Tackling Cancer: Melanoma's Biggest Current & Upcoming Players

As I noted five weeks ago, cancer statistics are both staggering and disappointing. Although cancer deaths per 100,000 people have been on the downswing since 1991 thanks to access to more effective medications and better awareness about the negative health effects of smoking, there is still a lot of research and progress yet to achieve. My focus in this 12-week series is to bring to light both the need for continued research in these fields, as well as highlight ways you can profit from the biggest current and upcoming players in each area.

Over the past four weeks, we've looked at the four cancer types most expected to be diagnosed this year:

• Prostate cancer
• Breast cancer
• Lung cancer
• Colorectal cancer

Today, we'll turn our attention to the projected fifth-most diagnosed cancer: melanoma.

The skinny on melanoma
Melanoma is a type of skin cancer expected to be diagnosed in 76,690 people this year and lead to approximately 9,480 deaths. In these figures, we can already see a vast improvement from many of the previous four most-common cancers in that melanoma, while deadly in its advanced stages, can be treated with great efficacy if caught early and in a localized state. Increased public awareness about the dangers of long-term sun exposure and an understanding of one's family history with regards to melanoma occurrences has helped boost five-year survival rates of melanoma from just 82% in 1975-1977 to 93% in 2002-2008, according to the American Cancer Society (link opens PDF).

Still, numerous cases aren't caught early enough, with five-year survival rates dipping to a dismal 15% if the disease has metastasized throughout the body. Unfortunately, while signs and symptoms are somewhat apparent -- taking the form of moles or areas of the skin that change color, shape, or appearance -- melanoma is a type of cancer known to spread aggressively if left untreated. In essence, its curability rate can be quite high if caught early, but it's not the type of cancer you take a wait-and-see approach with. It's also worth noting that men are increasingly more likely to get this aggressive form of skin cancer than women.

Typical treatment for early stage melanoma would involve either surgical excision, electrodessication and curettage (a fancy phrase meaning using an electric current to destroy the cancer cells, then removing them with a curette), or cryosurgery. In some cases, radiation therapy is given to ensure cancer cell death. In more advanced cases of melanoma, a combination of surgery, immunotherapy, chemotherapy, or radiation therapy may be administered. 

Where investment dollars are headed
As you might imagine, self-cancer diagnosis are often frowned upon by physicians, but there are few cancers where self-awareness is more paramount to early detection than skin cancer. Therefore, the majority of research and development dollars isn't being spent on early detection. Instead, biopharmaceutical companies have focused their efforts on bettering and extending the quality of life for patients with advanced melanoma.

• Zelboraf: Don't be shocked, but once again Roche (RHHBY +0.00%) has a go-to drug in a commonly diagnosed cancer. Zelboraf is a twice-daily oral medication approved by the FDA in August 2011 to treat metastatic melanoma. Specifically, Zelboraf targets a mutation known as BRAF-V600E, which it can detect through a test it provided by LabCorp. In a head-to-head trial with Dacarbazine (discussed below), Zelboraf delivered progression-free survival of 5.3 months and a median overall survival of 16 months. For Dacarbazine, its PFS was merely 1.6 months and median overall survival was 7.9 months. The biggest adverse side effect of Zelboraf was the development of non-melanoma skin cancers in 24% of clinical patients; however, non-melanoma cancers are considerably easier to treat. 
• Yervoy: Yervoy is an intravenous immunotherapy developed by Bristol-Myers Squibb (BMY 0.02%) that was approved in March 2011 for unresectable or metastatic melanoma. I know what you're thinking, "Why not take oral Zelboraf, because who wants an IV?" However, a full regimen of Yervoy would only be four infusions, each given three weeks apart from the last. In trials when compared against a tumor vaccine, median overall survival for Yervoy was 10 months compared to just six months for the tumor vaccine alone. Overall response rates were clearly in Yervoy's favor as well, with 5.7% of patients in the Yervoy plus vaccine arm responding compared to just 1.5% for the vaccine control arm. Adverse events were also considerably less severe with immunological side effects knocking just 10% of patients out of trials. The downside, of course, is Yervoy's outrageous $120,000 price, which can create patient, insurance, and physician reimbursement concerns.
• Dacarbazine (DTIC-Dome): Dacarbazine, known as DTIC-Dome, was originally developed by Bayer in the mid-1970s and is an intravenously administered chemotherapy agent. As you might imagine, its patents have long since expired and generic competition comes from numerous other producers, although Bayer still produces DTIC-Dome. The drug works in the liver and acts by altering the DNA of cancer cells to slow their growth. Fortunately, advancements in medication since DTIC-Dome have been impressive because the response rate for the drug is relatively low, and the side effects, including liver complications, can be fairly serious. 
• Proleukin: Like Dacarbazine above, you won't see Proleukin used as often anymore, but it's still a therapy worth mentioning. Developed originally by Chiron, which was purchased by Novartis in 2005, Proleukin is an intravenous agent administered three times daily for a total of five days. Depending on how well the patient responds, the dosing can be repeated after nine days. It was originally approved in January 1998 after a complete or partial response was noted in 16% of clinical patients. In 2010, Novartis sold its U.S. rights to Proleukin to Prometheus Laboratories.

As is the case with all the previous commonly diagnosed cancers that have preceded melanoma, there have been quite a few cases of failure. Synta Pharmaceuticals (NASDAQ: SNTA) lost 79% of its share value in a single day after halting a metastatic melanoma trial in 2009 for experimental drug Elesclomol. In trials, more patients died taking Elesclomol than in the paclitaxel control arm, thus prompting the company to halt development of the drug. Even Pfizer's Tremelimumab has felt the pangs of rejection -- twice! After dropping development of the drug in 2008 following its failure to show a statistical advantage over the placebo, Pfizer revived the program only to see similar non-statistically significant results as a first-line metastatic melanoma treatment in January of this year. 

What's coming down the pipeline
Now that we have a better idea of what types of treatments are available for those with metastatic melanoma, let's have a look at some of the revolutionary therapies that are coming down the pipeline.

• Talimogene laherparepvec: Aside from having a name that sounds like it was made up by a Klingon, this experimental drug is injected directly into the lesion tissue and then replicates until the cell membranes of cancer cells rupture in a process known as cell lysis. Upon cell death, GM-CSF is released, which is a white-blood cell growth factor that activates the body's own immune system to attack cancer cells. Owned by Amgen (AMGN 0.01%) through the purchase of BioVax, Talimogene laherparepvec delivered a durable response rate of at least six months in 16% of patients in late-stage trials compared to just 2% for the control arm. Although median overall survival rates have yet to be determined -- the initial results of this trial were released by Amgen just two weeks ago – it appears that median survival would be expected to improve for the Talimogene laherparepvec arm.
• Dabrafenib and Trametinib: The combination of Dabrafenib -- a BRAF inhibitor similar to Zelboraf -- and Trametinib -- an MEK 1/2 inhibitor -- recently delivered favorable results in a mid-stage study undertaken by GlaxoSmithKline (GSK 0.01%). BRAF mutations occur in about half of all metastatic melanoma cases, so this combo will target a good chunk of the advanced melanoma population, but patients often develop resistances to Dabrafenib after just five to seven months. The addition of Trametinib acts to extend the duration of response by blocking the MEK protein, which attacks BRAF and could help to reduce the adverse side effects often seen in BRAF-inhibitors, like non-melanoma cancer development. In trials, progression-free survival jumped to 9.4 months for the combo arm versus just 5.8 months for Dabrafenib alone. Even more impressively, at 12 months, 41% of patients in the combo trial had not seen any disease progression compared to only 9% in the Dabrafenib-only control arm.

Your best investment
Death risk associated with many skin cancers aren't very high, but the research and development dollars being poured into improving the quality of life with regard to melanoma therapies certainly isn't chump change.

If you're willing to roll the dice a bit, I'm very intrigued by the combination treatment in mid-stage development by GlaxoSmithKline. We've seen plenty of therapies fail in late-stage treatments, so don't count your chickens before they're hatched, but Glaxo appears to have discovered a novel way to counter a patients' BRAF resistance while also potentially reducing many of the serious side effects associated with BRAF-inhibiting drugs.

As much as it pains me to say this, because I feel CEO Lamberto Andreotti has done a miserable job leading his company, Bristol-Myers Squibb looks like the safest investment in treating melanoma. Yervoy has the advantage of being a first-line treatment which gives Bristol-Myers the opportunity to market to a much broader audience than many metastatic melanoma drugs. That, coupled with its $120,000 price tag and the potential for additional indications, makes it the most promising long-term melanoma treatment.

Stay tuned next week when we tackle the current and upcoming therapies for the treatment of bladder cancer in this Tackling Cancer series.