The 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.
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.
The combination was approved through the FDA’s Accelerated Approval programme and reviewed under a Priority Review designation. 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.
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 ), were as follows:
The investigator-assessed overall response rate ( ORR ) ( main efficacy endpoint ) was 76% for patients treated with the combination, and 54% for patients treated with single-agent Dabrafenib.
The median duration of response was 10.5 months for patients treated with the combination, and 5.6 months 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% for patients treated with the combination, and 46% for patients receiving single-agent Dabrafenib.
The median duration of response as assessed by the IRRC was 7.6 months for patients treated with the combination, and 7.6 months 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; tumour promotion in wild-type BRAF melanoma; haemorrhagic events; venous thromboembolic events; cardiomyopathy; ocular toxicities; interstitial lung disease; serious febrile drug reactions; serious skin toxicity; hyperglycaemia; haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase ( G6PD ) deficiency; and embryofoetal toxicity.
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 ( 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 ( 22% ).
The most common ( greater than or equal to 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% ). ( Xagena )
Source: GSK, 2014