FDA Approves Trametinib and Dabrafenib for Unresectable or Metastatic BRAF-Mutated Melanoma
Information about drugs approval and clinical trials that led to the approval, as well as approval of the assay for BRAF mutations detection
On May 29, 2013, the U.S. Food and Drug Administration (FDA) approved trametinib (MEKINIST tablet, GlaxoSmithKline, LLC), for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation as detected by an FDA-approved test. Concurrent with this approval, FDA approved the THxID BRAF assay (bioMerieux, Inc.) for detection of BRAF V600E and V600K mutations. Trametinib is not indicated for treatment of patients who have received prior BRAF inhibitor therapy.
Trametinib’s approval was based on the demonstration of an improved progression-free survival (PFS) in a multi-center, international, open-label, randomized (2:1) active-controlled trial enrolling 322 patients with histologically confirmed stage IIIc or IV melanoma determined to be BRAF V600E or V600K mutation-positive based upon centralized testing. No more than one prior chemotherapy regimen was permitted. Patients with prior exposure to BRAF inhibitors or MEK inhibitors were ineligible.
Patients were randomized to receive either trametinib 2 mg orally once daily (n=214) or chemotherapy consisting of either dacarbazine or paclitaxel administered intravenously every three weeks (n=108). At the time of disease progression, 51 patients (47%) randomized to chemotherapy received trametinib.
Of 322 patients enrolled, 54% were male, the median age was 54 years, all had baseline ECOG performance status of 0 or 1, and 64% had M1c disease. All patients had tumour tissue with mutations in BRAF V600E (87%), V600K (12%), or both (<1%) on centralized testing.
A statistically significant prolongation of investigator-assessed PFS was demonstrated for patients randomized to the trametinib arm compared to those receiving chemotherapy [HR 0.47 (95% CI: 0.34, 0.65); p<0.0001, log-rank test]. The median PFS was 4.8 and 1.5 months in the trametinib and chemotherapy arms, respectively. The PFS analysis assessed by blinded independent central review was consistent with the investigator results.
The investigator-assessed, objective response rates were 22% (95% CI: 17, 28) for the trametinib arm and 8% (95% CI: 4, 15) for the chemotherapy arm. The analysis of overall survival was not mature.
There was no evidence of anti-tumour activity with trametinib in patients who had received prior BRAF inhibitor therapy. This was evaluated in a single-arm, multicenter, international trial enrolling 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma, all of whom had received prior treatment with a BRAF inhibitor. None of these 40 patients achieved a confirmed partial or complete response, as determined by the clinical investigators.
The most frequent (≥20% incidence) adverse reactions from trametinib were rash, diarrhea and lymphedema.
Serious adverse drug reactions occurring in patients taking trametinib included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease and serious skin toxicity.
The recommended dose and schedule for trametinib is 2 mg orally once daily continued until disease progression or unacceptable toxicity. Trametinib should be taken at least one hour before or two hours after a meal.
On May 29, 2013, the U.S. FDA approved dabrafenib (TAFINLAR capsule, GlaxoSmithKline, LLC), for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma because of the potential risk of tumour promotion. Concurrent with this action, FDA approved the THxID BRAF assay (bioMerieux, Inc.) for detection of BRAF V600E mutations.
The approval of dabrafenib was based on demonstration of improved PFS in a multi-center, international, open-label, randomized (3:1), active-controlled trial. This trial enrolled 250 patients with previously untreated, histologically confirmed, unresectable stage III or stage IV melanoma determined to be BRAF V600E mutation-positive based upon centralized testing. Patients were randomized to receive either dabrafenib 150 mg orally twice daily (n=187) or dacarbazine 1000 mg/m2 intravenously once every 3 weeks (n=63). At the time of disease progression, 28 patients randomized to dacarbazine received dabrafenib.
Of 250 patients enrolled, 60% were male; the median age was 52 years, 67% had an ECOG performance status of 0, and 66% had M1c disease.
A statistically significant prolongation of investigator-assessed PFS was demonstrated for patients randomized to the dabrafenib arm [HR 0.33 (95% CI: 0.20, 0.54); p<0.0001, stratified log-rank test]. The median PFS times were 5.1 and 2.7 months in the dabrafenib and dacarbazine arms, respectively. The PFS analysis based on blinded independent central review was consistent with the investigator results.
The investigator-assessed objective response rates were 52% (95% CI: 45, 59) for the dabrafenib arm, which included a 3% complete response rate, and 17% (95% CI: 9, 29) for the dacarbazine arm. The median duration of response was approximately 5 months in both treatment arms. No statistically significant difference in overall survival between the two arms was demonstrated.
The most frequent (≥20% incidence) adverse reactions from dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome.
Serious adverse reactions were development of new primary skin cancers (cutaneous squamous cell carcinoma, new primary melanomas, and keratoacanthomas), febrile drug reactions requiring hospitalization, hyperglycemia, and uveitis/iritis. Dabrafenib is approved with a Medication Guide to inform patients of these serious potential risks.
The recommended dose and schedule for dabrafenib is 150 mg orally twice daily until disease progression or unacceptable toxicity. Dabrafenib should be taken at least one hour before or two hours after a meal. Confirmation of the presence of BRAF V600E is needed prior to initiation of dabrafenib because of the risks of potential risk of tumour promotion in patients with BRAF wild-type melanoma.
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