Issued: London, UK
Results published today in the New England Journal of Medicine show that treatment with the combination of trametinib (Mekinist™) and dabrafenib (Tafinlar™) significantly improved overall survival (OS) compared to vemurafenib monotherapy in previously untreated patients with BRAF V600E/K mutation-positive metastatic melanoma, without increased overall toxicity.
The COMBI-v study demonstrated a 31 per cent decrease in the risk of death for patients treated with the trametinib and dabrafenib combination compared to vemurafenib (Hazard Ratio [HR] 0.69; 95% Confidence Interval [CI] 0.53, 0.89; two-sided P=0.005). Median OS for the vemurafenib arm was 17.2 months; median OS for the combination arm had not been reached. At 12 months, the rate of OS was 72 per cent for the combination arm and 65 per cent for the vemurafenib arm.
Treatment with the combination increased median progression-free survival to 11.4 months compared to 7.3 months for the vemurafenib arm. Overall, treatment with the combination resulted in a 44 per cent reduction in risk of disease progression or death (HR, 0.56; 95% CI 0.46, 0.69; two-sided P-value <0.001) compared to vemurafenib.
The objective response rate was 64 per cent (95% CI 59.1%, 69.4%) for the combination and 51 per cent (95% CI 46.1%, 56.8%) for vemurafenib (P<0.001); the median duration of response was 13.8 months (95% CI 11.0, not reached) vs. 7.5 months (95% CI 7.3, 9.3), respectively. Additionally, 13 per cent of patients treated with the combination achieved a complete response, compared to 8 per cent of patients in the vemurafenib arm.
Dr. Rafael Amado, Head of Oncology R&D at GSK, said: “COMBI-v is the first phase III study that demonstrated a statistically significant improvement in overall survival for a combination of targeted MEK and BRAF therapies compared to a single agent in patients with BRAF V600-mutant melanoma. The data published today reinforce our confidence in the efficacy of this combination treatment. We are thankful to the patients, caregivers and investigators for their participation in this study.”
Overall the frequency of adverse events (AEs) (98% for the combination and 99% for vemurafenib), severe (grade 3 or 4) adverse events (52% for the combination vs. 63% for vemurafenib group), study drug discontinuations (13% for the combination vs. 12% for vemurafenib) and AEs leading to dose reduction (33% for the combination and 39% for vemurafenib) were comparable in both COMBI-v study arms. The most frequent AEs in the trametinib and dabrafenib combination arm were pyrexia (53%), nausea (35%), diarrhoea (32%), chills (31%), fatigue (29%), headache (29%) and vomiting (29%). Pyrexia was more frequent in the combination arm compared with the vemurafenib arm (53% vs. 21%, respectively).
In the vemurafenib arm, the most frequent AEs were arthralgia (51%), rash (43%), alopecia (39%), nausea (36%), diarrhoea (38%) and fatigue (33%). Skin AEs were more frequent in the vemurafenib arm compared with the trametinib and dabrafenib combination arm, in particular rash (43% vs. 22%), photosensitivity reaction (22% vs. 4%), hand-foot syndrome (25% vs. 4%), skin papillomas (23% vs. 2%), skin squamous cell carcinomas and keratoacanthomas (18% vs. <1%) and hyperkeratosis (25% vs. 4%).
This phase III, randomised (1:1), open-label study compared the combination of dabrafenib and trametinib to vemurafenib in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. COMBI-v enrolled 704 patients from investigative sites in the USA, Europe, Canada, Russia, Ukraine, Israel, Argentina, Brazil, Korea, New Zealand, Taiwan and Australia.
The primary objective of the study was to evaluate dabrafenib and trametinib combination therapy vs. vemurafenib with respect to OS. Secondary objectives evaluated and compared dabrafenib and trametinib combination therapy versus vemurafenib with respect to progression-free survival, overall response rate and duration of response. The safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma and other proliferative skin diseases, was also evaluated.
These interim analysis for the trametinib and dabrafenib combination—performed after 77 per cent of the total number of expected events—crossed the pre-specified interim-stopping boundary (P<0.0214). As a result, in July 2014, an independent data monitoring committee recommended that the study be stopped early, therefore this data represents the final analysis. At that time, eligible study patients randomised to the vemurafenib arm were allowed to cross over to receive treatment with the trametinib and dabrafenib combination.
About cutaneous melanoma
Cutaneous melanoma is the most aggressive form of all skin cancers. Worldwide, it is expected that over 132,000 people will be diagnosed with melanoma each year and more than 37,000 people are expected to die of this tumour disease annually. In the U.S. and most countries of the Western World including Australia, the incidence of melanoma continues to rise faster than any other type of cancer in men and the annual increase in the incidence of melanoma in women is second only to lung cancer.1,2
About trametinib (Mekinist) and dabrafenib (Tafinlar)
Combination use of trametinib and dabrafenib in patients with unresectable or metastatic melanoma who have BRAF V600E or K mutation is approved only in the U.S. and Australia.
Trametinib was in-licensed by GSK in 2006 from Japan Tobacco Inc. (JTI). GSK holds the worldwide exclusive rights to develop, manufacture, and commercialise trametinib, while JTI retains co-promotion rights in Japan.
Tafinlar and Mekinist are registered trademarks of the GSK group of companies.
Important Safety Information for Mekinist and Tafinlar combination
The following is a summary of Important Safety Information from the U.S. Prescribing Information related to use in patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.
Warnings and precautions: Mekinist and Tafinlar combination
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.
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 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.
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.
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% [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 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.
Tafinlar and Mekinist both can cause foetal harm when administered to a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.
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 2 mg once daily and dabrafenib 150 mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions
For U.S. Prescribing Information and Patient Information Leaflet for Mekinist® (trametinib):
For U.S. Prescribing Information and Medication Guide for Tafinlar® (dabrafenib):
For detailed Prescribing Information for Mekinist® (trametinib) in Australia: http://www.gsk.com.au/resources.ashx/prescriptionmedicinesproductschilddataproinfo/1990/FileName/A5A6DF2E45A98313AE02F68DA2B2203B/Trametinib_Tablet_PI_001_Approved.pdf
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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. Such factors include, but are not limited to, those described under Item 3.D ‘Risk factors’ in the company’s Annual Report on Form 20-F for 2013.
1. Linos E, Swetter SM, Cockburn MG, et al. Increasing burden of melanoma in the United States. J Invest Dermatol. 2009; 129 (7): 1666-1674.
2. Ries LAG, Melbert D, Krapcho M et al (eds). SEER cancer statistics review1975-2005: National Cancer Institute, Bethesda MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008.