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ECC 2015: Combination of Dabrafenib and Trametinib Superior to Vemurafenib Alone in Advanced Melanoma: Results of the COMBI-v Trial

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Key Points

  • Of the patients who received the combination treatment, 51% are alive after 2 years, compared with 38% of patients who received vemurafenib alone.
  • Median overall survival among patients with metastatic melanoma harboring V600 mutations in the BRAF gene who received the combination treatment was 25.6 months. Among patients who received vemurafenib alone, it was 18 months.
  • The European Commission approved the combination of dabrafenib and trametinib for use in Europe for these patients on September 1, 2015.

The latest results from a trial of a combination of two targeted therapies (dabrafenib [Tafinlar] and trametinib [Mekinist]) to treat advanced melanoma have shown that patients are living significantly longer on the combined therapy than patients treated with vemurafenib (Zelboraf) alone. Caroline Robert, MD, PhD, of the Institut Gustave Roussy, presented these results at the 2015 European Cancer Congress in Vienna, Austria (Abstracts 3301, 3345).

Survival Improvement

Dr. Robert reported that not only is the median overall survival longer for patients receiving the combination treatment but also that 51% of patients receiving the combination treatment are alive after 2 years, compared with 38% of patients receiving vemurafenib alone.

Analysis of data up to March 13, 2015, showed that the median overall survival among patients with metastatic melanoma harboring V600 mutations in the BRAF gene who received the combination treatment was 25.6 months. Among patients receiving vemurafenib alone, it was 18 months. On the basis of this finding, the European Commission approved the combination of dabrafenib and trametinib for use in Europe for these patients on September 1, 2015.

“We observed a statistically significant reduction of 34% in the risk of death among patients receiving the combination therapy,” Dr. Robert said. “The increased survival among these patients is remarkable, and this median overall survival of more than 2 years is the longest in this category of patients in a phase III randomized trial.”

Results From COMBI-v Trial

These new results come from an analysis of all data from the COMBI-v phase III trial, which randomized previously untreated patients with the V600E or V600K mutations of the BRAF gene to receive either 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily or 960 mg of vemurafenib alone twice daily.

By March 2015, approximately 50% (349 of 704) of patients had died, and the researchers had followed the patients for approximately 18 months.

“Since our last report from this trial we have an additional 11 months of follow-up and 127 more deaths. This provides data that are mature enough to demonstrate definitively the effect on overall survival and the benefit to patients,” said Dr. Robert.

The updated analysis also reported that patients receiving the combination treatment survived significantly longer without their disease progressing than patients receiving vemurafenib alone: 12.6 and 7.3 months, respectively. “The 12.6 months of progression-free survival for patients on the combination treatment is the longest achieved in a randomized study for patients with the BRAF V600 mutation to date,” said Dr. Robert.

Rates of severe side effects remain similar in both groups of patients, with no unexpected effects noted during the longer follow-up. Results from an associated study of the patients’ health-related quality of life showed significant and clinically meaningful improvements among those receiving the combination treatment, compared with those receiving vemurafenib alone. Overall health; physical and social functioning; and specific symptoms such as pain, insomnia, loss of appetite, diarrhea, and fatigue were all improved.

The international trial started in 2012, and patients recruited to it have unresectable and/or metastatic melanoma. Between 40% and 60% of patients with melanoma have mutations in the BRAF gene that are driving the cancer, and the majority of these patients have the V600E or V600K type of BRAF mutation.

Dabrafenib, vemurafenib, and trametinib are targeted therapies that block proteins playing key roles in the cell-signaling pathways that are often overactive in cancer; dabrafenib and vemurafenib block the BRAF protein, and trametinib blocks the MEK proteins. Because anti-BRAF treatment alone is associated with more than 50% of patients relapsing after 6 to 8 months, researchers wanted to see whether a combination of the BRAF and MEK inhibitors would produce better outcomes for patients. These latest results from the COMBI-v trial confirm this hypothesis.

Although the study was stopped in July 2014 when it became clear that the combination therapy was superior to vemurafenib alone, patients have the option to continue with their treatment, and the researchers are continuing to collect follow-up data.

“This combination therapy is already available in the United States, and now also in Europe, as a result of the European Commission’s decision to approve its use. This long-term benefit in terms of overall survival confirms the major potential of this combination in patients with metastatic melanoma. A further question to investigate is the combination treatment versus new immunotherapies or combined with them,” concluded Dr. Robert.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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