FDA Approves Mekinist
FDA Approves Mekinist (trametinib) for Advanced Melanoma
May 29, 2013 -- GlaxoSmithKline plc announced today that the U.S. Food and Drug Administration (FDA) has approved Mekinist (trametinib) as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations. Mekinist is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy. The mutation must be detected by an FDA-approved test, such as the companion diagnostic assay from bioMérieux S.A., THxID™-BRAF.
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.[i]
Mekinist is approved for patients with the BRAF V600E mutation, which accounts for approximately 85 percent of all BRAF V600 mutations in metastatic melanoma.[ii] It is also approved for patients with the V600K mutation, which makes up approximately 10 percent of all BRAF V600 mutations in metastatic melanoma.[ii]
As part of the FDA approval, which was based on clinical studies evaluating the efficacy and safety, warnings and precautions were also identified. 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 embryofetal toxicity.
GSK will be making 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.
Mekinist (trametinib) Clinical Data
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% CI: 0.34, 0.65], p<0.0001). The median PFS was 4.8 months for patients taking trametinib (95% CI: 4.3, 4.9) compared to 1.5 months for chemotherapy (95% CI: 1.4, 2.7). Fifty-one patients (47%) crossed over from the chemotherapy arm at the time of disease progression to receive trametinib.
The most common adverse reactions (greater than or equal to 10%) of any grade in patients receiving trametinib included rash (57%), diarrhea (43%), lymphedema (swelling of the face, arms or legs) (32%), dermatitis acneiform (acne-like rash) (19%), stomatitis (mouth sores) (15%), hypertension (new or worsening high blood pressure) (15%), abdominal pain (13%), hemorrhage (bleeding) (13%), dry skin (11%), pruritis (itching) (10%) and paronychia (nail infection) (10%).
About Melanoma and Metastatic Melanoma
Melanoma is the most serious and deadly form of skin cancer.[iii] According to statistics from the National Cancer Institute, in 2013 there will be an estimated 9,480 deaths resulting from melanoma in the United States.[iv] When melanoma spreads in the body, the disease is called metastatic melanoma.[v] Approximately half of all people with metastatic melanoma have a BRAF mutation, which is an abnormal change in a gene that can enable some melanoma tumours to grow and spread.2 One in two patients worldwide with metastatic melanoma is expected to survive for a year after diagnosis,[vi] while in the U.S., the five-year survival rate was 16 percent (2003-2009).[vii] The median age of a newly diagnosed metastatic melanoma patient is almost a decade younger than other cancers.[viii]
About Mekinist (trametinib)
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.
Important Safety Information for Mekinist (trametinib)
WARNINGS AND PRECAUTIONS
Cardiomyopathy In the pivotal trial of Mekinist (trametinib), cardiomyopathy [defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF)] occurred in 7% (14/211) of patients treated with trametinib; no chemotherapy-treated patient developed cardiomyopathy. The median time to onset of cardiomyopathy in patients treated with trametinib was 63 days (range 16 to 156 days); cardiomyopathy was identified within the first month of treatment with trametinib in five of these 14 patients. Four percent of patients in the pivotal trial of trametinib required discontinuation (4/211) and/or dose reduction (7/211) of trametinib. Cardiomyopathy resolved in 10 of these 14 (71%) patients.
Across clinical trials of trametinib at the recommended dose (n=329), 11% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF greater than or equal to 10% below baseline), and 5% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of greater than or equal to 20% below baseline.
Retinal Pigment Epithelial Detachments Retinal pigment epithelial detachments (RPED) can occur during treatment with Mekinist (trametinib).
In the pivotal trial of trametinib, where ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment, one patient (0.5%) receiving trametinib developed RPED and no cases of RPED were identified in chemotherapy-treated patients.
Across all clinical trials of trametinib, the incidence of RPED was 0.8% (14/1749).
Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina. RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range 3 to 71 days) following the interruption of dosing with trametinib, although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases.
Retinal Vein Occlusion (RVO) Across all clinical trials of Mekinist (trametinib), the incidence of RVO was 0.2% (4/1749). An RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.
Interstitial Lung Disease (ILD) In clinical trials of Mekinist (trametinib) at the recommended dose (n=329), interstitial lung disease (ILD) or pneumonitis occurred in 1.8% of patients.
In the pivotal trial of trametinib, 2.4% (5/211) of patients treated with trametinib developed ILD or pneumonitis; all five patients required hospitalization.
The median time to first presentation of ILD or pneumonitis was 160 days (range 60 to 172 days).
Serious Skin Toxicity In the pivotal trial of Mekinist (trametinib), the overall incidence of skin toxicity including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema was 87% in patients treated with trametinib and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with trametinib.
Skin toxicity requiring hospitalization occurred in 6% of patients treated with trametinib, most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin.
The median time to onset of skin toxicity in patients treated with trametinib was 15 days (range 1 to 221 days) and median time to resolution of skin toxicity was 48 days (range 1 to 282 days).
Reductions in the dose of trametinib were required in 12%, and permanent discontinuation of trametinib was required in 1% of patients with skin toxicity.
Embryofetal Toxicity Based on its mechanism of action, Mekinist (trametinib) can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose.
Adverse Reactions In the pivotal trial of Mekinist (trametinib), the most common adverse reactions (greater than or equal to 10%) of any grade were rash (57%), diarrhea (43%), lymphedema (32%), dermatitis acneiform (19%), stomatitis (15%), hypertension (15%), abdominal pain (13%), hemorrhage (13%), dry skin (11%), pruritis (10%) and paronychia (10%).
In the pivotal trial of trametinib, the most common serious adverse reactions (≥2%) grades 3 and 4 were hypertension (12%), rash (8%), pruritis (2%), and stomatitis (2%).
Females and Males of Reproductive Potential Mekinist (trametinib) may impair fertility in females.
[i] Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. NEJM. 2012;367:107-14.
[ii] Hong DS, Vence L, Falchook G, et al. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res. 2012;18:2326–35.
[iii] Skin Cancer Foundation. “What Is Melanoma?” May 2013. Available at: http://www.skincancer.org/skin-cancer-information/melanoma.
[iv] National Cancer Institute. “Melanoma.” May 2013. Available at: http://www.cancer.gov/cancertopics/types/melanoma.
[v] Melanoma Research Foundation. “Staging Melanoma.” May 2013. Available at: http://www.melanoma.org/learn-more/melanoma-101/staging-melanoma.
[vi] Tas, Faruk. Metastatic Behavior in Melanoma: Timing, Pattern, Survival, and Influencing Factors. Jour Oncology. 2012.
[vii] SEER Stat Fact Sheets: Melanoma of the Skin. The Surveillance, Epidemiology, and End Results (SEER). May 2013. Available at: http://seer.cancer.gov/statfacts/html/melan.html.
[viii] Brady MS, Kaushal A, Ko C. “Melanoma and Other Skin Cancers.” Cancer Network. 14th Ed. March 2013. Available at: http://www.cancernetwork.com/cancer-management/moles-melanomas/article/10165/1802671.
Posted: May 2013
- GSK Gains Accelerated FDA Approval for Combination Use of Mekinist (trametinib) and Tafinlar (dabrafenib) - January 9, 2014
- Regulatory Update: Trametinib US PDUFA Date Extended to 3 September 2013 - May 1, 2013