Dabrafenib confirms class effect of selective BRAF inhibitors
BRAF inhibitors to form the backbone of combination strategies in metastatic melanoma
- Date : 04 Sep 2012
- Topic : Melanoma
Dabrafenib is the second agent in the therapeutic class of selective BRAF inhibitors, and has shown efficacy in a BREAK-3, randomised phase III trial with improvements in progression-free survival and response rates. Differences in the safety profile exist compared with vemurafenib, but the future lies in combinatorial strategies and improved patient selection.
Inhibition of mutated BRAF in metastatic melanoma
The prevalence of BRAF mutations in metastatic melanoma discovered 10 years ago has already resulted in effective therapy. Selective BRAF inhibitors have dramatically shifted the landscape of melanoma therapy since the approval of vemurafenib for the treatment of patients with BRAF V600-mutated tumours.
In their article published online 14 August in the Nature Reviews Clinical Oncology, Drs Hussein Tawbi and John Kirkwood of the Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute and Division of Haematology/Oncology discuss several aspects of the BREAK-3 study that warrant attention in the context of the studies assessing vemurafenib.
The BREAK-3 study, recently reported in Lancet, present results from an international, open-label, multicentre, randomised, controlled phase III trial of dabrafenib in patients with BRAF V600E-mutated metastatic melanoma. A total of 733 patients were screened for the mutation and 250 patients were randomly assigned in a 3:1 ratio to dabrafenib or dacarbazine. The primary end point was investigator-assessed progression-free survival and the study reached its primary end point (p < 0.0001).
The efficacy of dabrafenib in terms of response rates and progression-free survival are similar to those of vemurafenib discussed Drs Tawbi and Kirkwood. They wrote that a choice of progression-free survival as a primary end point in this specific population was reasonable when considering the comparator was dacarbazine. The study design allowed patients to cross over at progression, and although the 3:1 randomisation is not the most efficient in terms of statistical design, it was appropriate. The study was designed with an expected hazard ratio of 0.33, and the fact that the expected effect size was so large, has facilitated the study and allowed robust conclusions despite the limited number of patients enrolled.
The observed objective response rate of 50% is similar with phase I–II studies of dabrafenib, as well as with the vemurafenib BRIM3 trial, with slight differences in complete response rate. The median progression-free survival is almost identical in the BREAK-3 and BRIM3 trials (5.5 months versus 5.3 months). The impact of dabrafenib on overall survival will be difficult to determine given the allowance of crossover in BREAK-3 study.
The toxicity profile of dabrafenib seems to be quite different from vemurafenib, with lower incidence of photosensitivity, cutaneous squamous-cell carcinomas or keratoacanthomas, arthralgia, and fatigue, as well as a similar incidence of pyrexia.
Drs Tawbi and Kirkwood noted that several patient populations have been excluded from this study, including patients with tumours that harbour non-V600E BRAF mutations and patients with active brain metastases. The efficacy of dabrafenib in these populations is being studied independently and the results of a phase II study in patients with asymptomatic active brain metastases (BREAK-MB) has shown similar efficacy and will be published soon.
Responses remain relatively short and development of secondary resistance curtails benefit
The results of this phase III study confirm the role of the BRAF V600E mutation as a therapeutic target in metastatic melanoma, and establish dabrafenib as the second member of this class of selective BRAF inhibitors. This trial also represents a landmark study in potentially being the last to use dacarbazine as a control arm in previously untreated patients with BRAF-mutated melanoma.
Although the single-agent activity of dabrafenib largely recapitulates that of vemurafenib, it is clear that both of these agents have suboptimal efficacy and limited duration of benefit, with disease progression and secondary resistance that occur at a median interval of 6 months on therapy. The mechanisms of secondary resistance are an area of active investigation. The combination of BRAF inhibitors and MEK inhibitors seems to be poised to become a first-line option for therapy if preliminary results of the combination of dabrafenib and trametinib are confirmed.
Single-agent BRAF inhibitors have set a standard, but it is proving to be transient. The future challenges include the development of a therapeutic algorithm to determine the optimal sequence of available therapies and the potential use of targeted agents in earlier disease settings. Drs Tawbi and Kirkwood predict that BRAF inhibitors will form the backbone of combination strategies with other targeted agents, immunotherapy, and even chemotherapy agents that may still have an impact in selected populations. The full article you can read through the ESMO Scientific Journal Access program.
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