-
Latest data confirm an
estimated 45% of patients who received
Tafinlar® +
Mekinist® combination
therapy are alive versus 31% of patients on BRAF
monotherapy[1]
-
Second trial to confirm
three-year landmark overall survival data for the
combination
-
Advanced melanoma is a serious,
life-threatening skin cancer, with typically low rates of survival
for patients with late-stage disease[2],[3]
Basel, October 8, 2016 -
Novartis today announced data from the Phase III COMBI-v study
demonstrating an overall survival (OS) and a progression-free
survival benefit for patients with BRAF V600 mutation-positive
advanced melanoma when treated first-line with the combination of
Tafinlar® (dabrafenib)
+ Mekinist® (trametinib)
compared to vemurafenib monotherapy[1]. The results of this study,
which was conducted in 704 patients[1], are being presented at the
European Society for Medical Oncology (ESMO) 2016 Congress in
Copenhagen.
"The three-year overall survival follow-up data
from COMBI-v is remarkable because it is the second Phase III study
this year to demonstrate a significant long-term survival benefit
for BRAF mutation-positive melanoma patients treated with Tafinlar
+ Mekinist combination therapy compared to BRAF inhibitor
monotherapy," said Caroline Robert, MD, PhD, Head of Dermatology,
Institute Gustave-Roussy. "The results of this trial continue to
reinforce Tafinlar + Mekinist as a standard of care and sets a new
benchmark for treating patients with BRAF V600 mutation-positive
advanced melanoma."
Results from the COMBI-v study found the estimated
three-year survival rate to be 45% of patients receiving the
combination of Tafinlar + Mekinist (95% CI, 39.1%-49.8%) compared
with 31% of patients who received vemurafenib monotherapy (95% CI,
26.1%-36.4%)[1]. There were 34 patients who crossed over from the
vemurafenib monotherapy arm to the combination arm after the
combination demonstrated a significant OS benefit in a prior
analysis[1]. Additionally, the estimated three-year
progression-free survival rate was 24% (95% CI, 19.4%-28.8%) for
the combination arm and 10% (95% CI, 5.9%-14.5%) for the
vemurafenib monotherapy arm[1].
"We are pleased to see the continued benefit of
Tafinlar + Mekinist targeted combination therapy beyond three-years
in another study," said Alessandro Riva, MD, Global Head, Oncology
Development & Medical Affairs. "As we've come to understand,
this combination of targeted inhibitors has demonstrated an
unprecedented ability to block the known resistance pathways and
extend overall survival for BRAF mutation-positive patients. These
results underscore our commitment to advancing the practice of
precision oncology and extending patients' lives through treatment
options that target the root cause of their cancer."
At three years of follow up, the combination of
Tafinlar + Mekinist continued to demonstrate a benefit on the
measures of duration of response (DoR) and overall response rate
(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 vemurafenib monotherapy; no new safety
concerns were observed.
About the COMBI-v
Study
COMBI-v is 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. The
Independent Data Monitoring Committee (IDMC) stopped the trial
early based on efficacy results observed in the Tafinlar + Mekinist
study arm as part of a planned interim analysis[1].
About Melanoma
Advanced melanoma is the most serious and life-threatening type of
skin cancer and is associated with low survival rates[2],[3]. Only
about 20% of people will survive for at least five years following
a 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, a key target in the treatment of
metastatic melanoma[2],[5]. Gene tests can determine whether a
tumor has a BRAF mutation[2],[6].
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 other
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 40 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.
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 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.
Mekinist, alone or in combination with Tafinlar,
may increase the risk of developing holes in the stomach or
intestine (gastrointestinal perforation). Treatment with Mekinist
alone or in combination with Tafinlar should be used with caution
in patients with risk factors for gastrointestinal perforation,
including concomitant use of medications with a recognised risk of
gastrointestinal perforation.
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 "to confirm," "continue,"
"commitment," "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 180 countries around the world.
For more information, please visit http://www.novartis.com.
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References
[1] Robert. C, Karaszewska b, Schachter J, et al. Three-year
estimate of overall survival in COMBI-v, a randomized phase 3 study
evaluating first-line dabrafenib (D) + trametinib (T) in patients
(pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous
melanoma. Abstract #LBA40. 2016 European Society of Medical
Oncology (ESMO) Annual Meeting, Copenhagen, Denmark.
[2] Melanoma Skin Cancer. American Cancer Society. Available at:
http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf.
Accessed May 31, 2016.
[3] A Snapshot of Melanoma. National Cancer Institute. Available
at: http://www.cancer.gov/research/progress/snapshots/melanoma.
Accessed May 31, 2016.
[4] GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and
Prevalence Worldwide in 2012.
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed
May 31, 2016.
[5] Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity
in V600R metastatic melanoma. Eur J Cancer. 2013;
49(5):1073-1079.
[6] 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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