BRAF Inhibitor Plus MEK Inhibitor Encouraging in Metastatic Melanoma

Georgina V. Long, BSc, PhD, MBBS

Combining the new drugs dabrafenib and trametinib provided a clinically meaningful improvement in patients with melanoma that had BRAF V600 mutations, according to results of a phase II study presented on Saturday at the 2012 ESMO Congress in Vienna, Austria.

Full-dose combination of a novel BRAF inhibitor (dabrafenib) and a novel MEK 1/2 inhibitor (trametinib) improved progression-free survival (PFS), response rate, and duration of response, said lead investigator Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney. In addition, the combination reduced the side effects associated with BRAF inhibitor monotherapy, which is highly unusual.

Both drugs act on the RAS kinase pathway, dabrafenib at an earlier point than trametinib. About 50% of patients with metastatic melanoma have a BRAF mutation. “Dabrafenib attacks that abnormality and works for about 5 to 7 months, and patients develop resistance to the drug. The rationale for adding a MEK 1/2 inhibitor is that it blocks the ‘escape route’ for the BRAF inhibitor and allows continued response,” Long explained.

The study randomized 162 patients with BRAF V600^E/K —positive metastatic melanoma to one of three treatment arms: monotherapy with dabrafenib 150 mg/bid; combination of dabrafenib 150 mg/bid with once-daily trametinib 1 mg; or full doses of both drugs (ie, dabrafenib 150 mg/bid; once-daily trametinib 2 mg).

Median time to follow-up was 14 months. Median PFS was 9.2 months for the full dose combination versus 5.8 months for the monotherapy arm (P <.0001), representing a 61% reduction in risk of disease progression. Median PFS was 9.2 months for the arm using half-dose trametinib, which was also significantly better than monotherapy (P = .005). At 12 months, 41% of the patients who received full-doses of both drugs had not progressed versus 9% of the monotherapy arm.

Analysis showed PFS benefit from full doses of both drugs for every category: age, sex, baseline disease stage, baseline LDH, or presence of brain metastasis

Looking at patients with the most common BRAF mutation, V600^E, PFS was 6.5 months with monotherapy, 7.3 months for the combination with half-dose trametinib, and 10 months for the full-dose combination (P=.0004, vs monotherapy).

Median overall survival (OS) had not been reached in any of the three arms at the time of the data were presented at ESMO. Twelve-month OS was 70% in the monotherapy arm, 68% in the combined therapy arm with half-dose trametinib, and 78% in the full-dose combination arm.

“This has never been seen before in metastatic melanoma,” Long noted.

Confirmed response rates were 54% for monotherapy, 50% for the combination of dabrafenib with half-dose trametinib, and 76% for the full-dose combination.

Median duration of response was 5.6 months for monotherapy, 9.5 months for the combination of full-dose dabrafenib and half-dose trametinib, and 10.5 months for the full dose combination of both drugs.

“Using one road block [ie, dabrafenib] and then adding an exit block [ie, trametinib] improves response and duration of response,” said Long.

Hyperproliferative skin toxicities (ie, alopecia hyperkeratosis, skin papilloma, and squamous cell carcinoma) associated with BRAF inhibition were reduced in both combination arms. Squamous cell carcinoma occurred in 10 patients on monotherapy, one patient in the combination arm that included half-dose trametinib, and four patients in the full-dose combination arm.

“This has never been seen before in the history of chemotherapy,” Long noted.

Pyrexia and nausea and vomiting were increased in the combination arm. The rate of pyrexia was 67% in the full-dose combination arm and 23% in the monotherapy arm. Long said that during the evolution of the study, it became clear that prophylaxis with corticosteroids was effective in preventing pyrexia, and going forward, that will be the practice. The median time to first episode of pyrexia was less than 6 weeks and only three patients in the full-dose combination arm developed grade 3 pyrexia. “The majority of patients develop only 1 episode of pyrexia,” explained Long.

The incidence of vomiting in the full-dose arm was 35%, but these were grades 1 and 2 and easily managed, said Long.

The distribution of other adverse events was similar in the three treatment arms.

Two phase III trials of this combination are now ongoing in metastatic melanoma: One comparing the full-dose combination versus dabrafenib alone and the other comparing the full-dose combination to trametinib alone.

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