Melanoma is the leading cause of death from skin disease. In metastatic melanoma, the disease spreads from its original lesion site to deeper parts of the skin, and eventually to other parts of the body distant from the primary lesion site.
An estimated 68,130 new cases of melanoma were diagnosed in the United States during 2010 and about 8,700 people died from the disease, according to the National Cancer Institute.
After a long period of stagnation, in 2011 two revolutionary drugs were approved for metastatic melanoma: Yervoy from Bristol Myers (BMY) and Zelboraf from Roche (RHHBY.PK).
Yervoy is a CTLA-4 inhibitor that strengthens the body's immune system and Zelboraf is a BRAF inhibitor.
Since both Yervoy and Zelboraf are cleared for metastatic melanoma therapy, a battle has ensued for dominance in first-line treatment and has stirred considerable debate in the field.
Yervoy is slow to take effect and only about one in four patients respond, but responses can be very long-lasting.
Zelboraf, on the other hand, usually demonstrates a lightning fast anti-tumor response, but it does not last and is often followed by treatment resistance.
Yervoy might turn out to be a better option for patients in earlier stages of disease, when immunotherapy has a better chance for success.
Patients who have aggressive disease or a large tumor burden, however, are not likely to benefit from Yervoy. For them, Zelboraf seems the better option.
In other words, Zelboraf is the drug for patients with a high risk of dying, for whom time is of the essence.
But Zelboraf does have a critical drawback. It can only be used for patients who have the BRAF mutation, which accounts for just half of all metastatic melanoma sufferers. Patients who do not have the mutation should not get Zelboraf, as data show that it could accelerate their disease.
Yervoy's effectiveness is not dependent on the BRAF mutation.
The FDA has approved a companion test, Roche's cobas 4800 V600 Mutation test, to determine which patients have the mutation.
According to Roche Molecular Diagnostics, testing for BRAF has been ordered for some 80% of eligible patients with late-stage melanoma.
The speed with which doctors have shown readiness to use the BRAF mutation diagnostic test demonstrates how quickly the field adapts to new treatments.
Because so many questions still surround the two drugs, more trials are needed. One trial, co-sponsored by Bristol-Myers Squibb and Roche-Genentech, is underway right now comparing the two drugs.
Administration of the drugs:
Yervoy is infused. It takes about 90 minutes to get a full dose. It is usually given every 3 weeks for up to 4 doses. The doctor may change how often the patient receives it and how long the infusion takes.
Zelboraf is taken in tablets, four 240 mg tablets taken twice a day, approximately 12 hours apart.
These medicines can do miracles but come with a price tag.
For US patients, according to the website destinationrx.com, Yervoy cost $6,480 a month (10 doses) and Zelboraf cost $11,055 a month, for 240 tablets.
The diagnostic test will cost around $120 to $150.
These figures do not include doctor's and hospital fees.
Analysts predict that the majority of BRAF wild-type (BRAF negative) patients will receive Yervoy as front-line therapy, allowing the drug to capture 60 percent of the US market versus 40 percent for Zelboraf.
Accordingly, consensus estimates from Thomson Reuters Forecast lists global Zelboraf sales of $174.1 million in 2012, rising to $641.9 million by 2016.
Yervoy sales reached $154 million in the first quarter of 2012 and sales in the first 12 months since its launch have reached $514 million.
For the first quarter of 2012, Roche reported sales of CHF 32 million ($33.7 million) for Zelboraf.
Several other new drugs are also being prepared for the market.
One downside of the BRAF-blocking drugs is that using them may activate certain growth pathways in healthy cells, leading to non-melanoma skin cancers. It turns out that adding the MEK drug can block the formation of these skin lesions.
Finding out that a second drug can cancel out the side effects of the first "was the cool part," said Glaxo's president. "Usually, when you combine two drugs they increase toxicity."
Approval of the two Glaxo drugs could generate as much as 1.5 billion pounds ($2.35 billion) by 2020, according to Andrew Baum, a London-based analyst at Citigroup Inc.
Glaxo will seek regulatory approval of both compounds later in 2012.
Recently Provectus Pharmacutecals (PVCT) presented final data from their phase 2 clinical trial of the PV-10 molecule, showing strong results.
This is a Rose Bengal compound that has been in use for over thirty years by ophthalmologists to assess damage to the eye. It has also been used as an intravenous diagnostic to detect ailments of the liver.
Rose Bengal has an established safety history, a short half-life in the bloodstream, and is excreted via the liver and kidneys.
The planned international phase 3 trial of PV-10 is expected to include up to 300 subjects with end stage melanoma. PV-10 will be compared with a control arm of chemotherapy with either dacarbazine or temozolomide, with progression-free survival as a primary endpoint.
Enrollment in the 30-month trial is scheduled to begin in the second half of 2012.
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