GlaxoSmithKline has received FDA approval for dabrafenib (Tafinlar) and trametinib (Mekinist), two single-agent oral drugs for patients with metastatic or unresectable melanoma. The drugs join vemurafenib (Zelboraf—Genentech) and ipilimumab (Yervoy—Bristol-Myers Squibb) as the third and fourth drugs FDA has approved for the treatment of advanced melanoma in the past 2 years.
Approximately one-half of melanomas have a BRAF gene mutation. FDA also approved a companion genetic diagnostic test, called the THxID BRAF test (bioMérieux S.A.), to determine if a patient’s melanoma cells have the V600E or V600K mutation in the BRAF gene. Approval of the THxID BRAF test was based on data from clinical studies that supported the dabrafenib and trametinib approvals. Currently, THxID BRAF test is the only FDA-approved test that detects the V600K mutation.
The safety and efficacy of dabrafenib were evaluated in two clinical trials. In trial 1, 250 previously untreated patients with BRAF V600E mutation–positive metastatic or unresectable melanoma were randomly assigned to receive dabrafenib 150 mg orally twice daily or the chemotherapy drug dacarbazine 1,000 mg/m2 I.V. every 3 weeks.
The median age of patients in trial 1 was 52 years, 60% were male, and 99% were white. The main efficacy outcome measure was progression-free survival (PFS). Patients treated with dabrafenib demonstrated a statistically significant increase in PFS, with a delay in tumor growth 2.4 months later than in patients receiving dacarbazine.
Two cohorts of 139 patients with BRAF V600E melanoma brain metastases were evaluated in trial 2. The median age of patients was 50 years, 72% were male, and 100% were white. All patients received dabrafenib 150 mg orally twice daily.
In this trial, patients in cohort A had received no prior local therapy for brain metastases, while patients in cohort B had received at least one local therapy for brain metastases. In addition, patients in cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. The primary outcome measure was estimation of the overall intracranial response rate in each cohort; both cohorts showed improvement.
The safety and efficacy of trametinib were evaluated in two clinical trials. The median age of all patients was 54 years, 60% were male, and more than 99% were white.
In trial 1, 322 patients with BRAF V600E or V600K mutation–positive unresectable or metastatic melanoma were randomly assigned to receive trametinib 2 mg orally once daily or chemotherapy consisting of either dacarbazine 1,000 mg/m2 I.V. every 3 weeks or paclitaxel 175 mg/m2 I.V. every 3 weeks. Patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor also was not permitted. The primary efficacy outcome measure in both trials was PFS.
Patients in trial 1 demonstrated a statistically significant increase in PFS, with a delay in tumor growth of 3.3 months more than patients on chemotherapy. In trial 2, clinical activity was evaluated in 40 patients with BRAF V600E or V600K mutation–positive unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. No patient in trial 2 achieved a confirmed partial or complete response as determined by the clinical investigators.
Both drugs will be available no later than the early third quarter of 2013, according to GlaxoSmithKline.
Drug class: Kinase inhibitor
Indication: Treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. The drug is not indicated for treatment of patients with wild-type BRAF melanoma.
Dosage: 150 mg orally twice daily (approximately 12 h apart), taken at least 1 hour before or at least 2 hours after a meal. A missed dose can be taken up to 6 hours prior to the next dose. Capsules should not be opened, crushed, or broken.
Of note: Dabrafenib can cause fetal harm and may impair fertility in male patients. Female patients should use highly effective contraception during treatment and for 4 weeks after treatment. In addition, they should use a nonhormonal method of contraception because the drug can render hormonal contraceptives ineffective. Advise patients to contact their health care provider if they become pregnant or suspect they are pregnant while taking the drug.
Drug class: Kinase inhibitor
Indication: Treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. Trametinib is not indicated for the treatment of patients who have received prior BRAF-inhibitor therapy.
Dosage: 2 mg orally once daily taken at least 1 hour before or at least 2 hours after a meal. A missed dose should not be taken within 12 hours of the next dose.
Of note: Trametinib can cause fetal harm and may impair fertility in female patients. Advise female patients to use highly effective contraception during treatment and for 4 months after treatment and to contact their health care provider if they become pregnant or suspect they are pregnant while taking the drug.
Refer patients to the Medication Guide. Caution patients about the risk of fetal harm and impaired fertility. Inform patients receiving dabrafenib that they have an increased risk of developing cutaneous squamous cell carcinoma, and notify patients receiving trametinib to be alert to symptoms of heart failure. Advise patients to report any signs or symptoms of these conditions to their health care provider immediately.