Melanoma is an increasingly common disease in the United States—with incidence up 33% in men and 23% in women in the past decade—and the prognosis for patients is generally poor when the disease is diagnosed in advanced stages.1
With the approval in 2011 of ipilimumab, a therapy targeting the immune checkpoint receptor CTLA-4, and the further clinical development of systemic immunotherapies, the prognosis for patients with metastatic melanoma has improved. In addition to ipilimumab, today therapies targeting BRAF mutations, MEK, and the programmed death-1 (PD-1) receptor are available.
The role of immunotherapies continues to evolve as new data emerge. A recent issue of The New England Journal of Medicine contained articles updating our knowledge of the role of combined BRAF-MEK inhibition and use of PD-1 inhibitors for patients with BRAF-negative disease.
Activating mutations of BRAF, an intracellular signaling kinase, are present in approximately 50% of patients with melanoma.1 Vermurafenib and dabrafenib specifically target mutated BRAF, inhibiting its activation of downstream pathways.
For patients with BRAF-mutated metastatic melanoma, treatment with BRAF inhibitors improves overall (OS) and progression-free survival (PFS) versus treatment with dacarbazine.2-4 A third BRAF-targeted agent, trametinib, is a small-molecule inhibitor of MEK 1 and MEK 2, which are components of the MAP-kinase pathway downstream of BRAF and thought to play a crucial role in BRAF-mediated oncogenesis.
In clinical trials, response rates with trametinib monotherapy among BRAF-mutant patients were lower than with vermurafenib, but improvements in OS and PFS compared with dacarbazine.2,5
In 2012, researchers published the results of a phase 1/2 trial that evaluated combined dabrafenib and trametinib treatment for melanoma with BRAF V600 mutations. On the primary efficacy endpoint (PFS), results showed that the combination of 150 mg dabrafenib plus 2 mg trametinib significantly prolonged survival when compared with dabrafenib monotherapy, with a high response rate (76% vs. 54%, respectively) and 12-month PFS of 41% versus 9% in the monotherapy group.6
A phase 3 study published last month in The New England Journal of Medicine found that combined therapy led to significant improvement in OS (the primary endpoint) over vemurafenib monotherapy (hazard ratio for death, 0.69; 95% CI: 0.53,0.89; P=0.005).7
In this study, lead author Caroline Robert, MD, PhD, of the Gustave Roussy Institute of Oncology and INSERM in Villejuif-Paris Sud, France, and colleagues randomly assigned patients with metastatic melanoma containing BRAF V600 mutations to treatment with the combination of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or vemurafenib monotherapy (960 mg twice daily).7
Median PFS was longer with combination therapy (11.4 months) than monotherapy (7.3 months), a significant reduction in risk for progression (P<0.001). Notably, OS was improved with combination therapy in all subgroups, with the exception of patients with ECOG performance status 1, where the treatments were equivalent; PFS was improved in all analyzed subgroups.7
Combination therapy presents a different pattern of adverse events than monotherapy with these agents. In the phase 1/2 study, adverse effects with the combination included more frequent and severe pyrexia and more frequent gastrointestinal events than seen with dabrafenib alone; interestingly, the combination resulted in a lower incidence of the cutaneous adverse effects, including acneiform dermatitis and cutaneous squamous-cell carcinoma (SCC), which are a dose-limiting toxicities associated with trametinib monotherapy.6
In the phase 3 study, treatment-related adverse events were common in both groups, and led to discontinuation in 13% of patients receiving combination therapy and 12% patients in the vemurafenib monotherapy groups.
Pyrexia and decreases in ejection fraction (a feature of trametinib monotherapy) were the most common reasons for discontinuation with combination therapy and arthralgia was the most common reason with vemurafenib. Grade 3 reactions occurring in more than1% of patients in the combination group were pyrexia (4%) and decreased ejection fraction (4%); in the monotherapy group these were arthralgia (4%), rash (9%), and cutaneous SCC (17%).
Of note, 1% or less of patients in the combination therapy group experienced grade 3 cutaneous reactions. About a third of patients in each group required dose reductions and half required dose interruptions. Pyrexia with combination therapy and rash with vemurafenib were the most common reasons for dose reduction or interruption.7
The results of this phase 3 study are consistent with the earlier phase 1/2 study and support the use of combination BRAF-MEK inhibition for treatment of metastatic melanoma with BRAF mutations. The combination improves both OS and PFS versus either of the BRAF inhibitors as monotherapy and is associated with low rates of serious adverse effects.