Tafinlar (Dabrafenib)/Mekinist (Trametinib) Combination Therapy Received Accelerated FDA Approval for the Treatment of Patients with Metastatic Melanoma

Loretta Fala

June 2014, Vol 5, No 5 - Drug Updates

Cutaneous melanoma, an aggressive form of skin cancer that develops in the melanocytes of the skin, is becoming increasingly prevalent in the United States.1 According to the American Cancer Society, an estimated 76,100 new cases of melanoma will be diagnosed in 2014, and approximately 9710 patients are expected to die from this cancer.2 In fact, melanoma causes more deaths than any other skin disease.3

As of 2011, there were an estimated 960,231 patients living with melanoma of the skin in the United States.4 However, the actual prevalence of melanoma may be underestimated because of underreporting of superficial and in situ melanomas treated in the outpatient setting.5

The risk factors for melanoma include family history of the disease; history of melanoma; more than 1 clinically atypical mole or dysplastic nevus; and, in rare cases, genetic mutations.6 In addition, exposure to ultraviolet radiation from the sun or from tanning beds and lamps is a major risk factor for most melanomas and having fair skin that burns easily also increases the risk for developing melanoma.6 However, melanoma can develop in individuals of any ethnic background and can occur anywhere on the body, including areas of the body not exposed to sun or ultraviolet light.1

Data from the Surveillance, Epidemiology, and End Results Program indicated that between 2004 and 2010, approximately 91.3% of patients with melanoma survived 5 years or more.4 Melanoma outcomes are linked directly to the stage at presentation.7 An estimated 82% to 85% of patients present with localized disease, 10% to 13% present with regional disease, and 2% to 5% present with distant metastases.7 The 5-year survival rates for stage III disease range from 20% to 70%, depending on the nodal tumor burden. In patients with distant metastases, long-term survival is <10%.7

Melanoma—metastatic disease in particular—is associated with substantial healthcare costs.8,9 The estimated annual cost of melanoma in 1991-1996 was $249 million; this figure increased to $390 million in the population aged ?65 years.8 According to a Medicare claims data analysis (1991-2005), patients with metastatic melanoma had a monthly average of more than $11,000 in total healthcare costs; the majority of these costs were related to inpatient hospital costs.9 In addition, productivity from melanoma mortalities accounted for $3.5 billion per year in 2000-2006 in the United States.10

Prevention and early detection of melanoma may improve outcomes and reduce the economic burden.10 Treatment for early-stage disease includes surgery to remove the melanoma.11 Therapeutic options for metastatic melanoma include surgery to remove the affected lymph nodes, chemotherapy, radiation therapy, immunotherapy (ie, interleukin-2, ipilim­umab), and signal transduction inhibitors (BRAF inhibitors, MEK inhibitors, multikinase inhibitors, and KIT inhibitors).11-13

The recent development of agents that inhibit the mitogen-activated protein (MAP) kinase pathway represents an important advance in treating metastatic melanoma.14 These include da­brafenib (Tafinlar) and vemurafenib (Zelboraf), which block MAP kinase signaling in patients with melanoma and with the BRAF V600E mutation; as well as trametinib (Mekinist), which inhibits MAP kinase (that is downstream of BRAF in the MAP kinase pathway) in patients with melanoma with BRAF V600E or BRAF V600K mutation.14

The First Combination Treatment Option for Metastatic Melanoma
On January 10, 2014, the combination of dabrafenib plus trametinib (both manufactured by GlaxoSmithKline) was granted accelerated US Food and Drug Administration (FDA) approval for the treatment of patients with unresectable melanoma or metastatic melanoma with BRAF V600E or BRAF V600K mutation as detected by an FDA-approved test.15

Dabrafenib and trametinib were previously approved by the FDA independently as single agents in May 2013 for the treatment of patients with metastatic or unresectable melanoma.16

Discussing the recent approval of the new combination, Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products at the FDA’s Center for Drug Evaluation and Research, said, “Mekinist and Tafinlar are the first drugs approved for combination treatment of melanoma. Their development for combination use is based on the strong understanding of the biological pathways of the disease. This approval illustrates the value of continuing to study drugs in combination for clinical development.”15

Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma.17 Trametinib (as a single agent) is not indicated for the treatment of patients who have received previous BRAF inhibitor therapy.18

After its FDA approval, the combination of dabrafenib and trametinib was added to the list of preferred systemic therapy options for metastatic melanoma by the National Comprehensive Cancer Network.7

Mechanism of Action
The RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling has an important role in transmitting signals that regulate gene expression and prevent programmed cell death.19 BRAF mutations, which are frequently present in various cancers, lead to overexpressed BRAF signaling and deregulated downstream signaling via the MEK/ERK pathway. This overactive BRAF signaling stimulates proliferation of malignant melanoma cells and results in resistance to cell apoptosis.19,20

Dabrafenib and trametinib target 2 different tyrosine kinases in the RAS/RAF/MEK/ERK pathway.17,18 Da­brafenib inhibits some mutations of BRAF kinases.17 Trametinib reversibly inhibits MEK1 and MEK2 activation as well as MEK1 and MEK2 kinase activity.18 The combination of dabrafenib and trametinib resulted in greater growth inhibition of BRAF V600 mutation–positive melanoma cell lines in vitro and prolonged the inhibition of tumor growth in BRAF V600 mutation–positive melanoma xenografts compared with either drug alone.17,18

Dosing and Administration
Before initiating treatment with the dabrafenib/trametinib combination, the presence of BRAF V600E or BRAF V600K mutation in tumor specimens must be confirmed. The FDA-approved THxID BRAF companion diagnostic assay (bioMérieux, Inc) is used to detect these mutations, and should be administered before the use of the combination therapy.17,18

The recommended dose of the combination therapy is dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily.17,18 Dabrafenib/trametinib is administered at least 1 hour before or at least 2 hours after a meal.17,18 Dabrafenib is available as a 50-mg or a 75-mg capsule.17 Trametinib is available in 3 tablet strengths: 0.5 mg, 1 mg, and 2 mg.18

Efficacy: Phase 1/2 Clinical Trial
The FDA approval of dabrafenib/trametinib combination therapy was based on demonstration of its durable objective responses in a multicenter, open-label, randomized, dose-ranging phase 1/2 clinical trial that also compared dabrafenib/tremetinib with dabrafenib as a single agent in select patients.14,17

In this trial, patients were randomized (1:1:1 ratio) to trametinib (at 2 different doses) in combination with dabrafenib compared with dabrafenib as a single agent, in 162 patients with BRAF V600E or BRAF V600K mutation–positive, unresectable or metastatic melanoma. Eligible patients were permitted to have had 1 previous chemotherapy regimen and previous aldesleukin; patients with previous exposure to BRAF or MEK inhibitors were not eligible for the study.14,17,18

Patients randomized to receive da­brafenib as a single agent were offered trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily at the time of investigator-assessed disease progression.14,17,18 The primary efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration response, independent radiology review committee (IRRC)-assessed ORR, and IRRC-assessed duration of response.14,17,18

The majority of patients had not received previous anticancer therapy for unresectable or metastatic disease.14,17,18 All patients had tumor-containing BRAF V600E or BRAF V600K mutation as determined by local laboratory or centralized testing; 85% had the BRAF V600E mutation, and 15% had the BRAF V600K mutation.14,17,18 The median follow-up duration was 14 months. Efficacy outcomes for the group receiving dabrafenib in combination with trametinib 2 mg daily and the group receiving dabrafenib as a single agent are shown in Table 1.14,17,18

Similar ORR results were achieved in subgroups defined by the BRAF mutation subtype. The ORR results were also similar to the intent-to-treat analysis, based on exploratory subgroup analyses of patients with retrospectively confirmed BRAF V600E or BRAF V600K mutation–positive melanoma using the THxID BRAF companion diagnostic assay.14,17,18

The most common adverse reactions (?20%) associated with da­brafenib/trametinib combination therapy are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.17,18 The distribution of these adverse events by grade is listed in Table 2.

Warnings and Precautions
There are no contraindications for the use of dabrafenib/trametinib combination therapy.

Drug interactions. Coadministration of trametinib 2 mg once daily and dabrafenib 150 mg twice daily is not associated with clinically relevant drug interactions. Concurrent administration of strong inhibitors or strong inducers of cytochrome (CY) P3A4 or CYP2C8 with dabrafenib should be avoided. Concomitant use of da­brafenib with sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in the loss of efficacy of these agents.17,18

A complete list of the warnings and precautions for dabrafenib and trametinib, alone and in combination, is outlined in Table 3.17,18

Use in Specific Populations
Pregnancy. Dabrafenib and trametinib can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be counseled about the potential hazard to the fetus.17,18

Nursing mothers. Because of the potential for serious adverse reactions from dabrafenib and trametinib in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.17,18

Females and males of reproductive potential. Female patients of reproductive potential should be advised to use highly effective contraception during treatment with dabrafenib/trametinib combination therapy. When the combination therapy is used, patients should be advised to use a nonhormonal method of contraception because dabrafenib can render hormonal contraceptives ineffective. Patients should be advised to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking the dabrafenib/trametinib combination therapy.17,18

Pediatric use. The safety and effectiveness of dabrafenib and trametinib as single agents or in combination have not been established in pediatric patients.17,18

Geriatric use. Across all clinical trials of dabrafenib/trametinib combination therapy, there was an insufficient number of patients aged ?65 years to determine whether they respond differently from younger patients.17,18

Hepatic impairment. Dose adjustments for dabrafenib and trametinib are not recommended for patients with mild hepatic impairment. The appropriate doses of dabrafenib and trametinib have not been established in patients with moderate or severe hepatic impairment.17,18

Renal impairment. Dose adjustments for dabrafenib and trametinib are not recommended for patients with mild or moderate renal impairment. The appropriate doses of da­brafenib and trametinib have not been established in patients with severe renal impairment.17,18

A new treatment option became available for patients with advanced melanoma with BRAF V600E or BRAF V600K mutation with the recent FDA accelerated approval of dabrafenib/trametinib combination therapy. This is the first combination therapy to receive FDA approval for use in patients with metastatic melanoma. Using these 2 agents together may improve patient outcomes by providing additional benefits that are not available with a single agent.

In the clinical trial that demonstrated the safety and clinical activity of dabrafenib/trametinib combination therapy, significantly more patients receiving the combination therapy had a cancer shrinkage or disappearance, which lasted 10.5 months, compared with patients receiving dabrafenib alone and whose response lasted only 5.6 months.


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