Combining Two Targeted Therapies Stalls Disease Progression in Melanoma Patients With BRAF Mutations

Jeffrey Weber, MD, PhD

A combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has shown promising activity in patients with advanced melanoma while resulting in fewer of the serious side effects associated with the use of the current standard single-agent BRAF-targeted therapy, vemurafenib.

The results of a phase I/II study exploring the combination of these two investigational targeted therapies were presented in a press briefing held on Wednesday by the American Society of Clinical Oncology (ASCO).

Nearly 50% of patients with melanoma harbor a V600E mutation in the BRAF gene. Those patients who carry the V600E mutation also have a highly active MEK pathway. The FDA approval of vemurafenib in August 2011 represented a major advancement in the treatment of melanoma; however, most patients eventually develop resistance to the drug. By targeting the active BRAF and MEK pathways, researchers hope to trigger a stronger response to fight the cancer and to prevent and/or delay resistance to treatment.

A new study of 125 melanoma patients who received varying doses of dabrafenib and trametinib included a subgroup analysis of 77 patients who had not been previously treated with any BRAF inhibitors, and therefore had no prior resistance to BRAF-targeted therapy.

Among the 77 patients who received the combination therapy, the overall response rate (ORR) was 56% (95% CI, 44.1%-67.2%), and the confirmed data showed that six patients achieved a complete response (CR), 38 patients achieved partial response (PR), and 29 patients achieved stable disease (SD).

The median overall progression-free survival (PFS) achieved by patients in this analysis was 7.4 months (95% CI, 5.5-9.2), which was comparable to results seen with single-agent vemurafenib treatment. However, doses of dabrafenib/trametinib were given at four different levels. The highest PFS was achieved in 24 patients who received 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily. In this group, the median PFS was 10.8 months, and 15 of the 24 patients (63%) achieved either CR or PR (95% CI, 40.6%-81.2%). This dosage (150/2 mg) will be evaluated further in a phase III clinical trial.

“We have to be cautious because of the small number of patients in this trial, but it looks extremely encouraging,” said Jeffrey S. Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and lead researcher on this study.

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While the use of BRAF inhibitors has been associated with serious adverse events, especially skin lesions, these side effects appeared less often in patients who received the combination therapy. Skin toxicity of at least grade 2 severity occurred in 17 (14%) of the 125 patients. Three patients (2%) developed cutaneous squamous cell carcinoma and two patients (2%) developed actinic keratoses.

While skin toxicities were generally lower with the dabrafenib/trametinib combination compared with what has been observed in patients who received single-agent BRAF inhibitors, Weber noticed that some toxicities experienced by patients in this study were higher than what is typically observed. Pyrexia, or fever, of grade 3 or higher was reported in 52% of patients, with 23% of patients reducing dosage as a result. Additionally, 38% of patients experienced chills of grade 3 or higher. Weber noted that most of the patients experiencing chills were also patients who reported experiencing pyrexia.

Weber said that the use of vemurafenib typically results in skin lesions in up to 25% of patients who receive it. Weber also noted that the PFS was about three months longer in patients who received this combination therapy than those who received single-agent vemurafenib to treat advanced melanoma.

“If the data from this study hold, they would look clearly superior to the figures that we’ve seen with vemurafenib,” Weber said.

More data on the use of dabrafenib as a single agent and vemurafenib in advanced melanoma patients are expected to be presented at ASCO’s meeting in June.

References

Weber JS, Flaherty KT, Infante JR, et al. Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naïve metastatic melanoma. J Clin Oncol 2011. (suppl; abstr 8510).

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