Dr. Ribas: Evidence, both preclinical and clinical for the combination of a BRAF inhibitor and a MEK inhibitor demonstrate that there is a benefit for doing the combined therapy.1-4 The reason is because when we give a BRAF and a MEK inhibitor, we're hitting melanoma twice where it really counts, which is on the pathway that leads to the oncogenic driver signal—the mitogen-activated protein [MAP] kinase pathway. We're preventing that melanoma cell from being able to escape with many of the mechanisms that lead to escape from single-agent BRAF inhibitor.5 So that leads to better initial responses, and that has been seen with the early studies with dabrafenib and trametinib,6 and also with the combination of vemurafenib and cobimetinib, and then it also leads to more durable responses. The very important features of these combinations are that, not only are they more efficacious, but they are also less toxic. And that's because adding a MEK inhibitor to a BRAF inhibitor avoids a feature of single-agent BRAF inhibitors, which is called paradoxical activation of the MAP kinase pathway. And that leads to decreased toxicities—in particular, decrease of the secondary squamous cell carcinomas that are seen with single-agent BRAF inhibitors; also decrease in most of the skin toxicities that are induced by skin proliferation; and also decrease in the joint pains which are a common feature of BRAF inhibitors.3,7 So, I think it's a winner combination, and I'm pretty sure that that will become our new standard of care.
The final proof of this will be available once the randomized clinical trials with dabrafenib-trametinib versus either dabrafenib alone or vemurafenib alone,8,9 or the clinical trial of vemurafenib and cobimetinib compared to vemurafenib alone10 will be reported, which we hope will be within the next year.
But I'm sure that we're not going to stop there, because we're starting to understand what happens when melanoma becomes resistant to BRAF and MEK inhibitors. And we're seeing that several signals from the outside can lead to a state where some melanoma cells harbor the secondary processes that lead to higher resistance. And blocking receptor tyrosine kinases like c-Met may lead to better initial responses and less ability of melanoma [cells] to persist and become truly resistant. And also, we're [now] understanding some of the processes of resistance that go through the activation of an alternative pathway, the PI3/Akt pathway, and how a BRAF inhibitor and an Akt inhibitor could lead to secondary benefits. And there's a clinical trial open at SWOG that is going to be testing such a combination.11
Narrator: Based upon an understanding of the underlying molecular pathogenesis, targeted therapies are being developed for other non-melanoma skin malignancies as well. For example, the hedgehog signaling pathway can cause basal cell proliferation and tumor growth.12 In adults, this pathway is normally inhibited by the patched homolog 1 (PTCH1). Signaling in this pathway is initiated by the cell surface receptor smoothened homolog (SMO).
Mutations of PTCH1 may prevent inhibition of SMO activation of the hedgehog pathway, or mutations of SMO may result in activation of the
Vismodegib is an oral small molecule inhibitor of SMO that blocks the activation of the hedgehog pathway and is approved for the treatment of basal cell carcinoma recurrence after surgery and locally advanced or metastatic disease.16-18 Other targeted agents are undergoing evaluation for basal cell carcinoma, including