DABRAFENIB-TRAMETINIB APPROVAL

Agents for Melanoma

Melanoma is the most dangerous type of skin cancer and is the leading cause of death from skin disease. The number of cases has been increasing as a consequence, in part, of unprotected sun exposure earlier in life and the increased use of tanning salons. According to the National Cancer Institute, approximately 77,000 Americans will be diagnosed with melanoma in 2013 and almost 10,000 will die from the disease. If identified at an early point, melanoma often is curable. However, the prognosis for patients with late-stage (metastatic) melanoma is very poor. Until recently, the treatment options for patients with metastatic melanoma have been limited in both numbers and effectiveness and have included agents such as dacarbazine, carboplatin, and paclitaxel.

In 2011, two important new drugs were marketed for the treatment of patients with metastatic melanoma. Ipilimumab (Yervoy) is a monoclonal antibody that binds to the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4). By blocking the action of CTLA-4, ipilimumab increases T-cell activation and proliferation, and its benefit is thought to result from T-cell–mediated antitumor responses. It was the first drug to be demonstrated to prolong survival in patients with metastatic melanoma.

A protein designated as BRAF is an important component of a pathway involved in normal cell growth and survival. Mutations that keep the BRAF protein in an active state may cause excessive signaling in the pathway, resulting in uncontrolled cell growth. These mutations, most often BRAF V600 mutations, occur in approximately one-half of melanomas, with an estimated 85% being of the V600E type and 10% of the V600K type. In late 2011, vemurafenib (Zelboraf), a BRAF kinase inhibitor, was marketed for treating patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDAapproved test that was approved at the same time that the drug was approved. In the clinical studies of vemurafenib, it was reported to increase progression-free survival and reduce the risk of death. However, although many patients experienced clinical benefit, it often was of a brief duration that is thought to be attributable to the development of resistance involving mitogen-activated extracellular signal–regulated kinase (MEK) pathways.

The important advances in the treatment of metastatic melanoma continued in 2013 with the approval of dabrafenib mesylate (Tafinlar— GlaxoSmithKline), a BRAF inhibitor; trametinib dimethyl sulfoxide (Mekinist—GlaxoSmithKline), a MEK inhibitor; and a companion diagnostic designated as the THxID BRAF test, which will help determine whether a patient's melanoma cells have the V600E or V600K mutation in the BRAF gene. Dabrafenib and trametinib have been approved as single agents and not for use as a combination regimen. However, studies of the combined use of the two agents have been conducted with results that suggest increased and extended benefit compared with the benefit anticipated with either drug used alone. A supplemental application for use of the two drugs in combination has been submitted to FDA, and approval is expected. In the meantime, the availability of both drugs permits "off-label" use in combination as the strategy some consider to be best for treating patients with metastatic melanoma with the BRAF mutation.

Dabrafenib and trametinib are considered individually in the following discussions.

Dabrafenib Mesylate

Dabrafenib mesylate (Tafinlar— GlaxoSmithKline) is an inhibitor of some mutated forms of BRAF kinases, including V600E, which may stimulate tumor cell growth. Its properties and use are most similar to those of vemurafenib. Like vemurafenib, it is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

The effectiveness of dabrafenib was demonstrated in a study in which it was compared with dacarbazine and in which the main efficacy outcome measure was progression- free survival as assessed by the investigator. The patients treated with dabrafenib had a delay in tumor growth that was 2.4 months later than those receiving dacarbazine (5.1 vs. 2.7 months). Dabrafenib was also evaluated in patients with brain metastases, whereas such patients were not included in the primary studies with vemurafenib. The overall intracranial response rate (OIRR) in patients with brain metastases was 18%, and the median duration of the OIRR was 4.6 months. Neither dabrafenib nor vemurafenib is indicated for the treatment of patients with wild-type BRAF melanoma because of the possibility of increased cell proliferation.

The use of BRAF inhibitors has been associated with the occurrence of new primary cutaneous malignancies, and 7% of the patients treated with dabrafenib experienced cutaneous squamous cell carcinomas and keratoacanthomas. Dermatologic evaluations should be performed before initiating therapy, every 2 months during therapy, and for up to 6 months following discontinuation of treatment.

Fever was experienced by 28% of the patients in the clinical study and serious febrile reactions in 4%. Treatment with dabrafenib should be withheld in patients having a serious febrile reaction or fever of 101.3°F or greater. Prophylaxis with an antipyretic agent may be needed when treatment is resumed.

Other commonly reported adverse events in the clinical study of dabrafenib included hyperkeratosis (37%), alopecia (22%), palmar–plantar erythrodysesthesia syndrome (20%), headache (32%), arthralgia (27%), and papilloma (27%). Some patients have experienced uveitis including iritis with the use of dabrafenib, and patients should be monitored for visual symptoms (e.g., change in vision, photophobia, eye pain). Because the dabrafenib molecule contains a sulfonamide moiety, a potential risk of hemolytic anemia exists in patients with glucose- 6-phosphate dehydrogenase deficiency.

Hyperglycemia was reported in 50% of the patients treated with dabrafenib; therefore, serum glucose concentrations should be monitored in patients with preexisting diabetes or hyperglycemia. Patients should be advised to report symptoms such as excessive thirst or increase in the volume or frequency of urination.

Dabrafenib may cause harm to the fetus if administered during pregnancy, and it is classified in Pregnancy Category D. Women of childbearing potential should use contraception during the period of treatment and for 4 weeks following discontinuation of treatment. Patients should be advised that the drug has the potential to cause infertility. Whether dabrafenib is excreted in human milk is unknown, and a decision should be made to discontinue nursing or not use the drug. The effectiveness and safety of the new drug in pediatric patients have not been established.

Following oral administration, the absolute bioavailability of dabrafenib is 95%. Its bioavailability is decreased when it is administered with a high-fat meal, and it should be administered at least 1 hour before or at least 2 hours after a meal. Drugs that increase gastric pH (e.g., antacids, H2 receptor antagonists [e.g., famotidine], proton pump inhibitors [e.g., omeprazole]) may reduce the bioavailability of dabrafenib, but studies of this potential interaction have not been conducted.

Dabrafenib is extensively metabolized, primarily via the CYP3A4 and CYP2C8 pathways. Concurrent use with strong inhibitors (e.g., clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin) of these metabolic pathways is not recommended. Dabrafenib is converted to numerous metabolites, several of which are likely to contribute to its clinical activity.

Fecal excretion is the major route of elimination of dabrafenib and accounts for approximately 70% of a dose of the drug, whereas urinary excretion accounts for almost 25% of a dose (as metabolites). Dabrafenib has not been formally studied in patients with hepatic or renal impairment. However, based on available data, no significant effect on systemic exposure occurs in patients with mild or moderate renal impairment or mild hepatic impairment.

Dabrafenib induces CYP3A4 and possibly other metabolic pathways. It has been reported to reduce the maximum concentration and bioavailability of midazolam, a substrate of CYP3A4. It also may reduce the concentration and efficacy of other medications such as warfarin, dexamethasone, and hormonal contraceptives. If other therapeutic options with a lesser potential for interaction are not available, concurrent use should be monitored closely.

The presence of the BRAF V600E mutation in tumor specimens must be confirmed before treatment with dabrafenib is initiated. Doses of the drug should be administered at least 1 hour before or at least 2 hours after a meal. The recommended dosage is 150 mg twice a day, approximately 12 hours apart, until disease progression or unacceptable toxicity occurs. A missed dose can be taken up to 6 hours before the next dose. The product labeling should be consulted for the recommended dosage modifications necessitated by the occurrence of adverse events.

Dabrafenib mesylate is supplied in capsules in amounts equivalent to 50 and 75 mg dabrafenib. The capsules should not be opened, crushed, or broken.

Trametinib Dimethyl Sulfoxide

MEKs are upstream regulators of the extracellular signal–related kinase pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2. Trametinib dimethyl sulfoxide (Mekinist— GlaxoSmithKline) is a kinase inhibitor that inhibits MEK1 and MEK2 activation and MEK1 and MEK2 kinase activity and is the first drug with this mechanism of action. It is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

The effectiveness of the new drug was demonstrated in a study in which patients received either trametinib or chemotherapy (dacarbazine or paclitaxel). Patients were not permitted to have more than one previous chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure of the study was progression-free survival. Patients treated with trametinib had a delay in tumor growth that was 3.3 months later than those receiving dacarbazine or paclitaxel (4.8 vs. 1.5 months). The objective response rate, almost all of which were partial responses, was 22% in patients treated with trametinib and 8% in those receiving dacarbazine or paclitaxel. Trametinib may be of greatest benefit in patients with the BRAF V600K mutation and in patients who would be at high risk for serious adverse events that have been associated with the BRAF inhibitors.

The activity of trametinib was also evaluated in a study in 40 patients who had received prior treatment with a BRAF inhibitor. However, no patient in the study achieved a partial or complete response. Accordingly, trametinib is not indicated for treating patients who received BRAF inhibitor therapy previously.

Trametinib has been initially approved for use as a single agent. However, investigational studies of its use in combination with dabrafenib have demonstrated significantly greater response rates, progression- free survival, and duration of response compared with dabrafenib monotherapy. It is anticipated that the use of the two drugs in combination will soon be approved and that the appropriate use, safety, and dosage recommendations will be provided. In the meantime, however, the two drugs are being used together on an "off-label" basis.

In the primary clinical trial of trametinib, 87% of the patients treated with the new drug experienced skin toxicity, including rash, dermatitis, acneiform rash, palmar–plantar erythrodysesthesia syndrome, and erythema. Severe skin toxicity occurred in 12% of patients, and some patients required hospitalization, most often for managing secondary infections.

Cardiomyopathy (e.g., cardiac failure, left ventricular dysfunction, decreased left ventricular ejection fraction [LVEF]) occurred in 7% of the patients. LVEF should be assessed before treatment, 1 month following initiation of treatment, and at 2- to 3-month intervals during treatment.

Other commonly experienced adverse events with the use of trametinib included diarrhea (43%), stomatitis (15%), lymphedema (32%), hypertension (15%), and hemorrhage (13%). Interstitial lung disease or pneumonitis occurred in 2% of patients, and patients should be advised to contact their physician if they experience symptoms such as dyspnea or cough. Retinal vein occlusion and retinal pigment epithelial detachment were reported infrequently, and ophthalmological evaluations should be performed in patients who report visual disturbances.

Trametinib may cause harm to the fetus if it is administered during pregnancy, and it is classified in Pregnancy Category D. Women of childbearing potential should use contraception during treatment and for 4 months following discontinuation of treatment. The new drug also may impair fertility in female patients. Whether trametinib is excreted in human milk is not known, and a decision should be made to discontinue nursing or not use the drug. The effectiveness and safety of the drug in pediatric patients have not been established.

Following oral administration, the absolute bioavailability of trametinib is 72%. Its bioavailability is decreased when it is administered with a high-fat meal, and it should be administered at least 1 hour before or at least 2 hours after a meal. It is metabolized predominantly via deacetylation, but the parent compound represents more than 50% of a dose of the circulating drug. Approximately 80% of a dose is recovered in the feces and 20% in the urine. No significant effect on systemic exposure of trametinib in patients with mild or moderate renal impairment or mild hepatic impairment has been reported.

The presence of the BRAF V600E or V600K mutation in tumor specimens must be confirmed before treatment with trametinib is initiated. The recommended dosage is 2 mg once a day at least 1 hour before or 2 hours after a meal, until disease progression or unacceptable toxicity occurs. A missed dose can be taken up to 12 hours before the next dose. The product labeling should be consulted for the recommended dosage modifications necessitated by the occurrence of adverse events.

Trametinib dimethyl sulfoxide is supplied in film-coated tablets in quantities equivalent to 0.5, 1, and 2 mg trametinib. The tablets should be stored in a refrigerator and protected from moisture and light. The drug should be dispensed in the original bottle and should not be placed in medication organizers or other containers. The packet of desiccant should not be removed from the container.