Expert Point of View: Dual BRAF and MEK Inhibition Is Active in Advanced Melanoma

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Commenting on the trial of combined BRAF and MEK inhibition in advanced melanoma, Michael K.K. Wong, MD, PhD, Professor of Medicine at Keck School of Medicine, University of Southern California, Los Angeles, called the findings “nothing short of extraordinary” and a potential “game changer.”

“Inducing complete responses in melanoma is impressive, and a near universal overall disease control rate is outstanding,” he told The ASCO Post. “In what other cancer do we see 100% disease control rates, especially in a phase I/II trial? These are game-changing results in any cancer, let alone melanoma. They change the way we think about this disease.”

The 3% rate of squamous cell carcinoma was particularly striking to Dr. Wong, who treats the disease himself and worries that the skin manifestations could be a harbinger of internal squamous cell carcinoma lesions. While this is only an unproven possibility, he said, “These drugs have not been out long enough to know the full extent of the impact of these squamous cell carcinomas.” 

Underlying Mechanism?

The rare skin toxicity with the dabrafenib/ trametinib combination suggests to him that (1) these lesions may flow through the MEK pathway, perhaps as a consequence of some pressure exerted by BRAF inhibitors, and (2) it is possible that squamous cell carcinomas might be amenable to treatment via MEK pathway inhibition. “As a drug developer,” he said, “I wonder if we should pursue MEK inhibitors for squamous cell carcinoma.”

Regarding the encouraging outcomes in patients with melanoma, Dr. Wong issued the usual caveat—that long-term follow-up is needed—but emphasized that this is especially true for treatment with BRAF and MEK inhibitors, whose biggest drawback has been that responses are frequently short-lived.

“The big unknown here is whether these responses will be durable,” he said. “Or will this be yet another example of how the plasticity of gene expression within cancer cells ends up finding a way around the obstruction put in its path by these inhibitor-type drugs?”

He continued, “The larger phase III trial will definitively prove or disprove the idea that this is a very active combination. If it is, we will be using dual inhibitors at some cost. To consume resources to this degree, we don’t just want to shrink tumors; we want to have them not recur.” ■

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

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