Combined BRAF and MEK inhibition in metastatic melanoma significantly improves progression free survival

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Key study points:

1. Approximately half of all patients with advanced melanoma have an activating BRAF mutation, which has been shown to be responsive to molecularly targeted systemic therapy.
2. In patients with an activating BRAF mutation, combination therapy of the selective BRAF inhibitor dabrafenib and the MEK inhibitor trametinib significantly improved median progression free survival in comparison to dabrafenib monotherapy.

Primer: Although only representing 10% of all skin cancers, melanoma is the leading cause of skin cancer mortality with 66,000 deaths worldwide annually, and its incidence is increasing faster than any other cancer. Clinically, it presents as a skin lesion that is often notable for ABCDE features: Asymmetry, Border irregularity, Color variegation, Diameter > 6mm, and Evolving in size/shape/color. While initial treatment is generally surgical excision with wide margins, metastatic melanoma often requires systemic therapy. At the molecular level, the MAPK (mitogen-activated protein kinase) pathway and one of its downstream mediators, serine/threonine kinase BRAF are activated in approximately half of all cases of advanced melanoma.

Both BRAF kinase inhibitors and MEK (MAPK Kinase) inhibitors have been utilized in patients with melanoma with BRAF V600E mutations and were associated with prolonged survival and progression free survival. Unfortunately, 50% of metastatic melanoma patients who are treated with BRAF or MEK inhibitors experience disease progression within 6-7 months. This is thought to be secondary to the re-activation of the MAPK pathway via BRAF inhibitor resistance. Hence combination therapy has been suggested to better inhibit this pathway and presumably prolong treatment effect. To evaluate this, a phase 1 and 2 study utilizing selective BRAF inhibitor, dabrafenib, and the selective MEK inhibitor, trametinib, was initiated for patients with metastatic melanoma with an activating BRAF V600 mutation.

Background reading:

1. The Molecular Biology of Melanoma. UpToDate. Accessed 11 October 2012.

2. Molecularly Targeted Therapy for Metastatic Melanoma. UpToDate. Accessed 11 October 2012.

3. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010;467:596-599

This [open label study]: A total of 247 patients with histologically confirmed metastatic melanoma who had not previously received BRAF-inhibitors were enrolled. The study confirmed the safety of escalating doses of dabrafenib (75 and 150 mg twice daily) plus trametinib (1, 1.5, and 2 mg once daily).

The remaining 162 patients were randomly assigned to receive dabrafenib plus trametinib or dabrafenib monotherapy. Median progression-free survival for patients was significantly improved in the combination group vs. monotherapy (9.4 months vs. 5.8 months; HR 0.39; p<0.001). The rate of complete or partial response was higher in the combination group vs. monotherapy (76% vs. 54% ; p<0.05). The incidence of cutaneous squamous-cell carcinoma during therapy was non-significantly reduced for combination therapy vs. monotherapy (7% vs. 19% ; P=0.09). In terms of adverse events, pyrexia was more common in combination group vs. monotherapy (25% vs. 2%).

In sum:  This study supports the combination of dabrafenib and trametinib in treating metastatic melanoma in patients with a known activating BRAF mutation: dabrafenib and trametinib can be safely combined at full doses with rare dose-limiting side effects. This combination therapy significantly improved progression free survival and higher rate of response in comparison the dabrafenib monotherapy. It should be noted that the rate of pyrexia was increased with combination therapy, and this should be assessed further in ongoing phase 3 clinical trials. While the results of these phase 1 and 2 trials are very promising in the use of combination of agents for metastatic melanoma for the subset of patients with an activating BRAF mutation, caution is warranted until phase 3, blinded randomized controlled trials are completed.

Click to read the study in NEJM

By [EP] and [RR]

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