This past Sunday clinicians from New York’s Memorial Sloan-Kettering Cancer Center presented the good news to their colleagues. At the annual meeting of the American Society of Clinical Oncology in Chicago, they reported on two separate studies carried out at Sloan-Kettering in which two new drugs had improved survival rates of patients with inoperable melanoma, the deadliest forms of skin cancer. Both drugs increased survival better than the chemotherapy currently used to treat inoperable melanoma patients. One of the drugs was so effective that trials were stopped early so all patients could benefit from it.
Melanoma is notoriously difficult to treat, let alone cure. It is the leading cause of death among skin diseases. It arises when melanocytes–the skin cells that produce the melanin that give skin its color–proliferate out of control and become tumors. If the tumor is localized to the skin it can be surgically removed. If, however, tumor cells spread to lymph nodes, the melanoma may spread systemically throughout the body. At this point the melanoma is typically not curable and patients will begin chemotherapy. Their prognosis is bleak: stage IV melanoma patients have a median survival time that ranges from 8 to 18 months following diagnosis. Last year there were 68,130 new cases of melanoma in the U.S. Of those, 8,700 died.
The only drug approved by the FDA to specifically treat inoperable (stage IV) melanoma is the chemotherapy drug dacarbazine. It slows the spread of cancer by inhibiting the growth of cancer cells, which are then destroyed by the body’s immune system. Patients will respond to the chemotherapy with decreases in tumor size but, say the authors of the study, chemotherapy has not resulted in improved rates of overall survival.
This past March was the first victory. The drug Yervoy (generic: ipilimumab), which had previously been shown to improve the survival times of inoperable melanoma patients, was approved by the FDA. The last time a drug was approved by the FDA to fight melanoma was in 1995. Unlike dacarbazine, Yervoy does not attack tumor cells directly but indirectly by boosting the body’s immune system. The one-two punch of chemotherapy combined with immune system boosters is a popular therapeutic approach that many labs are currently working to develop.
Led by Dr. Jedd Wolchok at the Memorial Sloan-Kettering Cancer Center in New York, the research team wasted no time in testing Yervoy and dacarbazine together. The phase 3 study, recently published in the New England Journal of Medicine, showed that treating inoperable melanoma patients with Yervoy and dacarbazine together prolonged survival longer than dacarbazine and a placebo. Five-hundred twelve patients participated in the study. The group receiving both drugs had a survival median of 11.2 months, which turned out to be statistically longer than the median of 9.1 months for patients treated with dacarbazine and the placebo. Survival rates for Yervoy were just under half at the 1 year point, compared to a 36.3 percent survival rate for dacarbazine. At two years Yervoy’s rate was 29 percent versus dacarbazine’s 18 percent, and at three years out, Yervoy’s 21 percent survival rate nearly doubled dacarbazine’s 12 percent.
Amazingly, another such breakthrough in melanoma research was published in the same issue. A collaborator of Dr. Wolchok, Dr. Paul Chapman ran a separate melanoma trial. Results from the second further boosts hopes of patients with melanoma.
In Dr. Chapman's study, researchers sought to compare another drug called vemurafenib to dacarbazine. Vemurafenib is unique in that it targets a specific subgroup of melanoma patients. Thirty to sixty percent of melanomas are thought to be caused by a mutation in a gene called BRAF. BRAF produces an enzyme that, when over-actived by the mutation, increases the chance that a melanocyte will turn cancerous. Vemurafenib is an antibody that binds to and inhibits mutated BRAF, thus constraining its tumorigenic powers over melanocytes. How well does it do this? After three months, patients who took vemurafenib were 63 less likely to die and 74 percent less likely to die or have their cancer return than those who took dacarbazine. At six months, overall survival for the vemurafenib group was 84 percent and 64 percent for the dacarabzine group. The vemurafenib treatment was so effective that the study was ended prematurely so that the patients taking dacarbazine could cross over and begin taking vemurafenib.
The video below is an interview with Drs. Wolchok and Chapman at the Society meeting discussing their exciting studies.
There are, however, some drawbacks.
Some side effects to vemurafenib include rash, fatigue, and hair loss–but these effects are generally considered to be mild. Ironically, though, vemurafenib may also cause non-melanoma skin cancer. While inhibiting mutated BRAF, the drug simultaneously activates wild-type BRAF and turns on the cellular machinery that makes a cell into a tumor. Thus, it will be very important to monitor patients for non-melanoma types of cancer while undergoing vemurafenib treatment.
In addition to the health risks, the shortened time of the study–median follow-up time was three months–means the final survival times are still to be determined. We don’t actually have all the data yet, and another evaluation of the drug will need to take place.
As I mentioned before the BRAF mutation targeted by vemurafenib is present in only 30 to 60 percent of melanoma patients. Vemurafenib is not expected to be effective against melanomas that do not carry the mutation.
Lastly, the cost. The LA Times reports that Yervoy, which is manufactured by Bristol-Myers Squibb, will cost patients $120,000 for a treatment regimen. Vemurafenib, made by Roche and Plexxikon Inc., is not yet FDA approved. The companies are expected to apply soon for approval but they have not yet set a price.
Vemurafenib is an example of ‘bench-to-bedside’ gone triumphant. Scientists and clinicians alike will often tout the “translational” relevance of their research–that is, playing with a dish of cells in the lab will translate to a treatment in the hospital. But examples are rare where the path from bench-to-bedside is as clear as it is for vemurafenib. Says Dr. Marc Ernstoff in an editorial about the vemurafenib study: “For patients with metastatic melanoma with the BRAF mutation, the availability of vemurafenib is a major defining moment that will have an important effect on survival and quality of life.”
And the best may be yet to come. Clinical trials are currently underway to test the combined effectiveness of vemurafenib and Yervoy. As each did separately, the two drugs together might brighten even more the prognoses of melanoma patients.