Metastatic melanoma is a deadly diagnosis - you are, to be frank, screwed. Any glimmer of hope, however murky, is thus latched onto fervently. Unfortunately, cancer treatments aren't a picnic, many providing only a little extra time on earth and awful side effects.

In diseases like metastatic melanoma, where the prognosis is dismal, it's easy to hype any drug that comes along. Words like "breakthrough" are tossed about the news media, which dilutes the power of the word when an actual advancement comes along.1 A new drug in clinical trials might just fit the bill, though, so I may take the word off the shelf and use it, albeit cautiously.

Metastatic melanoma - the not-so-good, bad and ugly

In your epidermis, cells called melanocytes are responsible for your skin pigmentation. Melanocytes produce melanin (the pigment), and when exposed to sunlight melanocytes leap into action and produce more melanin, and your skin tans. Melanocytes can cluster as well - you can see this as freckles or moles.

Courtesy National Cancer Institute

When a melanocyte malfunctions and turns cancerous, you could end up with one of three types of skin cancer2: melanoma, basal cell skin cancer, or squamous cell cancer (see the basal and squamous cells in the photo above).

Basal cell cancer is the most common form of skin cancer and rarely metastasizes, followed by squamous cell cancer, which can occur in a number of places around the body (since squamous cells are found in tissues throughout the body) and can metastasize. These two are considered the "non-melanoma" skin cancers.

Basal cell cancer (left)

Squamous cell cancer (right)

More than a million people in the U.S. will be diagnosed with the non-melanoma skin cancers each year. By contrast, only about 50,000 people in the U.S. (and 160,000 worldwide) will be diagnosed with melanoma. Deaths are disproportionate, though - about 75% of skin cancer deaths are from melanoma, whereas the remaining 25% die from all other skin cancers.

Catching melanoma early is critical to treating it - according to the American Cancer Society, the 5-year overall survival rate for patients with melanoma is 91%, because about 80% of melanomas are diagnosed at a localized (skin surface) stage. Survival rates for regional (within the skin nearby) and distant (metastatic) stage diseases are 65% and 15%, respectively.

Melanoma starts by burrowing deeper into the skin (Stages 0, I and II cancer) until it hits the lymph nodes (Stage III). Once it is able to circulate throughout the body and metastasized or set up shop in distant locations like your lungs, liver or intestines (Stage IV), you're in a lot of trouble and your chances of survival are extremely poor, and you typically have less than a year to live.

Treating melanoma - is PLX3042 the wunderkind?

There are three standard treatments for melanoma - surgery, the primary therapy for all stages of the disease; chemotherapy; and radiation therapy. In past years new options have surfaced, like biologics, chemoimmunotherapy (a combination of chemo- and immuno-therapy), and more recently targeted therapy. Targeted therapy has an advantage over the relatively more systemic biologic and chemoimmunotherapies in that it is specific to the cancer cell and presumably would have fewer side effects.

The distinct lack of validated targets for therapy has made it tough to personalize therapy for patients with melanoma. The two approved drugs for melanoma (a chemotherapy called dacarbazine  and an immunotherapy called IL-2) shrink tumors for only about 10 percent to 20 percent of patients, according to a great USA Today article. There are a few drugs in clinical trials, but one in particular stands out because it targets a mutation that occurs in roughly 50 percent of all melanomas, and about 8 percent of other solid tumors.

A drug called PLX4032, developed by Plexxikon, targets the serine–threonine protein kinase B-RAF (BRAF). BRAF is involved in cell signaling; a mutated BRAF accelerates tumor cell growth.

Experimental drugs don't work all that well in early trials, as there is a lot of trial and error in dosing - tumors only shrink in about 5 percent to 10 percent of patients. But in the phase I dose-escalation and extension trial with PLX4032, there was a fantastic response.

The researchers first tried to figure out the best (and highest) dose they could give 55 patients (49 of whom had melanoma) without too many side effects, and finally came upon 960 mg twice daily. They then tested that dose on 32 patients who had metastatic melanoma with the BRAF mutation.

Among the 49 patients in the first study, 16 had the BRAF mutation. Of those 16, ten had a partial response (meaning that their tumours shrank by 30 percent or more) and 1 had a complete response (meaning that there was no trace of the tumours after treatment) - 69 percent of patients had tumor shrinkage, dramatically more than what is normally seen.

Of the 32 patients with metastatic melanoma and the BRAF mutation, 24 had a partial response and 2 had a complete response - meaning over 80 percent of patients had tumor shrinkage. Even better, the duration of the response lasted up to 18 months. Tumors did become resistant, which is typical with genetically-targeted cancer therapies. However, the possibility of using PLX4032 in combination with other therapies (like patients with HIV do to combat resistance) is possible. Plus, this is an oral drug - the importance of being able to take a pill, instead of getting an IV in a hospital, cannot be overstated.

The drug is already in Phase II and Phase III trials, and if results continue to be positive, Plexxikon and partner Roche will apply for approval by the FDA in 2011.

Press release from Plexxikon
Article from the New England Journal of Medicine, August 26, 2010
1 Words like "breakthrough" and "miracle" are overused and often misused in health reporting, as I've mentioned elsewhere. "True breakthroughs are better measured over years, not overnight," Gary Schwitzer writes in his blog on Health News Review. Used sparingly, it can pack a punch.
2 Although rare, since melanocytes are present in your eye and intestine you could get melanoma there, but this article only deals with the skin.