Welcome!

News Feed Item

GSK gains accelerated FDA approval for combination use of Mekinist® (trametinib) and Tafinlar® (dabrafenib)

- First approved combination of oral targeted therapies for unresectable or metastatic melanoma with BRAF V600E or V600K mutations[1]

LONDON, Jan. 8, 2014 /PRNewswire/ -- GlaxoSmithKline plc [LSE/NYSE: GSK ] announced today that the U.S. Food and Drug Administration (FDA) has approved Mekinist® (trametinib) for use in combination with Tafinlar® (dabrafenib) for the treatment of patients with unresectable melanoma (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) with BRAF V600E or V600K mutations. These mutations must be detected by an FDA-approved test.1 Tafinlar is not indicated for treatment of patients with wild-type BRAF melanoma.2

The approval of the combination is based on the demonstration of response rate and median duration of response in a Phase I/II study. Improvement in disease-related symptoms or overall survival has not been demonstrated for Mekinist in combination with Tafinlar.1 The combination was approved through the FDA's Accelerated Approval programme and reviewed under a Priority Review designation.3 This accelerated approval is contingent on the results of the ongoing Phase III trial (referred to as MEK115306 or Combi-D), which is designed to evaluate the clinical benefit of the combination in this patient population.

"This approval marks another key moment in what continues to be a rapid evolution of the treatment landscape for metastatic melanoma patients. Combining agents that target different mechanisms regulating the growth of cancer cells is one of the promising areas in cancer research," said Dr. Paolo Paoletti, President of Oncology, GSK. "We are proud that the first approved combination of targeted therapies in metastatic melanoma is Mekinist and Tafinlar, and our hope is that it will become part of the new standard of care for appropriate patients with BRAF V600E or V600K mutation-positive metastatic melanoma." 

The results from the randomised Phase II part of the Phase I/II open-label study, which evaluated the combination of trametinib and dabrafenib at the recommended dose (150/2mg) (N=54) and single-agent dabrafenib (150mg) (N=54)1, were as follows:

  • The investigator-assessed overall response rate (ORR) (main efficacy endpoint) was 76% (95% CI, 62, 87) for patients treated with the combination, and 54% (95% CI, 40, 67) for patients treated with single-agent dabrafenib. The median duration of response was 10.5 months (95% CI, 7, 15) for patients treated with the combination, and 5.6 months (95% CI, 5, 7) for patients treated with single-agent dabrafenib.
  • Data analyses of the blinded independent radiologic review committee (IRRC) supported the investigator results. The IRRC-assessed ORR was 57% (95% CI, 43, 71) for patients treated with the combination, and 46% (95% CI, 33, 60) for patients receiving single-agent dabrafenib. The median duration of response as assessed by the IRRC was 7.6 months (95% CI, 7, NR) for patients treated with the combination, and 7.6 months (95% CI, 6, NR) for patients treated with single-agent dabrafenib.

Trametinib in combination with dabrafenib can cause serious side effects, some of which can be life threatening, including: new primary cutaneous malignancies (new skin cancers); tumour promotion in wild-type BRAF melanoma; haemorrhagic events (symptomatic bleeding in a critical area or organ); venous thromboembolic events (blood clots); cardiomyopathy (heart problems, including heart failure);  ocular (eye-related) toxicities; interstitial lung disease (ILD); serious febrile drug reactions (severe fevers); serious skin toxicity (rash); hyperglycaemia (blood sugar problems); haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; and embryofoetal toxicity (potential harm to the unborn baby in pregnant women).1,2

The most frequently occurring adverse reactions at the recommended dose of trametinib 2mg once daily in combination with dabrafenib 150mg twice daily (all grades in more than 20% of patients) in the randomised part of Phase I/II study included: pyrexia (fever) (71%), chills (58%), fatigue (53%), rash (45%), nausea (44%), vomiting (40%), diarrhoea (36%), abdominal pain (33%), oedema peripheral (swelling of tissues, usually in the lower limbs) (31%), cough (29%), headache (29%), arthralgia (27%), night sweats (24%), decreased appetite (22%), constipation (22%) and myalgia (muscular pain) (22%). The most common (>2%) Grade 3 or 4 adverse events observed in the combination group in this study were: renal failure (7%), pyrexia (5%), back pain (5%), haemorrhage (5%), fatigue (4%), chills (2%), nausea (2%), vomiting (2%), diarrhoea (2%), abdominal pain (2%), myalgia (2%) and urinary tract infection (2%).

Details Behind the Trametinib and Dabrafenib Combination Clinical Data
The safety of trametinib (2mg once daily) in combination with dabrafenib (150mg twice daily) was evaluated in 202 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma enrolled in a Phase I/II study. FDA approval of the combination therapy was based on the demonstration of response rate and median duration of response in a multicentre, open-label, randomised, active-controlled, dose-ranging part of the Phase I/II study enrolling patients with histologically-confirmed Stage IIIC or IV melanoma determined to be BRAF V600E or V600K mutation-positive. No more than one prior chemotherapy regimen and/or interleukin-2 were permitted. Patients with prior exposure to BRAF inhibitors or MEK inhibitors were ineligible. The main efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, IRRC-assessed ORR, and IRRC-assessed duration of response.1

Trametinib was in-licensed by GSK in 2006. GSK holds the worldwide exclusive rights to develop, manufacture and commercialise Mekinist, while Japan Tobacco retains co-promotion rights in Japan.

The PDUFA date for the update to the Tafinlar label is 9 January 2014.  

Important Safety Information for Mekinist in combination with Tafinlar

WARNINGS AND PRECAUTIONS: Mekinist and Tafinlar combination

New Primary Malignancies (cutaneous and non-cutaneous)1
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 Melanoma2
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

Haemorrhage1
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 treated with Tafinlar as a single agent. Intracranial haemorrhage was fatal in two (4%) patients receiving the combination.

Venous Thromboembolic Events1
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.

Cardiomyopathy1
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 Toxicities1
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)1
In clinical trials of Mekinist (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients.1

Serious Febrile Drug Reactions1
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 Toxicity1
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% [36/53]). Across all clinical trials of the combination (N = 202), severe skin toxicity requiring hospitalisation occurred in 2.5% (5/202) of patients.

Hyperglycaemia1
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 Deficiency2
Tafinlar, which contains a sulfonamide moiety, confers a potential risk of haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Embryofoetal Toxicity1,2
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 Dabrafenib2
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 Drugs2
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 dabrafenib1
Co-administration of trametinib 2mg once daily and dabrafenib 150mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions

Please see full Prescribing Information and Patient Information Leaflet for Mekinist:

The revised full U.S. Prescribing Information, including Patient Information Leaflet for Mekinist will be available soon at http://us.gsk.com/products/assets/us_mekinist.pdf. Prior to the revised label being posted online, a copy of the label may be requested from one of the GSK Media or Investor Relations contacts listed in the "GSK enquiries" section at the end of this document.

Please see full Prescribing Information and Medication Guide for Tafinlar:
http://us.gsk.com/products/assets/us_tafinlar.pdf

U.S. journalists, please click here for the U.S. electronic press kit: http://us.gsk.com/html/media-news/tafmekpress-kit.html

About GSK Patient Assistance Programmes GSK has a number of patient assistance programmes for eligible patients in the United States who need help affording their medicines and vaccines. Through our programmes, in 2012, more than 250,000 patients received GSK medicines and vaccines free of charge. Additionally, in 2012 we provided approximately 2.3 million prescriptions through our assistance programmes. GSK is committed to helping eligible patients who need Tafinlar and Mekinist receive therapy. Patients who qualify for the programmes may benefit from GSK's Commitment to Access programme for oncology and specialty medicines which offers services and programmes including co-pay assistance in addition to traditional patient assistance support.  For more information, patients can call 1-8ONCOLOGY1 (1-866-265-6491).

GSK – one of the world's leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.  For further information please visit www.gsk.com.

Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK' s operations are described under Item 3.D 'Risk factors' in the company's Annual Report on Form 20-F for 2012.

References
________________

1 Glaxosmithkline. Mekinist Prescribing Information 2014.
2 GlaxoSmithKline. Tafinlar Prescribing Information 2013.
3 U.S. Food and Drug Administration. Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. Accessed December 10, 2013. Available at: http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm

 

SOURCE GlaxoSmithKline

More Stories By PR Newswire

Copyright © 2007 PR Newswire. All rights reserved. Republication or redistribution of PRNewswire content is expressly prohibited without the prior written consent of PRNewswire. PRNewswire shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon.

Latest Stories
Predictive analytics tools monitor, report, and troubleshoot in order to make proactive decisions about the health, performance, and utilization of storage. Most enterprises combine cloud and on-premise storage, resulting in blended environments of physical, virtual, cloud, and other platforms, which justifies more sophisticated storage analytics. In his session at 18th Cloud Expo, Peter McCallum, Vice President of Datacenter Solutions at FalconStor, discussed using predictive analytics to mon...
The Internet of Things will challenge the status quo of how IT and development organizations operate. Or will it? Certainly the fog layer of IoT requires special insights about data ontology, security and transactional integrity. But the developmental challenges are the same: People, Process and Platform and how we integrate our thinking to solve complicated problems. In his session at 19th Cloud Expo, Craig Sproule, CEO of Metavine, demonstrated how to move beyond today's coding paradigm and sh...
Today we can collect lots and lots of performance data. We build beautiful dashboards and even have fancy query languages to access and transform the data. Still performance data is a secret language only a couple of people understand. The more business becomes digital the more stakeholders are interested in this data including how it relates to business. Some of these people have never used a monitoring tool before. They have a question on their mind like “How is my application doing” but no id...
@GonzalezCarmen has been ranked the Number One Influencer and @ThingsExpo has been named the Number One Brand in the “M2M 2016: Top 100 Influencers and Brands” by Onalytica. Onalytica analyzed tweets over the last 6 months mentioning the keywords M2M OR “Machine to Machine.” They then identified the top 100 most influential brands and individuals leading the discussion on Twitter.
DevOps is being widely accepted (if not fully adopted) as essential in enterprise IT. But as Enterprise DevOps gains maturity, expands scope, and increases velocity, the need for data-driven decisions across teams becomes more acute. DevOps teams in any modern business must wrangle the ‘digital exhaust’ from the delivery toolchain, "pervasive" and "cognitive" computing, APIs and services, mobile devices and applications, the Internet of Things, and now even blockchain. In this power panel at @...
Get deep visibility into the performance of your databases and expert advice for performance optimization and tuning. You can't get application performance without database performance. Give everyone on the team a comprehensive view of how every aspect of the system affects performance across SQL database operations, host server and OS, virtualization resources and storage I/O. Quickly find bottlenecks and troubleshoot complex problems.
IoT is rapidly changing the way enterprises are using data to improve business decision-making. In order to derive business value, organizations must unlock insights from the data gathered and then act on these. In their session at @ThingsExpo, Eric Hoffman, Vice President at EastBanc Technologies, and Peter Shashkin, Head of Development Department at EastBanc Technologies, discussed how one organization leveraged IoT, cloud technology and data analysis to improve customer experiences and effici...
In his session at 19th Cloud Expo, Claude Remillard, Principal Program Manager in Developer Division at Microsoft, contrasted how his team used config as code and immutable patterns for continuous delivery of microservices and apps to the cloud. He showed how the immutable patterns helps developers do away with most of the complexity of config as code-enabling scenarios such as rollback, zero downtime upgrades with far greater simplicity. He also demoed building immutable pipelines in the cloud ...
@DevOpsSummit taking place June 6-8, 2017 at Javits Center, New York City, is co-located with the 20th International Cloud Expo and will feature technical sessions from a rock star conference faculty and the leading industry players in the world. @DevOpsSummit at Cloud Expo New York Call for Papers is now open.
In IT, we sometimes coin terms for things before we know exactly what they are and how they’ll be used. The resulting terms may capture a common set of aspirations and goals – as “cloud” did broadly for on-demand, self-service, and flexible computing. But such a term can also lump together diverse and even competing practices, technologies, and priorities to the point where important distinctions are glossed over and lost.
As data explodes in quantity, importance and from new sources, the need for managing and protecting data residing across physical, virtual, and cloud environments grow with it. Managing data includes protecting it, indexing and classifying it for true, long-term management, compliance and E-Discovery. Commvault can ensure this with a single pane of glass solution – whether in a private cloud, a Service Provider delivered public cloud or a hybrid cloud environment – across the heterogeneous enter...
All clouds are not equal. To succeed in a DevOps context, organizations should plan to develop/deploy apps across a choice of on-premise and public clouds simultaneously depending on the business needs. This is where the concept of the Lean Cloud comes in - resting on the idea that you often need to relocate your app modules over their life cycles for both innovation and operational efficiency in the cloud. In his session at @DevOpsSummit at19th Cloud Expo, Valentin (Val) Bercovici, CTO of Soli...
Data is the fuel that drives the machine learning algorithmic engines and ultimately provides the business value. In his session at Cloud Expo, Ed Featherston, a director and senior enterprise architect at Collaborative Consulting, discussed the key considerations around quality, volume, timeliness, and pedigree that must be dealt with in order to properly fuel that engine.
Regulatory requirements exist to promote the controlled sharing of information, while protecting the privacy and/or security of the information. Regulations for each type of information have their own set of rules, policies, and guidelines. Cloud Service Providers (CSP) are faced with increasing demand for services at decreasing prices. Demonstrating and maintaining compliance with regulations is a nontrivial task and doing so against numerous sets of regulatory requirements can be daunting task...
Successful digital transformation requires new organizational competencies and capabilities. Research tells us that the biggest impediment to successful transformation is human; consequently, the biggest enabler is a properly skilled and empowered workforce. In the digital age, new individual and collective competencies are required. In his session at 19th Cloud Expo, Bob Newhouse, CEO and founder of Agilitiv, drew together recent research and lessons learned from emerging and established compa...