Combo BRAF and MEK Inhibitors Improve Survival in Melanoma

Roxanne Nelson

September 29, 2012

September 29, 2012 (Vienna, Austria) — Combination therapy with a BRAF inhibitor and an MEK inhibitor is more effective than monotherapy in metastatic melanoma.

Combining 2 investigational agents — BRAF inhibitor dabrafenib (GlaxoSmithKline) and MEK inhibitor trametinib (GlaxoSmithKline) — prolonged progression-free survival in patients with V600 BRAF mutation–positive metastatic melanoma, as compared with dabrafenib monotherapy.

Dr. Georgina Long

Of note, the combination therapy decreased the rate of cutaneous toxicities compared with dabrafenib monotherapy, explained Georgina Long, MD, professor of medicine at the University of Sydney, Australia. This was particularly true for the oncogenic cutaneous toxicity of squamous cell carcinoma.

Dr. Long presented the findings here at the 2012 Congress of the European Society of Medical Oncology.

Results were simultaneously published online September 28 in New England Journal of Medicine. Initial results were also presented earlier this year at the 2012 annual meeting of the American Society of Clinical Oncology, as reported by Medscape Medical News at that time.

"This is the first kinase/kinase combination showing activity over a single agent," she said. "It also showed reduced specific oncogenic toxicities with a biologic rationale. The combined treatment of dabrafenib with trametinib prolonged progression-free survival and response rate over dabrafenib monotherapy, and the combined treatment safety profile was tolerable and manageable."

Patients who received the full dose of trametinib (2 mg daily) plus 150 mg of dabrafenib had progression-free survival of 9.4 months, compared with 5.8 months for those on dabrafenib monotherapy (hazard ratio [HR], 0.39; P < .0001). The percentage of patients who were alive and progression-free at 1 year was also substantially higher (41% vs 9%; P < .001), noted Dr. Long.

The response rate for complete or partial response was 76% for the combination group vs 54% for those on single therapy (P = .03). The duration of response was also longer in the combination group — 10.5 months vs 5.6 months.

Median overall survival has not been reached for any cohort in this study, but the 12-month overall survival rate was 79% for the full-dose combination group compared with 70% for the single-therapy arm (80% of patients crossed over to the full-dose combination).

Resistance Common, New Therapies Needed

Inhibition of the mitogen-activated protein kinase (MAPK) pathway has proved to be a major advance in treating metastatic melanoma. Agents that block MAPK signaling in patients with melanoma with the BRAF V600E mutation have been associated with prolonging both survival and progression-free survival in randomized phase 3 trials, note the authors.

However, about half of those treated with BRAF or MEK inhibitors experience disease progression within 6 to 7 months after beginning treatment. Therefore, new therapeutic strategies are needed to address the resistance mechanisms that almost inevitably develop. In preclinical models, rapid recovery of MAPK pathway signaling has been associated with BRAF inhibitor resistance, the authors write. The MAPK pathway must be completely inhibited to induce cell death in BRAF V600 melanoma, and this can be accomplished by combining BRAF and MEK inhibitors.

Study Details

The safety and efficacy of dabrafenib and trametinib were evaluated in a 4-part phase 1-2 study, and safety and efficacy data from part C, a phase 2 randomized trial, were presented by Dr. Long.

In part C, 162 patients with metastatic melanoma and BRAF V600 mutations were randomly assigned in a 1:1:1 ratio to receive 150 mg of dabrafenib twice daily plus once-daily trametinib at a dose of either 1 mg (combination 150/1) or 2 mg (combination 150/2), or 150 mg of dabrafenib monotherapy twice daily. Those with progressive disease in the monotherapy group were allowed to cross over to receive combination 150/2.

Combining dabrafenib with trametinib provided a statistically significant and clinically meaningful improvement in progression-free survival, response rate, and duration of response as compared with patients in the monotherapy arm, concluded Dr. Long. "Every subgroup benefited from full-dose combination therapy."

"Toxicities were equally distributed among the 3 treatment arms, except for pyrexia, which occurred in over 60% of patients in the combination arms [and] was defined as a fever with a temperature of 38.5 degrees Celsius or more," said Dr. Long. "And it occurred in 23% of the darafenib monotherapy arm."

Nausea and vomiting were increased, but alopecia was decreased, in the combination arms. Other adverse events more commonly observed in the combination 150/2 group included fatigue (in 53% of patients), nausea (44%), vomiting (40%), and diarrhea (36%). However, these symptoms were rarely grade 3 or 4. The most frequently occurring grade 3 or 4 toxic effect in the combination 150/2 group was neutropenia (in 11% of patients), with 1 case of febrile neutropenia.

"Hyperproliferative skin toxicities were markedly lower in the 2 combination arms," said Dr. Long. The rate of cutaneous squamous cell carcinoma was 7% in the 150/2 group vs 19% in the monotherapy group, with lower rates of skin papilloma (4% vs 15%) and hyperkeratosis (9% vs 30%).

Paying Attention to Side Effects

In discussing the article, Reinhard Dummer, MD, PhD, noted that the reduction of cutaneous toxicities was a very important step. "We want to cure the patient, so we have to start paying attention to the side effects," said Dr. Dummer, who is a professor of dermatology at the University Hospital of Zürich, Switzerland.

Therapy with BRAF inhibitors has been observed to accelerate the development of secondary skin cancers in some patients, he noted. "We have observed keratoacanthomas, which are regarded as low-risk carcinomas of the skin, and we have observed new melanomas."

"We have to be concerned about the introduction of new tumors on the skin and also in other organs," Dr. Dummer said, noting that reports have described carcinomas in other locations.

"This is a critical issue and must be addressed," he added.

The study was funded by GlaxoSmithKline. Several of the authors have reported relevant financial relationships with industry, as noted in the paper.

Published September 29, 2012 at NEJM.org

European Society of Medical Oncology 2012 Congress. Presented September 29, 2012: Abstract 27LBA.

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