In the space of a few years, metastatic melanoma has been transformed from one of the most intractable cancer problems to one of the most promising areas in cancer therapy. With the approval of several new drugs and numerous ongoing trials, the field is building on the successful targeting of molecules within tumor cells and on the surface of immune cells to better control the disease. Targeting the MAP kinase pathway in melanomas that harbor a BRAF mutation has led to the dramatic resolution of tumors, often over a matter of weeks. At the same time, “checkpoint blockade” therapy has unleashed the power of the immune system to keep tumors in check, often for prolonged periods.
Yet challenges remain. For example, the responses of some patients to vemurafenib (ZelborafTM), which targets mutated BRAF, were so dramatic that they were reported on the front page of the New York Times and led to approval of the drug in 2011. However, the excitement has been tempered by the realization that these responses are seldom durable, and that the drug can paradoxically unleash other driver mutations resulting in keratoacanthomatype squamous cell carcinomas and new melanomas. In this issue of The Melanoma Letter, Dr. Caroline Robert and colleagues discuss exciting ongoing trials with new MEK inhibitors designed to increase theextent and durability of responses and mitigate the risk of carcinogenesis. The recent approval of trametinib (MekinistTM) was the first salvo fired for MEK inhibition in melanoma management, and many other MEK therapies are being tested.
While targeting the immune systems of patients, especially through anti-CTLA-4 therapy, has also improved survival, it has had similar drawbacks — especially adverse immunological events. Recent research points to another type of checkpoint blockade therapy, targeting the PD-1 ligand. In our second piece, Drs. Topalian and Lipson explain how blocking PD-1 may switch T cells back on to combat advanced melanomas, withoutthe global immunological effects that can halt therapy. With this new generation of therapies producing unprecedented survival benefits, we have undergone a paradigm shift in the treatment of advanced melanoma. Much remains to be explored and many obstacles overcome before these revolutionary methods can be considered “cures,” and the old cytotoxic therapies and biologics still have their place. But targeted therapies, alone and in combination, appear to be the wave of the future.
Allan C. Halpern, MD
Ashfaq A. Marghoob, MD