mutations in melanoma
patients: implications for molecular testing in clinical practice. British
Journal of Cancer. 2013.
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