Dabrafenib Improves PFS in Metastatic Melanoma Trial


In a phase III trial, the oral BRAF inhibitor dabrafenib, improved progression-free survival in previously untreated metastatic melanoma patients.

In a phase III trial, the oral BRAF inhibitor dabrafenib improved progression-free survival in previously untreated metastatic melanoma patients. The results of the trial, called BREAK-3, are published this week in the journal Lancet.

Patients who were given dabrafenib fared better than patients given the standard of care chemotherapy, dacarbazine. Median progression-free survival was 5.1 months for the dabrafenib arm compared to 2.7 months for the dacarbazine arm (hazard ratio = 0.3, P < .0001).

Approximately 50% of melanoma patients harbor the V600 BRAF mutation, resulting in a constitutively active BRAF protein, a driver of tumorogenesis in these patients. In the United States, an estimated 76,250 men and women will be diagnosed with melanoma, and approximately 9,180 will die of the disease. While most early-stage melanomas are cured with excision and do not progress, metastatic melanoma has been considered one of the deadliest cancers with few treatment options other than chemotherapy.

The last 2 years saw a change in the melanoma treatment paradigm with two new approved treatments. Vemurafenib (Zelboraf), another BRAF inhibitor, was approved in August of 2011 for metastatic melanoma patients whose tumors harbor the V600 mutation in the BRAF gene, based on measured improvement in overall survival. The immunotherapy ipilimumab (Yervoy) was approved just 5 months earlier than vemurafenib, for both treatment-naive and previously treated patients. If dabrafenib is approved by the US Food and Drug Administration (FDA), it will be the second BRAF inhibitor available, providing even more treatment options for patients.

Axel Hauschild, MD of the department of dermatology, Schleswig-Holstein University Hospital in Kiel, Germany had originally presented the BREAK-3 data at the annual meeting of the American Society of Clinical Oncology (ASCO) held earlier this month. “This trial is good news for our patients with metastatic melanoma. Competition in the field is appreciated since it accelerates new clinical trials, particularly in the combinational setting. This trial is a major step forward in the run for an improvement of the survival for this disease, which was thought to be untreatable for decades,” Hauschild said in a statement.

Trial Design and Results

The BREAK-3 trial randomized 250 patients in a 3:1 ratio to receive either dabrafenib or dacarbazine chemotherapy. At the time of data cut off, 57% of patients on dabrafenib and 22% of patients in the chemotherapy arm continue to be treated. In the dabrafenib arm, a partial response was seen in 47% of the patients and 3% of the patients had a complete response.  In the dacarbazine arm, a complete response was seen in 6% of patients. Overall survival results are not likely to be conclusive from this trial due to the crossover design.

Treatment-related toxicities included skin-related toxicities, fever, fatigue, headache, and arthralgia. Grade 3/4 toxicities were not frequent according to the publication.

Results with dabrafenib appear to be similar to the vemurafenib trial results, in terms of efficacy. According to the researchers, there are slight differences in skin toxicities, with dabrafenib-treated patients having fewer skin photosensitivity effects but higher incidence of fever compared to vemurafenib-treated patients.

In a commentary of the study publication, Kim Margolin, MD, of the University of Washington highlighted that future trials “should avoid the use of essentially inactive comparators such as cytotoxic drugs.” Margolin also noted that both dabrafenib and vemurafenib cross the blood–brain barrier and are active in treating those metastatic melanoma patients that have progressed to the brain.

The results of the BREAK-3 trial join “the rapidly growing list of classic articles in this exciting discipline, where the rewards from scientific discovery are increasing benefits for patients with melanoma,” concluded Margolin.

Dabrafenib is already being tested in a combination therapy with the MEK inhibitor trametinib. In early phase trials, treatment-naive patients treated with the combination had fewer skin toxicities and better rates of response. Phase III trials of this BRAF plus MEK inhibitor combination in metastatic melanoma patients have recently started.


1. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 June 25. [Epub ahead of print]

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