Combination of Novartis drugs Tafinlar® and Mekinist® shows significant survival benefit in patients with metastatic melanoma
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Novartis International AG /
Combination of Novartis drugs Tafinlar® and Mekinist® shows significant survival
benefit in patients with metastatic melanoma
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* Final analysis of COMBI-d confirms overall survival benefit of combination
therapy in patients with BRAF V600E/K mutation-positive metastatic melanoma
* Tafinlar and Mekinist in combination achieved a median overall survival of
25.1 months compared to 18.7 months for Tafinlar monotherapy in this Phase
III study
* Three-year data from Phase I-II study reinforce long-term overall survival
benefit of combination therapy
Basel, May 31, 2015 - Novartis today announced data from the Phase III COMBI-d
study showing a significant survival benefit for patients with BRAF V600E/K
mutation-positive metastatic melanoma when treated with the combination of
Tafinlar(®) (dabrafenib) and Mekinist(®) (trametinib) compared to Tafinlar
monotherapy alone. This is the first combination of BRAF/MEK inhibitors to
demonstrate a statistically significant overall survival benefit for this
patient population in two Phase III studies. Results are being presented today
at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO)
in Chicago.
"This final analysis from COMBI-d confirms prior results showing a statistically
significant improvement in overall survival among patients with BRAF V600E/K
mutation-positive metastatic melanoma receiving the combination of dabrafenib
and trametinib compared to dabrafenib monotherapy," said Georgina Long, B.Sc.,
Ph.D., M.B.B.S., F.R.A.C.P., medical oncologist, Melanoma Institute Australia,
The University of Sydney. "These findings further reinforce the rationale for
the treatment of metastatic melanoma with this combination."
The final analysis included the 423 patients enrolled in COMBI-d and showed that
the combination of Tafinlar and Mekinist achieved a statistically significant
overall survival (OS) benefit compared to Tafinlar monotherapy (median of 25.1
months vs 18.7 months)[1]. The analysis for the combination also showed median
progression-free survival (PFS) of 11.0 months, overall response rate (ORR) of
69%, and median duration of response (DoR) of 12.9 months[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]. 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[1].
"We are very pleased to have entered into a new disease area with the
acquisition of two medicines that are making a positive impact on the lives of
people with this serious form of skin cancer," said Bruno Strigini, President,
Novartis Oncology. "These COMBI-d data prove that these medicines can
significantly extend the lives of people with BRAF V600E/K mutation-positive
melanoma, and we are proud to be part of the progress in this disease."
In addition to results from the COMBI-d study, long-term data from a Phase I-II
study showed a three-year OS rate of 38% (95% CI, 25%, 51%) after treatment with
the combination of Tafinlar and Mekinist in all patients with BRAF V600 E/K
mutation-positive metastatic melanoma. Safety results from this study were
consistent with those observed in other trials evaluating the combination.
Other data being presented at the meeting, including oral presentations related
to the investigational use of dabrafenib and trametinib, include studies in BRAF
V600E-mutated metastatic colorectal cancer (CRC), non-small cell lung cancer
(NSCLC), and other rare cancers.
The results from the COMBI-d study are also being published online in The Lancet
on May 31.
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 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 PFS. Secondary
endpoints included OS, ORR, DoR, and safety. There was no crossover between
treatment arms.
The final OS analysis 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). A 33% reduction in the risk of progression
or death was demonstrated with the combination therapy compared to monotherapy
(median PFS of 11.0 months in the 211 patients receiving combination therapy vs
8.8 months in the 212 patients receiving monotherapy; HR 0.67 [95% CI,
0.53-0.84], p<0.001). The combination achieved ORR of 69% compared to 53% for
monotherapy [difference=15% (95% CI, 6.0%-24.5%), p=0.001]. The median DoR for
the 144 responders receiving combination therapy was 12.9 months [95% CI,
9.4-19.5] compared to 10.6 months in the 113 responders receiving monotherapy
[95% CI, 9.1-13.8].
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[1]. 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.
Completion of COMBI-d is a post-marketing requirement for the FDA's accelerated
approval for the combination in the US.
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, Chile and Canada.
Tafinlar and Mekinist target two different serine/threonine kinases - BRAF and
MEK, respectively - in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC
and melanoma, among other cancers. When Mekinist is used with Tafinlar, 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 conducted in study centers
worldwide.
In 2015, Novartis, as successor in interest to GlaxoSmithKline, purchased the
worldwide exclusive rights to develop, manufacture, and commercialize trametinib
from Japan Tobacco Inc. (JT). JT retains co-promotion rights in Japan.
Tafinlar and Mekinist are registered trademarks of Novartis Pharma AG or its
affiliates. The safety and efficacy profile of the Tafinlar and Mekinist
combination has not yet been established outside the approved indication.
Tafinlar and Mekinist Combination Important Safety Information
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 they experience any new or worsening
symptoms of lung or breathing problems, including shortness of breath or cough.
Tafinlar alone or in combination with Mekinist 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.
Rash is a common side effect of Tafinlar alone, or when used in combination with
Mekinist. Tafinlar alone, or in combination with Mekinist, can also cause other
skin reactions. In some cases these rashes and other skin reactions 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.
Some people may develop high blood sugar or worsening diabetes during treatment
with Tafinlar, alone or in combination with Mekinist. For patients who are
diabetic, their healthcare provider should check their blood sugar levels
closely during treatment. Their diabetes medicine may need to be changed.
Patients should be advised to tell their healthcare provider if they have any of
the following symptoms of severe high blood sugar: increased thirst or urinating
more often than normal, or urinating an increased amount of urine.
Tafinlar may cause healthy red blood cells to break down too early in people
with G6PD deficiency. This may lead to a type of anemia called hemolytic anemia
where the body does not have enough healthy red blood cells. Patients should be
advised to tell their healthcare provider if they have any of the following
signs or symptoms of anemia or breakdown of red blood cells: yellow skin
(jaundice), weakness or dizziness, or shortness of breath.
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 and Mekinist combination include fever,
nausea, tiredness, rash, chills, diarrhea, headache, vomiting, hypertension,
joint pain, peripheral edema 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 and
Mekinist combination. For more information, patients should ask their doctor or
pharmacist.
Patients should take Tafinlar and Mekinist combination exactly as their health
care provider tells them. Patients should not change their dose or stop taking
Tafinlar and 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 dose of Tafinlar should be
taken approximately 12 hours apart. Patients should take Tafinlar and 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," "investigational," "being investigated," "post-marketing
requirement," "ongoing," or similar terms, or by express or implied discussions
regarding potential new indications or labeling for Tafinlar and Mekinist, or
regarding potential future revenues from Tafinlar and Mekinist. 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 will be submitted or approved for any
additional indications or labeling in any market, or at any particular time. Nor
can there be any guarantee that Tafinlar and Mekinist will be commercially
successful in the future. In particular, management's expectations regarding
Tafinlar and Mekinist 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
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 2014, the Group achieved net
sales of USD 58.0 billion, while R&D throughout the Group amounted to
approximately USD 9.9 billion (USD 9.6 billion excluding impairment and
amortization charges). Novartis Group companies employ approximately 120,000
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] Long, G. Overall survival in COMBI-d, a randomized, double-blinded, Phase
III study comparing the combination of dabrafenib and trametinib with dabrafenib
and placebo as first-line therapy in patients (pts) with unresectable or
metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Abstract #102.
2015 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL,
USA.
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"Combination of Novartis drugs Tafinlar® and Mekinist® shows significant survival benefit in patients with metastatic melanoma"
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