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About Tafinlar® (dabrafenib) and Mekinist™ (trametinib)
Combination Therapy and Metastatic Melanoma
What is Metastatic Melanoma?
Melanoma is the most serious type of skin cancer and develops when unrepaired DNA damage to
skin cells triggers genetic changes that cause them to form malignant tumors 1. If melanoma
metastasizes, or spreads to other parts of the body, it becomes difficult to treat and can be fatal1.
There are about 200,000 new cases of melanoma diagnosed worldwide each year 2. While the
average age of a newly diagnosed melanoma patient is 61 3, it is the most common cancer in
young adults, ages 25-29 4. In some parts of the world, especially Western countries, melanoma is
becoming more common every year2. Due to their relative lack of skin pigmentation, Caucasian
populations have a much higher risk of getting melanoma than dark-skinned populations.
However, excessive exposure to intense sunlight can damage any skin type 5.
Melanoma is the most common cancer killer of young women, more common than breast cancer
in ages 29 – 34 6. About one in two patients worldwide with metastatic melanoma is expected to
survive for a year after diagnosis of metastatic disease, with approximately 46,000 annual
melanoma-related deaths worldwide2.
What Role Do Genes Play in Melanoma?
Melanoma is a complex genetic disease, and multiple genetic alterations have been reported to
play a role in the disease’s progression 7. In metastatic melanoma, approximately half of all
patients have a mutation known as BRAF. Of those, more than 70 percent have a BRAF V600E
mutation and approximately 20 percent have a BRAF V600K mutation 8,9.
Genetic tests should be performed on patients with melanoma to determine whether their tumor
demonstrates a gene mutation. Results can play a key role in prognosis and determining which
treatment is the most appropriate therapy for the genetic makeup of the tumor 10. New targeted
therapies are changing the treatment landscape for patients with metastatic melanoma.
About Tafinlar (dabrafenib) and Mekinist (trametinib) Combination
Therapy in Metastatic Melanoma
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Tafinlar (dabrafenib) and Mekinist (trametinib) are the first oral targeted therapies
approved in the United States as a combination treatment in adult patients with
unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as
detected by an FDA-approved test 11,12. They are not currently approved for this
indication anywhere else in the world.
Tafinlar and Mekinist are also indicated in more than 35 countries worldwide as single
agents to treat patients with unresectable or metastatic melanoma.
Tafinlar, targeting BRAF, and Mekinist, targeting MEK, target two different tyrosine
kinases in the RAS/RAF/MEK/ERK pathway 13. Cancer cells that do not respond to BRAF
inhibitors use alternate pathways to grow and divide, which can be targeted by Mekinist.
When used with Tafinlar, the combination has been shown to slow tumor growth more
effectively compared with either drug alone.
Novartis Pharma AG
CH-4002 Basel Switzerland
©2015 Novartis
2/15
G-MTA-1108331
Clinical Evidence Supporting Tafinlar and Mekinist in Metastatic
Melanoma
A multicenter, open-label, randomized Phase II study of 162 patients with BRAF V600E or V600K
mutation-positive unresectable or metastatic melanoma demonstrated the following results11,12:
Pivotal Phase II Study Results
Efficacy outcome measure
based on investigator
assessment
Tafinlar (150mg) +
Mekinist (2mg)
Tafinlar (150mg)
Overall Response Rate
The percentage of patients who
achieve a partial response or
better after starting treatment.
76%
(95% CI, 62, 87)
54%
(95% CI, 40, 67)
Median Duration of Response
The median length of time tumor
reduction lasted before disease
progression.
10.5 months
(95% CI, 7, 15)
5.6 months
(95% CI, 5, 7)
Safety Profile of Tafinlar and Mekinist Combination Therapy
The most common adverse reactions (≥20%) for Tafinlar in combination with Mekinist are pyrexia,
chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough,
headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia11,12.
Tafinlar and Mekinist Important Safety Information
Please see full Prescribing Information for Tafinlar and Mekinist at
https://www.gsksource.com/gskprm/en/US/images/gsk_content/TAFMEK/FBP/home/index.html.
New Primary Malignancies (cutaneous and non-cutaneous)
When Tafinlar was used in combination with Mekinist at the recommended dose, the incidence of
basal cell carcinoma was increased. The incidence of basal cell carcinoma was 9% (5/55) in
patients receiving the combination compared to 2% (1/53) in patients receiving Tafinlar as a single
agent. Tafinlar results in an increased incidence of cutaneous squamous cell carcinoma (cuSCC),
keratoacanthoma and melanoma. Cutaneous squamous cell carcinoma, including
keratoacanthoma, occurred in 7% of patients receiving the combination and 19% of patients
receiving Tafinlar as a single agent.
Tumour Promotion in Wild-Type BRAF Melanoma
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and
increased cell proliferation in wild-type BRAF cells that are exposed to BRAF inhibitors.2
Haemorrhage
Treatment with the combination resulted in an increased incidence and severity of haemorrhagic
events: 16% (9/55) of patients treated with the combination compared with 2% (1/53) of patients
Novartis Pharma AG
CH-4002 Basel Switzerland
©2015 Novartis
2/15
G-MTA-1108331
treated with Tafinlar as a single agent. Intracranial haemorrhage was fatal in two (4%) patients
receiving the combination.
Venous Thromboembolic Events
Treatment with the combination resulted in an increased incidence of deep vein thrombosis (DVT)
and pulmonary embolism (PE): 7% (4/55) of patients treated with the combination compared with
none of the 53 patients treated with Tafinlar as a single agent. Pulmonary embolism was fatal in
one (2%) patient receiving the combination.
Cardiomyopathy
When Mekinist was used in combination with Tafinlar at the recommended dose, cardiomyopathy
(defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection
fraction [LVEF]) occurred in 9% (5/55) of patients treated with the combination and in none of
patients treated with Tafinlar as a single agent.
Ocular Toxicities
Retinal Vein Occlusion (RVO): across clinical trials of Mekinist the incidence of RVO was 0.2%
(4/1,749). RVO may lead to macular oedema, decreased visual function, neovascularisation, and
glaucoma.
Retinal Pigment Epithelial Detachment (RPED): in the randomised Phase II part of the Phase I/II
open-label study 2% (1/55) of patients receiving Mekinist in combination with Tafinlar developed
RPED.
Uveitis and Iritis: across clinical trials of the combination, uveitis occurred in 1% (2/202) of
patients.
Interstitial lung disease (ILD)
In clinical trials of Mekinist (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of
patients.
Serious Febrile Drug Reactions
Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills,
dehydration or renal failure, can occur when Mekinist is used in combination with Tafinlar. The
incidence and severity of pyrexia are increased when Mekinist is given with Tafinlar compared
with Tafinlar alone.
The incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with the
combination and 26% (14/53) in patients treated with Tafinlar as a single agent. Febrile reactions
of any severity, accompanied by hypotension, rigors or chills, occurred in 25% (14/55) of patients
treated with the combination compared with 2% (1/53) of patients treated with Tafinlar as a single
agent.
Serious Skin Toxicity
The incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform
rash, palmar-plantar erythrodysesthesia syndrome or erythema, was similar for patients receiving
the combination (65% [36/55]) compared with patients receiving Tafinlar as a single agent (68%
Novartis Pharma AG
CH-4002 Basel Switzerland
©2015 Novartis
2/15
G-MTA-1108331
[36/53]). Across all clinical trials of the combination (N = 202), severe skin toxicity requiring
hospitalisation occurred in 2.5% (5/202) of patients.
Hyperglycaemia
Hyperglycaemia can occur when Mekinist is used in combination with Tafinlar. The incidence of
Grade 3 hyperglycaemia based on laboratory values was 5% (3/55) in patients treated with the
combination compared with 2% (1/53) in patients treated with Tafinlar as a single agent.
Glucose-6-Phosphate Dehydrogenase Deficiency
Tafinlar, which contains a sulfonamide moiety, confers a potential risk of haemolytic anaemia in
patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Embryofoetal Toxicity
Tafinlar and Mekinist both can cause foetal harm when administered to a pregnant woman.
Tafinlar can also render hormonal contraceptives ineffective.
Drug Interactions
Effects of Other Drugs on Dabrafenib
Drugs that Inhibit or Induce Drug-Metabolising Enzymes: dabrafenib is primarily metabolised by
CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or
decrease, respectively, concentrations of dabrafenib.
Drugs that Affect Gastric pH: Drugs that alter the pH of the upper GI tract (e.g., proton pump
inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its
bioavailability.
Effects of Dabrafenib on Other Drugs
Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased systemic exposures of
midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate) and R-warfarin (a
CYP3A4/CYP1A2 substrate). Coadministration of dabrafenib with other substrates of these
enzymes, including dexamethasone, or hormonal contraceptives, can result in decreased
concentrations and loss of efficacy.
Combination of trametinib with dabrafenib
Co-administration of trametinib 2mg once daily and dabrafenib 150mg twice daily resulted in no
clinically relevant pharmacokinetic drug interactions.
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4.
Melanoma Skin Cancer Foundation Web Site. http://www.skincancer.org/skin-cancer-information/melanoma.
Last Updated 2014. Accessed December 11, 2014.
Melanoma Facts and Figures. Aim at Melanoma Foundation Web Site. http://www.aimatmelanoma.org/en/aimfor-answers/about-melanoma-and-other-lesions/melanoma-statistics/facts-and-figures.html. Accessed
December 11, 2014.
What are the key statistics about melanoma skin cancer? American Cancer Society Web Site.
http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics. Last
revised on 9/5/2014. Accessed on December 11, 2014.
Skin Cancer Facts. Skin Cancer Foundation Web Site. http://www.skincacer.org/skin-cancer-information/skincancer-facts. Last Updated in 2014. Accessed on December 15, 2014.
Novartis Pharma AG
CH-4002 Basel Switzerland
©2015 Novartis
2/15
G-MTA-1108331
5.
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Skin Cancers. World Health Organization Web Site. http://www.who.int/uv/faq/skincancer/en/index2.html. Last
Updated in 2014. Accessed on December 15, 2014.
Melanoma International Foundation. Melanoma Facts. Available at:
http://melanomainternational.org/melanoma-facts/#.VInbjTHF8uc. Accessed December 11, 2014.
BRAF in metastatic melanoma. Biooncology Web Site. http://www.biooncology.com/researcheducation/braf/metastatic-melanoma. Accessed on December 11, 2014.
Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity in V600R metastatic melanoma. Eur J Cancer;
2013; 49(5) 1079-1079. Doi: 10.1016/j.ejca.2012.
Fedorenko IV, Gibney GT, Sondak VK, Smalley KSM. Beyond BRAF: where next for melanoma therapy?
British Journal of Cancer. 2014; 1-10. doi: 10.1038/bjc.2014.476
The Genetics of Skin Cancer. National Cancer Institute. Web Site.
http://www.cancer.gov/cancertopics/pdq/genetics/skin/HealthProfessional/page4#_393_toc. Last updated
December 18, 2014. Accessed on December 22, 2014.
Mekinist™ Prescribing Information. GlaxoSmithKline. January 2014.
Tafinlar® Prescribing Information. GlaxoSmithKline. January 2014.
Flaherty, KT, Infante, JR, C, Daud, A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF
V600 Mutations. New England Journal of Medicine. 2012.
Novartis Pharma AG
CH-4002 Basel Switzerland
©2015 Novartis
2/15
G-MTA-1108331