Unlike FDA, Europe Does Not Like Melanoma Combo Yet

Nick Mulcahy

March 27, 2014

Three months after the US Food and Drug Administration (FDA) approved the first-ever combination therapy for advanced melanoma, its European counterpart has found the same data on the paired therapy to be unsatisfactory.

In January, the combination of the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline) and the BRAF inhibitor dabrafenib (Tafinlar, GlaxoSmithKline) was approved through the FDA Accelerated Approval Program.

However, this week, the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) indicated that the data provided to date by GSK did not allow the committee to conclude on a "positive benefit–risk balance of the combination," according to a company press statement.

GSK intends to resubmit the Marketing Authorization Application for the combined use of 2 therapies when additional data from ongoing phase 3 clinical trials become available.

The specific indication sought is for trametinib in combination with the previously approved dabrafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation.

Story on FDA Approval

In the United States, the combination was approved on the basis of the response rate and median duration of response seen in a phase 1/2 study. The combination has not yet demonstrated an improvement in disease-related symptoms or overall survival.

In a randomized phase 2 open-label study, patients treated with the combination had an overall response rate (ORR) of 76%, compared with 54% for patients treated with single-agent dabrafenib.

In addition, the median duration of response was longer with the combination than with single-agent dabrafenib (10.5 vs 5.6 months).

These were the findings reported by the investigators.

However, a blinded independent radiologic review committee (IRRC) assessed the same results somewhat differently, as previously reported by Medscape Medical News.

The IRRC-assessed ORR was 57% for patients treated with the combination and 46% for patients treated with single-agent dabrafenib. The IRRC-assessed median duration of response was 7.6 months for both the combination and the single agent.

Increase in Basal Cell Carcinoma an Adverse Effect

In the phase 2 study, the most common adverse effects (all grades in more than 20% of patients) at the recommended dose — trametinib 2 mg once daily plus dabrafenib 150 mg twice daily — were pyrexia (71%), chills (58%), fatigue (53%), rash (45%), nausea (44%), vomiting (40%), diarrhea (36%), abdominal pain (33%), edema peripheral (31%), cough (29%), headache (29%), arthralgia (27%), night sweats (24%), decreased appetite (22%), constipation (22%), and myalgia (22%).

Trametinib in combination with dabrafenib can cause serious adverse effects, including new primary cutaneous and noncutaneous malignancies.

The combination comes with a warning that the therapy is associated with an increased incidence of basal cell carcinoma. The incidence was 9% (5 of 55) in patients receiving the combination, compared with 2% (1 of 53) in patients receiving dabrafenib alone.

Dabrafenib also resulted in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma. Cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 7% of patients receiving the combination and 19% of patients receiving single-agent dabrafenib.

However, the secondary cutaneous squamous cell carcinomas and keratoacanthomas are relatively benign, compared with melanoma, and are no reason to discontinue BRAF inhibition, according to melanoma experts.

Other serious adverse effects seen in patients treated with the combination include hemorrhagic events, venous thromboembolic events, cardiomyopathy, ocular toxicities, interstitial lung disease, serious febrile drug reactions, serious skin toxicity, hyperglycemia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency, and embryo-fetal toxicity.

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