The US Food and Drug Administration (FDA) has approved GlaxoSmithKline's Tafinlar (dabrafenib) and Mekinist (trametinib). Tafinlar is indicated as a single-agent oral treatment for unresectable melanoma (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) in adult patients with BRAF V600E mutation while, Mekinist is indicated as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations.

Tafinlar is not indicated for the treatment of patients with wild-type BRAF melanoma while Mekinist is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy. These mutations must be detected by an FDA-approved test, such as the companion diagnostic assay from bioMérieux SA, THxID-BRAF.

“With today’s FDA approvals, GSK can now offer two new single-agent therapies to selected patients who have metastatic melanoma, a devastating disease with very low survival rates and few treatment options,” said Paolo Paoletti, MD, president, GlaxoSmithKline Oncology. “GSK Oncology has been focused on progressing research in the most efficient manner possible, and we’re pleased to bring Tafinlar and Mekinist to physicians and their patients in rapid development times.”

Among those with metastatic melanoma, approximately half have a BRAF mutation, which is an abnormal change in a gene that can enable some melanoma tumours to grow and spread.

Tafinlar and Mekinist are each approved for patients with the BRAF V600E mutation, which accounts for approximately 85 per cent of all BRAF V600 mutations in metastatic melanoma. Mekinist is also approved for patients with the V600K mutation, which makes up approximately 10 per cent of all BRAF V600 mutations in metastatic melanoma.

“MEK has been pursued as a therapeutic target in cancer for more than a decade,” said Keith Flaherty, MD, director of Developmental Therapeutics, Massachusetts General Hospital Cancer Centre, and principal investigator of the phase III METRIC trial. “Based on the clear improvement versus chemotherapy in progression-free survival, trametinib represents the first validated MEK inhibitor. We welcome it as a new treatment option for patients with this disease.”

As part of the FDA approval, which was based on clinical studies evaluating the efficacy and safety of these products, warnings and precautions were also identified. Dabrafenib can cause serious side effects, some of which can be life threatening, including increasing the risk of developing new primary cutaneous malignancies (new skin cancers), tumour promotion in BRAF wild-type melanoma, serious febrile drug reactions (severe fevers), hyperglycaemia (blood sugar problems), uveitis and iritis (severe eye problems), haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and embryofoetal toxicity (potential harm to the unborn baby in pregnant women). Trametinib can cause serious side effects, some of which can be life threatening, including cardiomyopathy (heart problems, including heart failure), retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) (eye problems including blindness), interstitial lung disease or pneumonitis (lung or breathing problems), serious skin toxicity (rash) and embryofoetal toxicity.

GSK will be making Tafinlar and Mekinist available for prescription no later than in the early third quarter of 2013.

In 2010, GSK entered a collaboration with bioMérieux to develop a companion diagnostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma. bioMérieux has received FDA pre-market approval of THxID-BRAF. Currently, it is the only FDA-approved test that detects the V600K mutation.

The approval of dabrafenib is based on results from one multi-centre, international trial, specifically the pivotal, open-label phase III BREAK-3 study that randomised 250 previously untreated adult patients with BRAF V600E mutation-positive unresectable or metastatic melanoma to receive dabrafenib or dacarbazine (chemotherapy) in a 3:1 ratio, respectively. The primary endpoint was progression-free survival (PFS) as assessed by the investigator. Other pre-specified endpoints included independent radiology review committee (IRRC) assessed PFS, confirmed objective response rate (ORR) and duration of response. Twenty-eight patients (44 per cent) crossed over from the dacarbazine arm at the time of disease progression to receive dabrafenib.

The study demonstrated a statistically significant increase in PFS in patients treated with dabrafenib, compared to dacarbazine (HR=0.33; [95 per cent CI: 0.20, 0.54], p<0.0001). The median PFS was 5.1 months with dabrafenib (95 per cent CI: 4.9, 6.9) compared to 2.7 months with dacarbazine (95 per cent CI: 1.5, 3.2). The ORR with dabrafenib was 52 percent (95 per cent CI: 44, 59) versus 17 percent with dacarbazine (95 per cent CI: 9, 29).

Dabrafenib was also prospectively evaluated in adult patients with BRAF V600E mutation-positive melanoma, metastatic to the brain. The single-arm, open-label phase II trial enrolled patients into two cohorts. Patients in Cohort A (n=74) had received no prior local therapy for brain metastases, while patients in Cohort B (n=65) had received at least one local therapy for brain metastases, including but not limited to surgical resection, whole brain radiotherapy or stereotactic radiosurgery such as gamma knife, linear-accelerated-based radiosurgery, charged particles or CyberKnife. In addition, patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease.

The primary outcome measure was the estimation of the overall intracranial response rate (OIRR) in each cohort. The OIRR for Cohort A was 18 per cent (95 per cent CI: 9.7, 28.2). For Cohort B, the OIRR was also 18 per cent (95 per cent CI: 9.9, 30.0). The median duration of response was 4.6 months (95 per cent CI: 2.8, Not Reached) and 4.6 months (95 per cent CI: 1.9, 4.6) in Cohort A and Cohort B, respectively.

The approval of trametinib is based on results from the open-label, international phase III METRIC study.  In this study, 322 unresectable or metastatic melanoma adult patients with a BRAF V600E or V600K mutation, who had no more than one prior chemotherapy regimen for advanced or metastatic disease and no prior BRAF or MEK inhibitor treatment, were randomised to receive trametinib or chemotherapy in a 2:1 ratio, respectively.

The study demonstrated a statistically significant increase in PFS in patients treated with trametinib, compared to chemotherapy (HR= 0.47; [95 per cent CI: 0.34, 0.65], p<0.0001). The median PFS was 4.8 months for patients taking trametinib (95 per cent CI: 4.3, 4.9) compared to 1.5 months for chemotherapy (95 per cent CI: 1.4, 2.7). Fifty-one patients (47 per cent) crossed over from the chemotherapy arm at the time of disease progression to receive trametinib.

Melanoma is the most serious and deadly form of skin cancer. When melanoma spreads in the body, the disease is called metastatic melanoma. One in two patients worldwide with metastatic melanoma is expected to survive for a year after diagnosis, while in the US, the five-year survival rate was 16 per cent (2003-2009). The median age of a newly diagnosed metastatic melanoma patient is almost a decade younger than other cancers.

Tafinlar (dabrafenib) is now approved for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of use: Tafinlar is not recommended for use in patients with wild-type BRAF melanoma.

Tafinlar is not approved or licensed in Europe and may not be approved in other parts of the world for the treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic melanoma.

Mekinist (trametinib) is now approved for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600E and V600K mutations as detected by an FDA-approved test. Limitation of use: Mekinist is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy.

Mekinist 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.Mekinist is not approved or licensed in Europe and may not be approved in other parts of the world for the treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic melanoma.

GSK has a number of patient assistance programs 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 approximately 2.3 million prescriptions for GSK medicines and vaccines free of charge. GSK is committed to helping eligible patients who need Tafinlar and Mekinist receive therapy. In the United States, patients who qualify for the programs may benefit from GSK’s Commitment to Access program for oncology and specialty medicines which offers services and programmes including co-pay assistance in addition to traditional patient assistance support.