Nothing seems simple in melanoma. For every success there seems to be an unexpected bump or turn in the road. And the recent dramatic results with the targeted B-RAF inhibitor PLX4032 are no exception.
The majority of patients in Phase I and II trials showed objective response. But many developed resistance within several months. Now two papers in the December 16 issue of Nature (Nazarian et al: Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation; and Johannessen et al: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation) show that the mechanisms melanoma cells use to evade the drug are different from what has been commonly seen following treatment with other targeted therapies in other disease settings.
Rather than developing a secondary mutation in B-RAF, the melanoma cells find a way to simply go around the blocked protein and reactivate the signaling pathway downstream, or they activate an altogether different growth receptor pathway to compensate for the blockade.
What is surprising to investigators involved in the work and to Charles Sawyers, MD, Howard Hughes Medical Investigator and Chair of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center, who cowrote (with David Solit) an accompanying News & Views piece about the studies (Sawyers C, Solit D: Drug discovery: How melanomas bypass new therapy Nature 2010;468:902-903) is that so far no secondary mutations in the B-RAF have been found at all.
Of course, researchers have studied only a dozen or so patient samples, so there is plenty of opportunity for such mutations to show up.
But even if they do, they probably won't be the primary mechanism of resistance as might have been predicted.
"It is a sharp contrast between what we are seeing and what we expected prior to the start of our study," said the senior author of the Nazarian et al paper, Roger Lo, MD, PhD, Assistant Clinical Professor of Medicine at UCLA.
In fact, the lack of secondary B-RAF mutations seemed so odd that Dr. Sawyers and Dr. Solit, the Elizabeth and Felix Rohatyn Chair for Junior Faculty at Memorial Sloan-Kettering, sat down with the gene sequence to look for sites where a mutation would lead to resistance.
They found that a single nucleotide change would be sufficient, and other scientists have forced such mutations into the B-RAF gene in the laboratory.
"So the fact that you can make it happen in a lab and it is not happening in people is a little strange," Dr. Sawyers said. "There must be some selection pressure against it happening."
The Good News
The good news, melanoma experts agree, is that the new data point to drug combinations that might slow resistance.
The two most likely combinations are a B-RAF inhibitor plus an inhibitor of the PI3K/AKT pathway or an inhibitor of MAP kinase pathway proteins downstream of B-RAF, such as MEK or ERK.
And because the combinations made theoretical sense even before these new data appeared, some of the combination trials are already going on.
For example, GlaxoSmithKline already has a Phase I trial (NCT01072175) testing the safety of the combination of their B-RAF inhibitor and their MEK inhibitor.
Also, the leader of the Johannessen et al trial, Levi Garraway, MD, PhD, Assistant Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School, says he has heard that at least one company is getting ready to test a MEK-AKT inhibitor combination, which blocks the two pathways in question, although it relies on a MEK inhibitor instead of a B-RAF inhibitor.
"I can't imagine that the B-RAF-PI3K combination is far behind," he said.
It remains an open question whether a two-drug combination will be adequate to slow resistance in patients, given that the tumor cells have found multiple ways around the B-RAF blockade. But even if it only gains patients several months, that is an improvement over where the field has been.
"For so long, we have been combining drugs together that have no activity and trying to see if we can get activity," said Michael Davies, MD, PhD, Assistant Professor of Melanoma Medical Oncology and Systems Biology at the University of Texas MD Anderson Cancer Center, who was not involved in either of the current studies.
"But now it is a different problem. We have activity, and now we have to make it work better. This is a step forward over years and years of negative clinical trials."
Maybe the road for melanoma is finally going to straighten out-or at least have a little more distance between the curves.
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