Two new GSK oral oncology treatments, BRAF-inhibitor Tafinlar® (dabrafenib) capsules and the first MEK-inhibitor Mekinist™ (trametinib) tablets, approved by FDA as single-agent therapies

LONDON and PHILADELPHIA, May 29, 2013 /PRNewswire/ -- GlaxoSmithKline plc [LSE/NYSE: GSK] announced today that the U.S. Food and Drug Administration (FDA) has approved both 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. Tafinlar is not indicated for the treatment of patients with wild-type BRAF melanoma. Mekinist is indicated 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. These mutations must be detected by an FDA-approved test, such as the companion diagnostic assay from bioMerieux S.A., 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, M.D., 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.¹ Tafinlar and Mekinist are each approved for patients with the BRAF V600E mutation, which accounts for approximately 85 percent of all BRAF V600 mutations in metastatic melanoma.² Mekinist is also approved for patients with the V600K mutation, which makes up approximately 10 percent of all BRAF V600 mutations in metastatic melanoma.²

"MEK has been pursued as a therapeutic target in cancer for more than a decade," said Keith Flaherty, M.D., Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, 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 bioMerieux to develop a companion diagnostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma. bioMerieux has received FDA pre-market approval of THxID™-BRAF. Currently, it is the only FDA-approved test that detects the V600K mutation.

Tafinlar (dabrafenib) Clinical Data
The approval of dabrafenib is based on results from one multicenter, 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%) 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% CI: 0.20, 0.54], p<0.0001). The median PFS was 5.1 months with dabrafenib (95% CI: 4.9, 6.9) compared to 2.7 months with dacarbazine (95% CI: 1.5, 3.2). The ORR with dabrafenib was 52 percent (95% CI: 44, 59) versus 17 percent with dacarbazine (95% CI: 9, 29).

In this study, the most common adverse reactions (greater than or equal to 10%) of any grade for dabrafenib included hyperkeratosis (thickening of the outer layer of the skin) (37%), headache (32%), pyrexia (fever) (28%), arthralgia (joint aches) (27%), papilloma (warts) (27%), alopecia (hair loss) (22%), palmar-plantar erythrodysesthesia (redness, swelling, peeling or tenderness of hands or feet) (20%), rash (17%), back pain (12%), cough (12%), myalgia (muscle aches) (11%), constipation (11%) and nasopharyngitis (cold-like symptoms) (10%).

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 percent (95% CI: 9.7, 28.2). For Cohort B, the OIRR was also 18 percent (95% CI: 9.9, 30.0). The median duration of response was 4.6 months (95% CI: 2.8, Not Reached) and 4.6 months (95% CI: 1.9, 4.6) in Cohort A and Cohort B, respectively.

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%), diarrhoea (43%), lymphoedema (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%), haemorrhage (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.³ 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.⁴ When melanoma spreads in the body, the disease is called metastatic melanoma.⁵  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,⁶ while in the U.S., the five-year survival rate was 16 percent (2003-2009).⁷ The median age of a newly diagnosed metastatic melanoma patient is almost a decade younger than other cancers.⁸

About Tafinlar^® (dabrafenib)
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.

Full U.S. Prescribing Information and Medication Guide will be available soon at us.gsk.com. Prior to the 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 "GlaxoSmithKline Inquiries" section at the end of this document.

About Mekinist^TM (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.

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.

Full U.S. Prescribing Information and Medication Guide will be available soon at us.gsk.com. Prior to the 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 "GlaxoSmithKline Inquiries" section at the end of this document.

IMPORTANT SAFETY INFORMATION FOR TAFINLAR^® (dabrafenib)

WARNINGS AND PRECAUTIONS

New Primary Cutaneous Malignancies
TAFINLAR^® (dabrafenib) results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma and melanoma. In the pivotal trial of dabrafenib, cuSCC occurred in 7% (14/147) of patients treated with dabrafenib and in none of the patients treated with dacarbazine. Across clinical trials of dabrafenib (n=586), the incidence of cuSCC was 11%. The median time to first cuSCC was 9 weeks (range: 1 to 53 weeks). Of those, patients who developed a cuSCC, approximately 33% developed one or more cuSCC with continued dabrafenib. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.

In the pivotal trial of dabrafenib, the incidence of new primary malignant melanomas was 2% (3/187) for patients receiving dabrafenib while no chemotherapy-treated patient was diagnosed with new primary malignant melanoma.

Tumour Promotion in BRAF Wild-Type Melanoma
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors.

Serious Febrile Drug Reactions
In the pivotal trial of Tafinlar (dabrafenib), serious febrile drug reactions, defined as serious cases of fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause (e.g., infection) occurred in 3.7% (7/187) of patients treated with dabrafenib and in none of the patients treated with dacarbazine. The incidence of fever (serious and non-serious) was 28% in patients treated with dabrafenib and 10% in patients treated with dacarbazine. In patients treated with dabrafenib, the median time to initial onset of fever (any severity) was 11 days (range: 1 to 202 days), and the median duration of fever was 3 days (range 1 to 129 days).

Hyperglycaemia
Hyperglycaemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycaemic agent therapy, can occur with Tafinlar (dabrafenib). In the pivotal trial of dabrafenib, 5 of 12 patients with a history of diabetes required more intensive hypoglycaemic therapy while taking dabrafenib. The incidence of Grade 3 hyperglycaemia based on laboratory values was 6% (12/187) in patients treated with dabrafenib compared to none of the dacarbazine-treated patients.

Uveitis and Iritis
Uveitis (including iritis) occurred in 1% (6/586) of patients treated with Tafinlar (dabrafenib) across clinical trials.

Glucose-6-Phosphate Dehydrogenase Deficiency
Tafinlar (dabrafenib), which contains a sulfonamide moiety, confers a potential risk of haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Embryofoetal Toxicity
Based on its mechanism of action, Tafinlar (dabrafenib) can cause foetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose.

Most Common Adverse Reactions
The most common adverse reactions (greater than or equal to 10%) of any grade included hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), papilloma (27%), alopecia (22%), palmar-plantar erythrodysesthesia (20%), rash (17%), back pain (12%), cough (12%), constipation (11%), myalgia (11%), and nasopharyngitis (10%).

The most common serious adverse reactions (greater than or equal to 2%) of grades 3 and 4 include cuSCC (4%), back pain (3%), pyrexia (3%), constipation (2%), and palmar-plantar erythrodysesthesia (2%).

Drug Interactions

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. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib.

Effects of Dabrafenib on Other Drugs
Dabrafenib induces CYP3A4 and may induce other enyzmes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters. Dabrafenib decreased the maximum concentration (C_max) and area under the curve (AUC) of midazolam (a substrate of CYP3A4) by 61% and 74%, respectively. Coadministration of Tafinlar with other substrates of these enzymes, including warfarin, dexamethasone, or hormonal contraceptives, can result in decreased concentrations and loss of efficacy.

Females and Males of Reproductive Potential
Tafinlar (dabrafenib) may impair fertility in males.

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.

Embryofoetal Toxicity
Based on its mechanism of action, Mekinist (trametinib) can cause foetal 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%), diarrhoea (43%), lymphoedema (32%), dermatitis acneiform (19%), stomatitis (15%), hypertension (15%), abdominal pain (13%), haemorrhage (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.

About GSK Patient Assistance Programs
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 programs, 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 programs including co-pay assistance in addition to traditional patient assistance support.  For more information, patients can call 1-8ONCOLOGY1 (1-866-265-6491).

GlaxoSmithKline – 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.

[1] Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. NEJM. 2012;367:107-14.
[2] 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.
[3] Skin Cancer Foundation. "What Is Melanoma?" May 2013. Available at: http://www.skincancer.org/skin-cancer-information/melanoma.
[4] National Cancer Institute. "Melanoma." May 2013. Available at: http://www.cancer.gov/cancertopics/types/melanoma.
[5] Melanoma Research Foundation. "Staging Melanoma." May 2013. Available at: http://www.melanoma.org/learn-more/melanoma-101/staging-melanoma.
[6] Tas, Faruk. Metastatic Behavior in Melanoma: Timing, Pattern, Survival, and Influencing Factors. Jour Oncology. 2012.
[7] 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.
[8] 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.  

SOURCE GlaxoSmithKline

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