Jeffrey S. Weber, MD, PhD
In an interview with OncLive, Jeffrey S. Weber, MD, PhD, from the Moffitt Cancer Center, University of South Florida, Tampa, explored the utilization of molecular and immune-targeted therapies as treatments for patients with advanced melanoma. Weber has focused his research on translational clinical trials including development of novel trials in melanoma, including the monitoring and characterization of T-cell responses to vaccination in cancer patients and the establishment of in-vitro models to facilitate an understanding of how immune modulating antibodies amplify T-cell responses in patients. He is interested in the mechanisms by which achieving autoimmunity induces regression of cancer.
OncLive: What are some of the important advances in terms of targeted therapies for metastatic melanoma that we have seen in recent years?Dr. Weber:
There’s no question that there have been huge numbers of advances made in the field over the last 5 years or so. All of this began a little more than 10 years ago. In 2002, an article in Nature
demonstrated that BRAF
mutations were commonly present in cancers and that they could be drivers of tumor cell growth, proliferation, and oncogenesis. If you overcame them, eliminated them, or blocked the influence of the mutated BRAF
, you would reverse or transform cell behavior in the test tube.
The race began to come up with BRAF inhibitors, and sorafenib was one of the first. However, sorafenib turned out not to be a very good BRAF inhibitor, as it didn’t really have much activity in melanoma. It was a bit of a disappointment, but meanwhile, a number of companies were pursuing more selective BRAF inhibitors that had higher potency. It turned out that sorafenib wasn’t very potent, and that, in terms of inhibition of BRAF
, it wasn’t very selective.
A small company was synthesizing a variety of compounds to inhibit BRAF
at the time. This company came up with a drug around 7 years ago that looked promising in early testing: They could see some evidence of tumor regression, but when they looked at the pharmacokinetics, the drug formulation wasn’t very bioavailable. The blood levels went up a little bit after a dose, but then they sank down quickly, and the drug just wasn’t doing the job. However, it did have some promise, as there was some evidence of tumor regression early on. They stopped the trial, and at this point the company was bought out by Roche.
The chemists at Roche made a bioavailable formulation of the drug. When they evaluated pharmacokinetics, modest oral doses of the drug, given twice a day produced very high levels in the bloodstream. They started increasing the dose and did another phase I study, and very early on they were seeing some very large responses. So they were off and running with PLX4032, otherwise known as vemurafenib
(Zelboraf). Between the BRAF
discovery in 2002 and the approval of Zelboraf, it was 9 years, which is very impressive. This drug has a solid 50%-plus objective response rate and 80% rate of stability or regression. However, it had about a 6-month progression-free survival. Patients were having fantastic responses, but eventually almost everyone was relapsing, which was a little bit depressing.
Nonetheless, there were other targeted drugs that seemed to have activity in BRAF
-mutated melanoma, such as MEK inhibitors. There is the MAP kinase pathway that signaled and was overly active in melanoma, either through mutation or through other alterations. It is a cascade—Ras-Raf-MEK-ERK. Therefore, if you could block it at any step of the way, theoretically you could shut down melanoma growth, proliferation, and invasion. It turns out that BRAF inhibition worked the best, but MEK inhibition, which is downstream, also worked.
Then it turned out that if you added the MEK drug to the BRAF drug, you could block at two places in the cascade, and it worked extremely well; in fact, in the test tube, it worked synergistically so that both added together were better than either one alone. It also reduced some of the skin side effects that were beginning to be seen with the BRAF inhibitors. At this time, the BRAF inhibitors vemurafenib and dabrafenib were developed, as well as a very good MEK inhibitor called trametinib
. A trial was done with around 400 patients for these combination agents, which was eventually a multiple phase I trial with extension cohorts, and later a fairly large phase II trial was done. They found fantastic results, with around a 75% response rate with longer progression-free survival. The survival data are about to come out, but will almost surely look very impressive. That led to a couple of registration trials that are completed, and the results of these studies will be out soon.