Perfecting the Targeted Therapies

While checkpoint blockade immunotherapies have steadily surged to the forefront for advanced melanoma patients, targeted therapies for those with the cancer-producing mutant BRAF gene have also made notable, if more complicated, progress.

In general, targeted therapies use drugs or other substances to identify and attack specific types of cancer cells, or to block the action of certain genes, enzymes, proteins or other molecules that promote the growth and spread of cancer cells. Unlike chemotherapy, this allows the cancer to be treated without killing healthy cells.

The past few years have brought several notable successes with targeted melanoma therapy. The first was the BRAF inhibitor vemurafenib (Zelboraf®), FDA-approved in 2011. BRAF, part of the mitogen-activated protein kinase (MAPK) signaling pathway, produces a protein that normally regulates skin cells, causing them to multiply only when growth is needed. However, a mutated version of BRAF called V600E (found in about half of all melanoma patients) produces an abnormal version of the protein that stays switched on. (There are also smaller subsets of patients with related mutant BRAF versions called V600K and V600D.) This leads to out-of-control growth of melanocytes, the pigment cells where melanomas arise.

In patients with the mutated BRAF gene, vemurafenib can bind to the defective protein and deactivate it. Studies have shown that it produces rapid, striking antitumor activity in patients with BRAF V600E- and V600K-mutated melanoma, increasing the length of time before the disease advances as well as overall survival (OS) in vemurafenib patients compared to standard chemotherapy (median OS of 13.6 months for vemurafenib patients vs. 9.7 for chemotherapy patients).

While this is a significant increase in survival, and while some patients go much longer before recurrence, most patients eventually develop resistance to the treatment, and the melanoma starts to grow and advance again.

To help solve the problem, in 2013 two other targeted treatments were approved by the FDA, one also directed at BRAF and one at a related molecule called MEK, downstream of BRAF in the MAPK cascade: the BRAF inhibitor dabrafenib (Taflinar®) and the MEK inhibitor trametinib (Mekinist®).

All three of these targeted therapies can be used only in patients who have the defective BRAF gene. The idea is that even when the BRAF inhibitors vemurafenib and dabrafenib meet with resistance in inhibiting melanoma, trametinib will inhibit its progression at MEK further down the MAPK cascade, at least delaying the melanoma’s advance.

In 2014, the FDA also approved the use of dabrafenib and trametinib in combination for patients with inoperable or metastatic melanoma with a BRAF V600E or V600K mutation. The hope is that different drugs and drug combinations will increase tumor shrinkage and extend the length of time before the melanoma becomes resistant and starts growing again.

Results from the latest studies show that a remarkable 45 percent of BRAF-mutated metastatic melanoma patients on dabrafenib alone are still alive at two years, while patients on dabrafenib and trametinib combined have a significantly longer time before the disease advances compared to those on dabrafenib alone.

In addition, a Phase III study of a new BRAF/MEK inhibitor combination – the BRAF inhibitor vemurafenib plus an experimental MEK inhibitor called cobimetinib – found that patients with advanced melanoma lived significantly longer (almost four months longer) on average than patients on vemurafenib alone. Based on these results, cobimetinib has now been submitted to the FDA, and could be approved in 2015. All these findings have driven researchers to anticipate a time in the near future when the combination BRAF-MEK inhibitors will become standard treatment for BRAF-mutant melanoma, phasing out the single-drug therapies. 

Combining Targeted Therapy and Immunotherapy

Both targeted drugs and immunotherapy are now important treatment options, though the best ways to use them are not yet clear. By killing melanoma cells, BRAF and MEK inhibitors may increase activation of immune cells to attack any remaining melanoma cells, so it may be attractive to combine them with checkpoint blockade immunotherapies such as ipilimumab or pembrolizumab.

Initial attempts to combine a BRAF inhibitor (vemurafenib) with an immune-checkpoint blockade therapy (ipilimumab) were deemed unsafe, so this combination should not currently be used in standard practice. Clinical trials are now evaluating different combinations of these drugs used in different ways – for example, in sequence rather than concurrently. The goal will be to determine which combinations and methods shrink melanoma most effectively, maintain the best possible quality of life, and extend patients’ lives as long as possible.

Published on June 16, 2015