Nick Mulcahy

June 04, 2012

June 4, 2012 (Chicago, Illinois) — For the first time, a new approach to targeted therapy for BRAF-mutated melanoma, known as MEK inhibition, has been shown to slow disease progression and extend overall survival in patients with metastatic disease, according to the results of a new study.

However, just how the studied therapy, trametinib (GlaxoSmithKline), and other experimental MEK inhibitors will fit into the treatment of metastatic melanoma remains to be seen, according to a number of experts.

Part of the complexity is that both MEK inhibitors and BRAF inhibitors, which include the approved vemurafenib (Zelboraf, Roche), are designed for melanoma patients with BRAF mutations. In at least one other study, the 2 types of inhibitors are being used in combination.

"Trametinib provides an alternative treatment option for patients with BRAF metastatic melanoma," said Caroline Robert, MD, PhD, head of dermatology at the Institut Gustave Roussy in Paris, France, who is lead coauthor of the phase 3 METRIC (MEK vs DTIC or Taxol in Metastatic Melanoma) trial.

She discussed the study at a press conference here at the 2012 Annual Meeting of the American Society of Clinical Oncology.

Dr. Robert celebrated the fact that the treatment options in metastatic melanoma continue to grow.

Trametinib, an oral investigational drug, is an experimental agent that inhibits the protein MEK, which ispart of the MAP kinase signaling pathway, of which BRAF is a component.

All 322 patients in the METRIC study had melanoma with a V600E or V600K BRAF mutation.

Median progression-free survival was 4.8 months in the trametinib group (n = 214) and 1.5 months in the chemotherapy group (n = 108), which consisted of dacarbazine or paclitaxel (P < .001). The difference translated into a 55% reduction in the risk for progression, said Dr. Robert. The median follow-up was 4.9 months.

In terms of overall survival, 81% of patients in the trametinib group were alive after 6 months of follow-up, compared with 67% in the chemotherapy group (P = .01).

"The difference in survival was apparent at this early time point despite the humane and highly laudable trial design that allowed crossover," writes Edward Sausville, MD, PhD, in an editorial published online June 4 in the New England Journal of Medicine. He is from Greenebaum Cancer Center at the University of Maryland in Baltimore. The editorial accompanies the online publication of the study results.

Ultimately, 68% of patients in the chemotherapy group crossed over to trametinib, which might have tamped down the survival benefit seen with the new treatment, Dr. Sausville writes.

The treatment groups were generally well balanced. However, there was a higher percentage of stage IV patients in the trametinib group than in the chemotherapy group (67% vs 58%).

Notably, trametinib was effective without the troubling adverse event of secondary cutaneous neoplasms, which are associated with vemurafenib and other BRAF inhibitors.

On the downside, only 22% of patients treated with trametinib had either a complete or partial response, Dr. Sausville points out.

However, Dr. Robert accented the positive. "The findings show that targeting the MEKmolecular pathway is a viable strategy for treating many people with the disease," she said in a press statement. "Trametinib is likely to become another first-line treatment option for patients with advanced melanoma."

Given the fact that there is more than one MEK inhibitor in development, Dr. Sausville wonders in his editorial "what is so special about trametinib."

He explains that preclinical studies have indicated that trametinib has "very desirable mechanistic and pharmacologic attributes."

Dr. Sausville also explains the connection between BRAF-mutated melanomas and MEK inhibition. "BRAF-mutated melanomas should be particularly dependent on active MEK since active BRAF requires MEK function to amplify its signal," he writes.

A New Era Begins

The simultaneous development of multiple MEK inhibitors, BRAF inhibitors, and other therapies for melanoma signifies the "beginning of a new era," said Axel Hauschild, MD, from the University Hospital in Kiel, Germany. He is an investigator of the new BRAF inhibitor dabrafenib (GlaxoSmithKline).

At the press conference, he told reporters that algorithms will be needed to keep up with the targeted and immune-based therapy options for metastatic melanoma. Currently, the approved treatment options are ipilimumab (Yervoy, Bristol-Myers Squibb) for wild-type BRAF patients and vemurafenib for patients with BRAF-mutated tumors, according to Dr. Hauschild. In other words, trametinib and other experimental agents do not yet have a place, he said.

The METRIC authors, led by both Dr. Robert and Keith Flaherty, MD, from the Massachusetts General Hospital Cancer Center in Boston, suggest that trametinib has a way to go to find its niche. "Further work will be needed to determine the optimal role for trametinib in the treatment of metastatic melanoma," they write.

Toxicity Manageable

Overall, the adverse effects of trametinib were manageable, the authors report.

The most commonly reported serious events were hypertension (12%), skin rash (7%), fatigue (4%), and pruritus (2%). Other adverse events of note, despite being less serious, were ejection fraction decrease/ventricular dysfunction (7%) and chorioretinopathy.

Severe adverse events (grade 3/4) occurred in less than 1% of all patients (both groups) in the study. Patients in the trametinib group received the oral agent once a day (2 mg). Patients in the chemotherapy group received either dacarbazine (1000 mg/m² body-surface area) or paclitaxel (175 mg/m² per body-surface area).

The study was funded by GlaxoSmithKline. Dr. Robert reports financial ties with GlaxoSmithKline, Bristol-Meyers Squibb, and Roche Diagnostics. Dr. Flaherty reports financial ties with GlaxoSmithKline. Dr. Hauschild reports financial ties with GlaxoSmithKline.

N Engl J Med. Published online June 4, 2012. Abstract

2012 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA8509. To be presented June 4, 2012.

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