Novartis landmark study of Tafinlar® + Mekinist® demonstrates durable survival benefit at five years in patients with BRAF mutation-positive metastatic melanoma
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Novartis International AG /
Novartis landmark study of Tafinlar® + Mekinist® demonstrates durable survival
benefit at five years in patients with BRAF mutation-positive metastatic
melanoma
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The issuer is solely responsible for the content of this announcement.
* Study is longest follow-up to date of a BRAF and MEK inhibitor combination
therapy in patients with BRAF V600-mutant metastatic melanoma[1]
* Study shows stable overall survival and progression-free survival lasting
more than five years with consistent tolerability[1]
* Initial data from separate Phase II trial of BRAF and MEK inhibitors showed
positive results in BRAF V600-mutant melanoma patients with metastatic brain
metastases[2]
Basel, June 4, 2017 - Novartis today announced results from a Phase II study
showing a durable survival benefit for some patients with BRAF V600 mutation-
positive metastatic melanoma (MM) when treated with the combination of
Tafinlar(®) (dabrafenib) + Mekinist(®) (trametinib)[1]. The findings from the
landmark five-year analysis of the trial, BRF113220, represent the longest
follow-up to date of a BRAF and MEK inhibitor combination therapy in this
patient population, and were presented today at the 53(rd) Annual Meeting of the
American Society of Clinical Oncology (ASCO) in Chicago (Abstract #9505).
A total of 162 patients received either Tafinlar monotherapy (150 mg BID) (n =
54) or the Tafinlar + Mekinist combination (150 mg BID/2 mg QD) (n = 54). After
five years, 20 patients (37%) remain in the study, including seven (13%) in the
Tafinlar monotherapy arm and 13 (24%) in the combination therapy arm,
demonstrating that overall survival (OS) with combination therapy is superior to
monotherapy[1]. The four-and five-year OS rates with monotherapy were 23% and
21%, respectively. The four- and five-year OS rates with combination therapy
were 30% and 28%, respectively, reflecting a stabilization of OS in patients
enrolled in the study[1]. Progression-free survival (PFS) in the monotherapy arm
was consistently 3% whereas PFS at both four and five years was 13%, also
demonstrating stabilization[1]. Forty-five of 54 patients (83%) in the Tafinlar
monotherapy arm included in this updated analysis had crossed over to Tafinlar +
Mekinist combination (150 mg BID/2 mg QD); the survival outcomes in these
crossover patients continued to be followed under the Tafinlar arm.
"These recent results from the longest follow-up of a BRAF and MEK inhibitor
targeted study show that a significant cohort of patients with metastatic
melanoma positive for the BRAF V600 mutation can achieve long-term survival with
Tafinlar + Mekinist combination therapy," said lead investigator Jeff Weber, MD,
PhD, Deputy Director, Laura and Isaac Perlmutter Cancer Center, Co-Director,
Melanoma Program & Head of Experimental Therapeutics NYU Langone Medical Center.
"This combination of targeted therapy should be considered by physicians when
making treatment decisions."
Adverse events were consistent with other Tafinlar + Mekinist studies, and
additional follow-up revealed no new safety signals[1].
"These data demonstrate the long-term benefit of Tafinlar in combination with
Mekinist for certain patients living with metastatic melanoma," said Vas
Narasimhan, Global Head Drug Development and Chief Medical Officer, Novartis.
"We are gratified to see these data showing that patients can benefit long-term
from Tafinlar + Mekinist, and we look forward to evaluating additional Phase III
long-term survival data."
Additionally, Novartis presented results from a Phase II study showing a
positive, statistically significant intracranial response for patients with BRAF
V600 mutation-positive metastatic melanoma (MM) when treated with the
combination of Tafinlar + Mekinist (Abstract #9506)[2]. The findings from the
30-month trial, COMBI-MB, represent the first report of a Phase II trial
evaluating a BRAF and MEK inhibitor combination therapy in patients with BRAF
V600-mutant melanoma brain metastases (MBM).
The COMBI-MB study evaluated Tafinlar + Mekinist in 125 patients enrolled in
four cohorts. In Cohort A (patients who were BRAF V600E mutation-positive, had
asymptomatic MBM and no local prior treatment), investigator-assessed
intracranial response rate (IRR) was 58% (95% CI: 46, 69)[2]. Extracranial
response rate (ERR) was 55% (95% CI: 43, 67) and overall response rate (ORR) was
58% (95% CI: 46, 69)[2]. Median PFS was 5.6 months (95% CI: 5.3, 7.4)[1]. Six-
month OS was 79%; with 31 patients (41%) still in follow-up. Preliminary median
OS was 10.8 months (95% CI: 8.7, 19.6)[2].
Adverse events across cohorts (any, 98%; grade 3/4, 48%) were consistent with
prior Tafinlar + Mekinist studies; 10% of patients (8% in cohort A) discontinued
due to adverse events[2].
Results of the COMBI-MB study were simultaneously published in the June issue of
The Lancet Oncology, available online on Sunday, June 4, at 10:00 AM[8].
Additional poster and oral presentations related to the investigational use of
Tafinlar and Mekinist were also presented at the meeting, including an updated
five year landmark analysis of Phase II (BREAK-2) and Phase III (BREAK-3)
studies evaluating Tafinlar monotherapy in patients with BRAF V600-mutant
melanoma, and studies in BRAF V600E-mutated advanced thyroid cancer (ATC) and
non-small cell lung cancer (NSCLC).
About BRF113220
The BRF113220 study is an open-label, Phase II trial. Patients with BRAF V600-
mutant MM were randomly assigned to receive Tafinlar monotherapy (150 mg BID),
Tafinlar + Mekinist (150 mg BID/1 mg QD), or Tafinlar + Mekinist (150 mg BID/2
mg QD). Patients who progressed on Tafinlar alone could cross over to the
Tafinlar + Mekinist 150/2 arm. Patient disposition, patient demographics, and
four- and five-year efficacy and safety were analyzed for the Tafinlar
monotherapy and Tafinlar + Mekinist (approved 150/2 dose) arms.
About COMBI-MB
The COMBI-MB study is an open-label, Phase II trial and included four patient
cohorts based on mutation status, MBM symptoms and history of treatment: (A)
BRAF V600E, asymptomatic MBM, and no prior local therapy (76 patients); (B) BRAF
V600E, asymptomatic MBM, and prior local therapy (16 patients); (C) BRAF
V600D/K/R, asymptomatic MBM, with or without prior local therapy (16 patients);
and (D) BRAF V600D/E/K/R, symptomatic MBM, with or without prior local therapy
(17 patients).
The primary endpoint was intracranial response (IR) in cohort A patients.
Secondary endpoints included IR in cohorts B, C, and D; intracranial disease
control; extracranial response (ER); overall response (OR); duration of IR, ER,
and OR; PFS; OS; and safety.
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],[4]. There are about 200,000 new cases of melanoma diagnosed
worldwide each year, approximately half of which have BRAF mutations, a key
target in the treatment of metastatic melanoma[3],[5],[6]. Gene tests can
determine whether a tumor has a BRAF mutation[3],[7].
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 50 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 and MEKINIST, in combination, may cause serious side effects such as
the risk of new cancers, including both skin cancer and non-skin cancer.
Patients should be advised to contact their doctor immediately for a new wart,
skin sore, or bump that bleeds or does not heal, or a change in the size or
color of a mole.
When TAFINLAR is used in combination with MEKINIST, it can cause serious
bleeding problems, especially in the brain or stomach, and can lead to death.
Patients should be advised to call their health care 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," or have
red or black stools that look like tar.
MEKINIST, alone or in combination with TAFINLAR, can cause inflammation of the
colon and bleeding in the stomach or intestines that can lead to death. Patients
should report to their health care provider immediately if they have diarrhea,
stomach or abdominal pain, fever, or nausea.
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.
The combination of TAFINLAR and 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 health care 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, can cause severe eye problems that can
lead to blindness. Patients should be advised to call their health care provider
right away if they get: 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, can cause lung or breathing problems.
Patients should be advised to tell their health care provider if they have new
or worsening symptoms of lung or breathing problems, including shortness of
breath or cough.
Fever is common during treatment with TAFINLAR in combination with MEKINIST, but
may also be more serious. 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 health care
provider right away if they get a fever.
Rash is a common side effect of TAFINLAR in combination with MEKINIST. TAFINLAR,
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 health care 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, or
skin redness.
Some people may develop high blood sugar or worsening diabetes during treatment
with TAFINLAR in combination with MEKINIST. For patients who are diabetic, their
health care 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 health care provider if they have increased thirst,
urinate more often than normal, or produce an increased amount of urine.
TAFINLAR, in combination with MEKINIST, 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 health care provider if
they have yellow skin (jaundice), weakness or dizziness, or shortness of breath.
TAFINLAR, in combination with MEKINIST, can cause new or worsening high blood
pressure (hypertension). A patient's blood pressure should be checked during
treatment. Patients should be advised to tell their health care provider if they
develop high blood pressure, their blood pressure worsens, or if they have
severe headache, lightheadedness, or dizziness.
The most common side effects of TAFINLAR, in combination with MEKINIST, include
nausea, chills, diarrhea, vomiting, high blood pressure (hypertension), swelling
of the face, arms, or legs, headache, joint aches, and cough.
Please see full prescribing information for TAFINLAR and MEKINIST at
https://www.hcp.novartis.com/products/tafinlar-mekinist/advanced-metastatic-
melanoma.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by words such as "should," "can," "look forward," "later this year,"
"investigational," "will," "being investigated," "ongoing," "yet," or similar
terms, or by express or implied discussions regarding potential new indications
or labeling for Tafinlar + Mekinist, or regarding potential future revenues from
Tafinlar and Mekinist, both as single agents and in combination with the other.
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 + 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, either as
single agents or in combination with the other will be commercially successful
in the future. In particular, management's expectations regarding Tafinlar and
Mekinist, both as single agents and in combination with the other could be
affected by, among other things, the uncertainties inherent in research and
development, including clinical trial results and additional analysis of
existing clinical data; 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 and reimbursement
pressures; 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,
cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has
leading positions globally in each of these areas. In 2016, the Group achieved
net sales of USD 48.5 billion, while R&D throughout the Group amounted to
approximately USD 9.0 billion. Novartis Group companies employ approximately
118,000 full-time-equivalent associates. Novartis products are sold in
approximately 155 countries around the world. For more information, please visit
http://www.novartis.com.
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References
[1] Long GV, Eroglu Z, Infante J, et al. 5-year overall survival (OS) update
from a phase 2, open-label trial of dabrafenib (D) and trametinib (T) in
patients (pts) with BRAF V600-mutant unresectable or metastatic melanoma (MM).
Abstract #9505. 2017 American Society of Clinical Oncology (ASCO) Annual
Meeting, June 2-6, 2017, Chicago, IL, USA.
[2] Davies MA, Robert C, Long GV, et al. COMBI-MB: a phase 2 study of
combination dabrafenib and trametinib in patients with BRAF V600-mutant melanoma
brain metastases. Abstract #9506. 2017 American Society of Clinical Oncology
(ASCO) Annual Meeting, June 2-6, 2017, Chicago, IL, USA.
[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.
[8] [Results of the COMBI-MB study.] The Lancet Oncology. June 2017. Available
at: http://www.thelancet.com/journals/lanonc/article/PIIS1470-
2045(17)30429-1/fulltext?elsca1=tlpr.
# # #
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Datum: 04.06.2017 - 15:00 Uhr
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