Although the effects of BRAF inhibition were initially unprecedented in patients with BRAF-mutated metastatic melanoma, “the problem is that the effect is not durable,” said formal discussant of this trial, Reinhard Dummer, MD, University Hospital of Zurich, Switzerland. The development of resistance occurs mainly as a result of reactivation of the pathway, which has led to the use of MEK inhibition to prevent escape.

In addition to resistance, another important issue is the development of secondary cancers with these drugs, he continued. He noted that the combination appears to reduce these cancers.

The combination of both therapies added about 10 months to progression-free survival in the phase II trial, which Dr. Dummer said was promising. He was also impressed by results of the phase Ib study, with every patient having some degree of response. “I have never seen this before, but we need to have mature data,” he emphasized.

Future Studies

Even though these findings are encouraging, Dr. Dummer emphasized the complexity of resistance and the inability to predict which patients will develop resistance.

“In the near future, this type of combination will be first choice for BRAF-mutated melanoma, but resistance will emerge and the question is what will be the next step. We will need individual biomarkers and we will need to communicate with radiologists to get tumor tissue. We also need markers to make subsequent choices with other drugs targeted to these mechanisms. The future will depend on longitudinal personalized cancer evolution,” he stated. ■

Disclosure: Dr. Dummer reported no potential conflicts of interest.