BASEL, Switzerland,
June 4, 2019 /PRNewswire/ -- Novartis
announced today results from the landmark COMBI-d and COMBI-v
clinical trials, concluding that first-line treatment with Tafinlar
(dabrafenib) and Mekinist (trametinib) offers both overall and
progression-free long-term survival benefits to patients with
unresectable or metastatic BRAF-mutation positive melanoma.
Researchers reported that 34% (95% CI: 30-38%) of all patients in
the pooled analysis who were treated with Tafinlar + Mekinist
survived at five years1. Study authors also reported on
prolongation in progression-free survival (PFS), with 19% (95% CI:
15-22%) of patients showing no sign of disease progression or death
at five years. Five-year overall survival and PFS were similar in
the pooled patient population1,4.
The results, from a pooled analysis of 563 patients from the
COMBI-d and COMBI-v trials, represented the largest collection of
data and longest follow-up among patients with advanced melanoma
with BRAF V600-mutated unresectable or metastatic melanoma who were
treated with Tafinlar + Mekinist. These data were presented at the
2019 ASCO Annual Meeting (Abstract #9507) and published
simultaneously in The New England Journal of
Medicine1,4.
"Our analysis demonstrates that first-line therapy with Tafinlar
+ Mekinist leads to five-year disease control in about one-fifth of
the patients and five-year survival in about one-third of those
treated," said Caroline Robert, MD,
Ph.D., Head of the Dermatology Unit at the Institut
Gustave Roussy in Paris. "While
metastatic melanoma has historically had a very poor prognosis for
patients, there are many reasons to be encouraged today. Our
analysis demonstrates a clinically meaningful and positive impact
on patient survival. These results show that targeted therapies may
provide long-term survival and offer durable outcomes."
Of patients who achieved a complete response with Tafinlar +
Mekinist, 19% (n=109) had five-year PFS and overall survival rates
of 49% and 71%, respectively, compared with 19% and 34% in the
overall population. Researchers also observed that the efficacy of
subsequent treatment was preserved in patients who progressed on
study treatment and subsequently received immune checkpoint
inhibitor therapy.
Adverse events (regardless of causality) were reported in 548 of
559 patients (98%) with no new safety signals. Adverse events (AEs)
led to permanent discontinuation of study treatment in 99 of 559
patients (18%); the most common events were pyrexia (4%), decreased
ejection fraction (4%) and increased alanine aminotransferase (1%).
No treatment-related deaths were reported in patients treated with
dabrafenib plus trametinib.
"The five-year COMBI-d/v analysis is truly gratifying, as it
shows us that many BRAF+ melanoma patients on Tafinlar + Mekinist
are living much longer than what may have been expected when
originally diagnosed," said John
Tsai, MD, Head of Global Drug Development and Chief Medical
Officer, Novartis. "Other Novartis-sponsored melanoma research at
ASCO this week illustrates our drive to do even more in melanoma.
Efficacy results from the study of the immunotherapy spartalizumab
were encouraging as the oncology community learns more about how
immunotherapies may be combined with established targeted therapies
to provide an even greater benefit to patients."
About COMBI-d and COMBI-v
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 422 patients from 121 investigative
sites.
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 (NCT01597908). The primary endpoint of this
study was OS1.
Efficacy Findings for Investigational Anti-PD-1 Antibody
Spartalizumab (PDR001) Used in Combination With Tafinlar + Mekinist
Also Reported
Also presented at ASCO were findings from the
COMBI-i study evaluating Tafinlar + Mekinist in combination with
spartalizumab in metastatic melanoma patients with known BRAF
mutation (Abstract #9531). Results from the 36 patients enrolled in
the safety run-in cohort (part 1) and biomarker cohort (part 2)
showed a confirmed objective response rate by investigator
assessment of 78% (n=28), with 42% (n=15) of patients exhibiting
complete responses. All patients experienced at least one AE, 28
had grade ≥ 3 AEs and six had AEs leading to discontinuation of all
three study drugs. The most common AEs (≥20%) included pyrexia,
cough, arthralgia, rash, chills and fatigue. One patient died of
cardiac arrest that was not considered related to study treatment.
The clinical trial is ongoing5.
About the COMBI-i Study
COMBI-i is a pivotal Phase
III, double-blinded global study (NCT02967692) comparing the
combination of Tafinlar + Mekinist to the same combination along
with the investigational anti-PD1 therapy spartalizumab as
first-line therapy in patients with unresectable (Stage IIIC) or
metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous
melanoma. The study is being conducted in three parts. In the
safety run-in (part 1), the primary endpoint was incidence of
dose-limiting toxicities, and in the biomarker cohort (part 2), the
primary endpoint was immune microenvironment and biomarker
modulation. The randomized portion of the study (part 3) is
ongoing, and the primary endpoint is investigator-assessed
progression-free survival5.
About Melanoma
There are about 280,000 new diagnoses
of melanoma (Stages 0-IV) worldwide each year6,
approximately half of which have BRAF mutations7.
Biomarker tests can determine whether a tumor has a BRAF
mutation8.
One way melanoma is staged is by how far it has metastasized. In
Stage III melanoma, tumors have spread to the regional lymph nodes,
presenting a higher risk of recurrence or metastases9.
Patients who receive surgical treatment for Stage III melanoma may
have a high risk of recurrence because melanoma cells can remain in
the body after surgery10,11. Patients should ask their
doctor if they are at risk for melanoma returning.
About Tafinlar + Mekinist
Tafinlar + 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 melanoma and NSCLC, among other cancers. When
Tafinlar is used with Mekinist, the combination has been shown to
slow tumor growth more than either drug alone.
Tafinlar + Mekinist have been investigated for the treatment of
a variety of cancers as part of an ongoing clinical trial program.
Tafinlar + Mekinist are approved in more than 60 countries, for
uses including:
- as monotherapy and in combination for the treatment of subjects
with unresectable or metastatic melanoma with a BRAFV600
mutation
- in combination for the adjuvant treatment of patients with
Stage III melanoma with a BRAFV600 mutation, following complete
resection
- in combination for the treatment of patients with advanced
NSCLC with a BRAFV600 mutation
- in combination for the treatment of patients with locally
advanced or metastatic ATC with a BRAFV600 mutation
Approved indications vary worldwide. Please refer to local
labeling for indication language in a particular country.
Tafinlar + Mekinist Combination Important Safety
Information
Tafinlar and Mekinist, in combination, may
cause serious side effects such as the risk of new cancers,
including both skin cancer and nonskin cancer. Patients should be
advised to contact their health care provider 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 that
can lead to death. Patients should be advised to call their health
care provider and get medical help right away if they have any
signs of bleeding, including headaches, dizziness, or feel weak,
cough up blood or blood clots, vomit blood or their vomit looks
like "coffee grounds," or red or black stools that look like
tar.
Mekinist, alone or in combination with Tafinlar, can cause
inflammation of the intestines or tears in the stomach or
intestines that can lead to death. Patients should report to their
health care provider immediately if they have any of the following
symptoms: bleeding, diarrhea (loose stools) or more bowel movements
than usual, stomach-area (abdomen) pain or tenderness, 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 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 and other skin reactions are common side effects of
Tafinlar in combination with Mekinist. In some cases, these rashes
and other skin reactions can be severe or serious, 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
glucose-6-phosphate dehydrogenase 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, blurry vision, or dizziness.
The most common side effects of Tafinlar, in combination with
Mekinist, include fever, rash, nausea, fatigue, headache, chills,
diarrhea, vomiting, high blood pressure (hypertension), joint
aches, muscle aches, swelling of the face, arms, or legs, and
cough.
Please see full Prescribing Information for Tafinlar and
Mekinist.
Disclaimer
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statements within the meaning of the United States Private
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References
- Paul D. Nathan, et al. Five-year
analysis of dabrafenib plus trametinib (D+T) in patients with BRAF
V600–mutant unresectable or metastatic melanoma confirms long-term
benefit. Abstract #9507. 2019 American Society of Clinical Oncology
Annual Meeting, May 31-June 4,
Chicago, IL.
- Melanoma Skin Cancer. American Cancer Society. Available
at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf.
Accessed May 31, 2016.
- A Snapshot of Melanoma. National Cancer Institute. Available
at: http://www.cancer.gov/research/progress/snapshots/melanoma.
Accessed May 31, 2016.
- Robert C, et al. N Engl J Med. 2019 June
4. doi: 10.1056/NEJMoa1904059. [Epub ahead of print].
- Georgina V. Long, et al. The
anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib
(D) and trametinib (T) in previously untreated patients (pts) with
advanced BRAF V600–mutant melanoma: updated efficacy and safety
from parts 1 and 2 of COMBI-i. Abstract #9531. 2019 American
Society of Clinical Oncology Annual Meeting, May 31-June 4, Chicago,
IL.
- Globocan. World Fact Sheet. Available at:
http://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf.
Accessed October 10, 2018.
- Schandendorf D, et al. Melanoma. Nature reviews Disease
Primers. 2015.
- Wilson MA, Molecular Testing in Melanoma. NCBI. 2012.
- American Cancer Society. Melanoma Skin Cancer Stages. Available
at:
https://www.cancer.org/cancer/melanoma-skin-cancer/detection-diagnosis-staging/melanoma-skin-cancer-stages.html.
Accessed October 10, 2018
- Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib
Plus Trametinib for Stage III BRAF V600E/K-Mutant Melanoma. New
England Journal of Medicine. 2017.
- Melanoma Research Alliance. Adjuvant Therapy. Available at
http://www.curemelanoma.org/about-melanoma/melanoma-treatment/adjuvant-therapy/.
Accessed October 10, 2018.
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